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Handbook of Pharmaceutical Excipients

Fifth Edition 
Edited by 
Raymond C Rowe, Paul J Sheskey and Sian C Owen
London . Chicago 


Contents 
International Steering Committee ix 
Editorial Staff ix 
Contributors x 
About the Editors xii 
New Monographs xiii 
Related Substances xiv 
Preface xvi 
Arrangement xvii 
Acknowledgments xix 
Notice to Readers xix 
Bibliography xx 
Abbreviations xx 
Units of Measurement xxii 
Monographs 
Acacia 1 
Acesulfame Potassium 4 
Acetic Acid, Glacial 6 
Acetone 8 
Acetyltributyl Citrate 10 
Acetyltriethyl Citrate 12 
Agar 14 
Albumin 16 
Alcohol 18 
Alginic Acid 21 
Aliphatic Polyesters 24 
Alitame 28 
Almond Oil 30 
Alpha Tocopherol 32 
Aluminum Hydroxide Adjuvant 36 
Aluminum Oxide 38 
Aluminum Phosphate Adjuvant 40 
Aluminum Stearate 42 
Ammonia Solution 44 
Ammonium Alginate 46 
Ascorbic Acid 48 
Ascorbyl Palmitate 51 
Aspartame 53 
Attapulgite 56 
Bentonite 58 
Benzalkonium Chloride 61 
Benzethonium Chloride 64 
Benzoic Acid 66 
Benzyl Alcohol 69 
Benzyl Benzoate 72 
Boric Acid 74 
Bronopol 76 
Butylated Hydroxyanisole 79 
Butylated Hydroxytoluene 81 
Butylparaben 83 
Calcium Alginate 86 
Calcium Carbonate 89 
Calcium Phosphate, Dibasic Anhydrous 93 
Calcium Phosphate, Dibasic Dihydrate 96 
Calcium Phosphate, Tribasic 100 
Calcium Stearate 102 
Calcium Sulfate 105 
Canola Oil 108 
Carbomer 111 
Carbon Dioxide 116 
Carboxymethylcellulose Calcium 118 
Carboxymethylcellulose Sodium 120 
Carrageenan 124 
Castor Oil 128 
Castor Oil, Hydrogenated 130 
Cellulose, Microcrystalline 132 
Cellulose, Powdered 136 
Cellulose, Silicified Microcrystalline 139 
Cellulose Acetate 142 
Cellulose Acetate Phthalate 145 
Ceratonia 148 
Cetostearyl Alcohol 150

Cetrimide 152 
Cetyl Alcohol 155 
Cetylpyridinium Chloride 157 
Chitosan 159 
Chlorhexidine 163 
Chlorobutanol 168 
Chlorocresol 171 
Chlorodifluoroethane (HCFC) 174 
Chlorofluorocarbons (CFC) 176 
Chloroxylenol 180 
Cholesterol 182 
Citric Acid Monohydrate 185 
Colloidal Silicon Dioxide 188 
Coloring Agents 192 
Copovidone 201 
Corn Oil 204 
Cottonseed Oil 206 
Cresol 208 
Croscarmellose Sodium 211 
Crospovidone 214 
Cyclodextrins 217 
Cyclomethicone 222 
Denatonium Benzoate 224 
Dextrates 226 
Dextrin 228 
Dextrose 231 
Dibutyl Phthalate 234 
Dibutyl Sebacate 236 
Diethanolamine 238 
Diethyl Phthalate 240 
Difluoroethane (HFC) 242 
Dimethicone 244 
Dimethyl Ether 246 
Dimethyl Phthalate 248 
Dimethyl Sulfoxide 250 
Dimethylacetamide 253 
Disodium Edetate 255 
Docusate Sodium 257 
Edetic Acid 260 
Erythorbic Acid 264 
Erythritol 266 
Ethyl Acetate 268 
Ethyl Lactate 270 
Ethyl Maltol 272 
Ethyl Oleate 274 
Ethyl Vanillin 276 
Ethylcellulose 278 
Ethylene Glycol Palmitostearate 283 
Ethylene Vinyl Acetate 285 
Ethylparaben 287 
Fructose 290 
Fumaric Acid 293 
Gelatin 295 
Glucose, Liquid 299 
Glycerin 301 
Glyceryl Behenate 304 
Glyceryl Monooleate 306 
Glyceryl Monostearate 308 
Glyceryl Palmitostearate 311 
Glycofurol 313 
Guar Gum 315 
Hectorite 318 
Heptafluoropropane (HFC) 321 
Hexetidine 323 
Hydrocarbons (HC) 325 
Hydrochloric Acid 328 
Hydroxyethyl Cellulose 330 
Hydroxyethylmethyl Cellulose 334 
Hydroxypropyl Cellulose 336 
Hydroxypropyl Cellulose, Low-substituted 341 
Hydroxypropyl Starch 344 
Hypromellose 346 
Hypromellose Acetate Succinate 350 
Hypromellose Phthalate 354 
Imidurea 359 
Inulin 362 
Iron Oxides 364 
Isomalt 366 
Isopropyl Alcohol 371 
Isopropyl Myristate 374 
Isopropyl Palmitate 376 
Kaolin 378 
Lactic Acid 381 
Lactitol 383 
Lactose, Anhydrous 385 
Lactose, Monohydrate 389 
Lactose, Spray-Dried 396 
Lanolin 399 
vi Contents

Lanolin Alcohols 402 
Lanolin, Hydrous 404 
Lauric Acid 406 
Lecithin 409 
Leucine 412 
Linoleic Acid 414 
Macrogol 15 Hydroxystearate 416 
Magnesium Aluminum Silicate 418 
Magnesium Carbonate 422 
Magnesium Oxide 426 
Magnesium Silicate 428 
Magnesium Stearate 430 
Magnesium Trisilicate 434 
Malic Acid 436 
Maltitol 438 
Maltitol Solution 440 
Maltodextrin 442 
Maltol 445 
Maltose 447 
Mannitol 449 
Medium-chain Triglycerides 454 
Meglumine 457 
Menthol 459 
Methylcellulose 462 
Methylparaben 466 
Mineral Oil 471 
Mineral Oil, Light 474 
Mineral Oil and Lanolin Alcohols 476 
Monoethanolamine 478 
Monosodium Glutamate 480 
Monothioglycerol 482 
Myristic Acid 484 
Neohesperidin Dihydrochalcone 486 
Nitrogen 488 
Nitrous Oxide 490 
Octyldodecanol 492 
Oleic Acid 494 
Oleyl Alcohol 496 
Olive Oil 498 
Palmitic Acid 501 
Paraffin 503 
Peanut Oil 505 
Pectin 507 
Petrolatum 509 
Petrolatum and Lanolin Alcohols 512 
Phenol 514 
Phenoxyethanol 517 
Phenylethyl Alcohol 519 
Phenylmercuric Acetate 521 
Phenylmercuric Borate 524 
Phenylmercuric Nitrate 526 
Phosphoric Acid 530 
Polacrilin Potassium 532 
Poloxamer 535 
Polycarbophil 539 
Polydextrose 542 
Polyethylene Glycol 545 
Polyethylene Oxide 551 
Polymethacrylates 553 
Poly(methyl vinyl ether/maleic anhydride) 561 
Polyoxyethylene Alkyl Ethers 564 
Polyoxyethylene Castor Oil Derivatives 572 
Polyoxyethylene Sorbitan Fatty Acid Esters 580 
Polyoxyethylene Stearates 585 
Polyvinyl Acetate Phthalate 589 
Polyvinyl Alcohol 592 
Potassium Alginate 594 
Potassium Benzoate 596 
Potassium Bicarbonate 598 
Potassium Chloride 600 
Potassium Citrate 603 
Potassium Hydroxide 605 
Potassium Metabisulfite 607 
Potassium Sorbate 609 
Povidone 611 
Propionic Acid 617 
Propyl Gallate 619 
Propylene Carbonate 622 
Propylene Glycol 624 
Propylene Glycol Alginate 627 
Propylparaben 629 
2-Pyrrolidone 633 
Raffinose 635 
Saccharin 638 
Saccharin Sodium 641 
Saponite 644 
Sesame Oil 646 
Shellac 649 
Contents vii

Simethicone 652 
Sodium Acetate 654 
Sodium Alginate 656 
Sodium Ascorbate 659 
Sodium Benzoate 662 
Sodium Bicarbonate 665 
Sodium Borate 669 
Sodium Chloride 671 
Sodium Citrate Dihydrate 675 
Sodium Cyclamate 678 
Sodium Hyaluronate 681 
Sodium Hydroxide 683 
Sodium Lactate 685 
Sodium Lauryl Sulfate 687 
Sodium Metabisulfite 690 
Sodium Phosphate, Dibasic 693 
Sodium Phosphate, Monobasic 696 
Sodium Propionate 699 
Sodium Starch Glycolate 701 
Sodium Stearyl Fumarate 705 
Sodium Sulfite 708 
Sorbic Acid 710 
Sorbitan Esters (Sorbitan Fatty Acid Esters) 713 
Sorbitol 718 
Soybean Oil 722 
Starch 725 
Starch, Pregelatinized 731 
Starch, Sterilizable Maize 734 
Stearic Acid 737 
Stearyl Alcohol 740 
Sucralose 742 
Sucrose 744 
Sugar, Compressible 748 
Sugar, Confectioners 750 
Sugar Spheres 752 
Sulfobutylether b-Cyclodextrin 754 
Sulfuric Acid 758 
Sunflower Oil 760 
Suppository Bases, Hard Fat 762 
Talc 767 
Tartaric Acid 770 
Tetrafluoroethane (HFC) 772 
Thaumatin 775 
Thimerosal 777 
Thymol 780 
Titanium Dioxide 782 
Tragacanth 785 
Trehalose 788 
Triacetin 790 
Tributyl Citrate 792 
Triethanolamine 794 
Triethyl Citrate 796 
Vanillin 798 
Vegetable Oil, Hydrogenated 800 
Water 802 
Wax, Anionic Emulsifying 807 
Wax, Carnauba 809 
Wax, Cetyl Esters 811 
Wax, Microcrystalline 813 
Wax, Nonionic Emulsifying 815 
Wax, White 817 
Wax, Yellow 819 
Xanthan Gum 821 
Xylitol 824 
Zein 828 
Zinc Acetate 830 
Zinc Stearate 832 
Appendix I: Suppliers Directory 835 
Appendix II: List of Excipient E Numbers 882 
Appendix III: List of Excipient EINECS Numbers 884 
Appendix IV: List of Excipient Molecular Weights 886 
Index 889 
viii Contents

International Steering Committee 
Gregory E Amidon 
Pharmacia Corporation 
Kalamazoo, MI, USA 
Graham Buckton 
University of London 
London, UK 
Colin G Cable 
Western General Hospital 
Edinburgh, UK 
Brian A Carlin 
FMC Biopolymer 
Princeton, NJ, USA 
Walter Cook 
AstraZeneca 
Loughborough, UK 
Henk J de Jong 
Servier International Research Institute 
Courbevoie, France 
Stephen Edge 
DMV International 
Veghel, The Netherlands 
Roger T Guest 
GlaxoSmithKline 
Ware, Hertfordshire, UK 
Bruno Hancock 
Pfizer Inc 
Groton, CT, USA 
Stephen W Hoag 
University of Maryland at Baltimore 
Baltimore, MD, USA 
Arthur H Kibbe 
Wilkes University 
Wilkes-Barre, PA, USA 
William J Lambert 
Eisai Inc 
Research Triangle Park, NC, USA 
M Jayne Lawrence 
Kings College, University of London 
London, UK 
John MacLaine 
Boots Contract Manufacturing 
Nottingham, UK 
Colin P McCoy 
Queens University Belfast 
Belfast, UK 
R Christian Moreton 
Idenix Pharmaceuticals 
Cambridge, MA, USA 
Sandeep Nema 
Pfizer Inc 
Chesterfield, MO, USA 
Sia.n C Owen 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
Anthony Palmieri III 
University of Florida 
Gainesville, FL, USA 
Raymond C Rowe 
Intelligensys Ltd 
Billingham, UK 
Shirish A Shah 
Watson Pharmaceuticals 
Corona, CA, USA 
Bob Sherwood 
JRS Pharma 
Patterson, NY, USA 
Paul J Sheskey 
The Dow Chemical Co 
Midland, MI, USA 
Kamalinder K Singh 
SNDT Womens University 
Mumbai, India 
Paul J Weller 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
Tim Wood 
GlaxoSmithKline 
Ware, Hertfordshire, UK 
Mukund Yelvigi 
Wyeth Research 
Pearl River, NY, USA 
Editorial Staff 
Editorial Staff of the Pharmaceutical Press: 
Laurent Y Galichet 
Louise ME McIndoe 
Sia.n C Owen 
Paul J Weller

Contributors 
O AbuBaker 
Pfizer Inc 
Ann Arbor, MI, USA 
KS Alexander 
University of Toledo 
Toledo, OH, USA 
LV Allen 
International Journal of Pharmaceutical 
Compounding 
Edmond, OK, USA 
GE Amidon 
Pharmacia Corporation 
Kalamazoo, Michigan, USA 
GP Andrews 
The Queens University of Belfast 
Belfast, UK 
NA Armstrong 
Harpenden, Hertfordshire, UK 
ME Aulton 
De Montford University 
Leicester, UK 
S Behn 
AstraZeneca 
Macclesfield, UK 
M Bond 
Danisco Sweeteners Ltd 
Redhill, Surrey, UK 
CG Cable 
Western General Hospital 
Edinburgh, UK 
E Cahill 
AstraZeneca 
Macclesfield, UK 
W Camarco 
ISP Corp 
Wayne, NJ, USA 
WG Chambliss 
University of Mississippi 
University, MS, USA 
RK Chang 
Shire Laboratory 
Rockville, MD, USA 
R Chen 
Pfizer Inc 
Groton, CT, USA 
JH Chu 
Pfizer Inc 
Groton, CT, USA 
JH Collett 
University of Manchester 
Manchester, UK 
JT Colvin 
Pfizer Inc 
Groton, CT, USA 
W Cook 
AstraZeneca 
Loughborough, UK 
DQM Craig 
The University of East Anglia 
Norwich, UK 
TC Dahl 
Gilead Sciences 
Foster City, CA, USA 
A Day 
AstraZeneca 
Loughborough, UK 
HJ de Jong 
Servier International Research Institute 
Courbevoie, France 
SP Denyer 
University of Cardiff 
Cardiff, UK 
X Duriez 
Roquette Fre`res 
Lestrem, France 
S Edge 
DMV International 
Veghel, The Netherlands 
K Fowler 
Schering-Plough Healthcare Products 
Memphis, TN, USA 
SO Freers 
Grain Processing Corporation 
Muscatine, IA, USA 
B Fritzsching 
Palatinit GmbH 
Mannheim, Germany 
G Frunzi 
Bristol-Myers Squibb 
New Brunswick, NJ, USA 
LY Galichet 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
SR Goskonda 
Sunnyvale, CA, USA 
JL Gray 
The Queens University of Belfast 
Belfast, UK 
RT Guest 
GlaxoSmithKline 
Ware, Hertfordshire, UK 
RR Gupta 
SNDT Womens University 
Mumbai, India 
VK Gupta 
Tyco HealthCare Mallinckrodt 
St Louis, MO, USA 
G Haest 
Cargill Cerestar BVBA 
Mechelen, Belgium 
BC Hancock 
Pfizer Inc 
Groton, CT, USA 
RJ Harwood 
Bensalem, PA, USA 
S Hem 
Purdue University 
West Lafayette, IN, USA 
L Hendricks 
Rhodia Inc 
Cranbury, NJ, USA 
SE Hepburn 
Bristol Royal Infirmary 
Bristol, UK

NA Hodges 
University of Brighton 
Brighton, UK 
JT Irwin 
Perrigo Corporation 
MI, USA 
BR Jasti 
University of the Pacific 
Stockton, CA, USA 
R Johnson 
AstraZeneca 
Loughborough, UK 
DS Jones 
The Queens University of Belfast 
Belfast, UK 
AS Kearney 
GlaxoSmithKline 
King-of-Prussia, PA, USA 
SW Kennedy 
Morflex Inc 
Greensboro, NC, USA 
VL Kett 
The Queens University of Belfast 
Belfast, UK 
AH Kibbe 
Wilkes University 
Wilkes-Barre, PA, USA 
V King 
Rhodia Inc 
Cranbury, NJ, USA 
PB Klepak 
Reheis Inc 
Berkley Heights, NJ, USA 
JJ Koleng 
University of Texas at Austin 
Austin, TX, USA 
K Kussendrager 
DMV International 
Veghel, The Netherlands 
WJ Lambert 
Eisai Inc 
Research Triangle Park, NC, USA 
BA Langdon 
Pfizer Inc 
Groton, CT, USA 
MJ Lawrence 
Kings College, University of London 
London, UK 
JC Lee 
Cellegy 
San Jose., CA, USA 
MG Lee 
Medicines and Healthcare products 
Regulatory Agency 
London, UK 
X Li 
University of the Pacific 
Stockton, CA, USA 
EB Lindblad 
Brenntag Biosector 
Frederikssund, Denmark 
O Luhn 
Palatinit GmbH 
Mannheim, Germany 
PE Luner 
Pfizer Inc 
Groton, CT, USA 
HJ Mawhinney 
The Queens University of Belfast 
Belfast, UK 
CP McCoy 
The Queens University of Belfast 
Belfast, UK 
OS McGarvey 
The Queens University of Belfast 
Belfast, UK 
JW McGinity 
University of Texas at Austin 
Austin, TX, USA 
LME McIndoe 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
LA Miller 
Pfizer Inc 
Groton, CT, USA 
RW Miller 
Bristol-Myers Squibb 
New Brunswick, NJ, USA 
J-P Mittwollen 
BASF Aktiengesellschaft 
Ludwigshafen, Germany 
RC Moreton 
Idenix Pharmaceuticals 
Cambridge, MA, USA 
G Mosher 
CyDex Inc 
Lenexa, KS, USA 
C Mroz 
Colorcon Ltd 
Dartford, Kent, UK 
MP Mullarney 
Pfizer Inc 
Groton, CT, USA 
S Murdande 
Pfizer Inc 
Groton, CT, USA 
RA Nash 
St Johns University 
Jamaica, NY, USA 
S Nema 
Pfizer Inc 
Chesterfield, MO, USA 
SC Owen 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
A Palmieri 
University of Florida 
Gainesville, FL, USA 
D Parsons 
ConvaTec Ltd 
Clwyd, UK 
Y Peng 
University of Tennessee 
Memphis, TN, USA 
JD Pipkin 
CyDex Inc 
Lenexa, KS, USA 
D Pipkorn 
Pfizer Inc 
Ann Arbor, MI, USA 
JC Price 
University of Georgia 
Athens, GA, USA 
MA Repka 
University of Mississippi 
University, MS, USA 
B Sarsfield 
Bristol-Myers Squibb 
New Brunswick, NJ, USA 
T Schmeller 
BASF Aktiengesellschaft 
Ludwigshafen, Germany 
A Schoch 
Palatinit GmbH 
Mannheim, Germany 
CJ Sciarra 
Sciarra Laboratories Inc 
Hicksville, NY, USA 
Contributors xi

JJ Sciarra 
Sciarra Laboratories Inc 
Hicksville, NY, USA 
SA Shah 
Watson Pharmaceuticals 
Corona, CA, USA 
RM Shanker 
Pfizer Inc 
Groton, CT, USA 
PJ Sheskey 
The Dow Chemical Co 
Midland, MI, USA 
AJ Shukla 
University of Tennessee 
Memphis, TN, USA 
KK Singh 
SNDT Womens University 
Mumbai, India 
R Steer 
AstraZeneca 
Loughborough, UK 
JT Stewart 
University of Georgia 
Athens, GA, USA 
Y Sun 
University of Tennessee 
Memphis, TN, USA 
AK Taylor 
Baton Rouge, LA, USA 
MS Tesconi 
Wyeth Research 
Pearl River, NY, USA 
D Thassu 
UCB Pharma Inc 
Rochester, NY, USA 
BF Truitt 
Pfizer Inc 
Groton, CT, USA 
CK Tye 
Pfizer Inc 
Kalamazoo, MI, USA 
HM Unvala 
Bayer Corporation 
Myerstown, PA, USA 
KD Vaughan 
Boots Healthcare International 
Nottingham, UK 
H Wang 
Pfizer Inc 
Groton, CT, USA 
PJ Weller 
Royal Pharmaceutical Society of Great 
Britain 
London, UK 
AJ Winfield 
Aberdeen, UK 
AW Wood 
GlaxoSmithKline 
Research Triangle Park, NC, USA 
M Yelvigi 
Wyeth Research 
Pearl River, NY, USA 
PM Young 
University of Sydney 
Sydney, Australia 
About the Editors 
Raymond C Rowe 
BPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MInstP 
Raymond Rowe has been involved in the Handbook of 
Pharmaceutical Excipients since the first edition was published 
in 1986, initially as an author then as a Steering Committee 
member. In addition to his position as Chief Scientist at 
Intelligensys, UK, he is also Professor of Industrial Pharmaceutics 
at the School of Pharmacy, University of Bradford, UK. He 
was formerly Senior Principal Scientist at AstraZeneca, UK. In 
1998 he was awarded the Chiroscience Industrial Achievement 
Award, and in 1999 he was the British Pharmaceutical 
Conference Science Chairman. He has contributed to over 
350 publications in the pharmaceutical sciences including a 
book and eight patents. 
Paul J Sheskey 
BSc, RPh 
Paul Sheskey has been involved in the Handbook of Pharmaceutical 
Excipients as an author and member of the Steering 
Committee since the third edition. He is a Technical Service 
Leader in the Water Soluble Polymers, Pharmaceutical R&D 
Group at The Dow Chemical Company in Midland, Michigan, 
USA. Paul received his BSc degree in pharmacy from Ferris 
State University. Previously, he has worked as a research 
pharmacist in the area of solid dosage form development at the 
Perrigo Company and the Upjohn (Pharmacia) Company. Paul 
has authored numerous journal articles in the area of 
pharmaceutical technology. He is a member of the AAPS, 
Controlled Release Society, and the Institute for Briquetting and 
Agglomeration. 
Sia.n C Owen 
BSc, MA 
Sia.n Owen has been involved with the Handbook of 
Pharmaceutical Excipients since the fourth edition, as a 
contributor and Steering Committee member. Sia.n received 
her BSc degree in pharmacology from the University of 
Sunderland, and her MA in biotechnological law and ethics 
from the University of Sheffield. 
xii Contributors

New Monographs 
The following new monographs have been added to the Handbook of Pharmaceutical Excipients, 5th edition. 
Acetone 
Agar 
Aluminum Hydroxide Adjuvant 
Aluminum Oxide 
Aluminum Phosphate Adjuvant 
Ammonium Alginate 
Aluminum Stearate 
Boric Acid 
Calcium Alginate 
Cetylpyridinium Chloride 
Copovidone 
Dimethylacetamide 
Disodium Edetate 
Erythorbic Acid 
Erythritol 
Ethyl Lactate 
Ethylene Vinyl Acetate 
Hectorite 
Hydroxypropyl Starch 
Hypromellose Acetate Succinate 
Inulin 
Iron Oxides 
Isomalt 
Lactose, Anhydrous 
Lactose, Monohydrate 
Lactose, Spray-Dried 
Lauric Acid 
Leucine 
Linoleic Acid 
Macrogol 15 Hydroxystearate 
Myristic Acid 
Neohesperidin Dihydrochalcone 
Octyldodecanol 

Oleyl Alcohol 
Palmitic Acid 
Pectin 
Polycarbophil 
Poly(methylvinyl ether/maleic anhydride) 
Potassium Alginate 
2-Pyrrolidone 
Raffinose 
Saponite 
Sodium Acetate 
Sodium Borate 
Sodium Hyaluronate 
Sodium Lactate 
Sodium Sulfite 
Sulfobutylether b-Cyclodextrin 
Thaumatin 
Thymol 
Zinc Acetate

Related Substances 
Acetic acid 
Activated attapulgite 
Aleuritic acid 
d-Alpha tocopherol 
d-Alpha tocopheryl acetate 
dl-Alpha tocopheryl acetate 
d-Alpha tocopheryl acid succinate 
dl-Alpha tocopheryl acid succinate 
Aluminum distearate 
Aluminum monostearate 
Amylopectin 
a-Amylose 
Anhydrous citric acid 
Anhydrous sodium citrate 
Anhydrous sodium propionate 
Artificial vinegar 
Bacteriostatic water for injection 
Bentonite magma 
Beta tocopherol 
Beta-carotene 
n-Butyl lactate 
Butylparaben sodium 
Calcium ascorbate 
Calcium cyclamate 
Calcium polycarbophil 
Calcium propionate 
Calcium silicate 
Calcium sorbate 
Calcium sulfate hemihydrate 
Capric acid 
Carbon dioxide-free water 
Cationic emulsifying wax 
Ceratonia extract 
Cetylpyridinium bromide 
Chlorhexidine acetate 
Chlorhexidine gluconate 
Chlorhexidine hydrochloride 
Chlorodifluoromethane 
Chlorophenoxyethanol 
Corn syrup solids 
m-Cresol 
o-Cresol 
p-Cresol 
Crude olive-pomace oil 
Cyclamic acid 
De-aerated water 
Dehydrated alcohol 
Delta tocopherol 
Denatured alcohol 
Dextrose anhydrous 
Diazolidinyl urea 
Dibasic potassium phosphate 
Diethylene glycol monopalmitostearate 
Dilute acetic acid 
Dilute alcohol 
Dilute ammonia solution 
Dilute hydrochloric acid 
Dilute phosphoric acid 
Dilute sulfuric acid 
Dimethyl-b-cyclodextrin 
Dioctyl phthalate 
Dipotassium edetate 
Docusate calcium 
Docusate potassium 
Dodecyl gallate 
Dodecyltrimethylammonium bromide 
Edetate calcium disodium 
Eglumine 
Ethyl gallate 
Ethylene glycol monopalmitate 
Ethylene glycol monostearate 
Ethyl linoleate 
Ethylparaben potassium 
Ethylparaben sodium 
Extra virgin olive oil 
Fine virgin olive oil 
Fuming sulfuric acid 
Gamma tocopherol 
Hard water 
Hesperidin 
Hexadecyltrimethylammonium bromide 
High-fructose syrup 
Hyaluronic acid 
Hydrogenated lanolin 
Hydrogenated vegetable oil, type II 
2-Hydroxyethyl-b-cyclodextrin 
2-Hydroxypropyl-b-cyclodextrin 
3-Hydroxypropyl-b-cyclodextrin 
Indigo carmine 
Invert sugar 
Isotrehalose 
Lampante virgin olive oil 
Lanolin alcohols ointment 
DL-Leucine 
Liquefied phenol 
Liquid fructose 
Magnesium carbonate anhydrous 
Magnesium carbonate hydroxide 
Magnesium lauryl sulfate 
Magnesium metasilicate 
Magnesium orthosilicate 
Magnesium trisilicate anhydrous 
D-Malic acid 
L-Malic acid 
d-Menthol 
l-Menthol 
Methyl lactate 
Methyl linoleate 
Methyl methacrylate 
Methyl oleate

Methylparaben potassium 
Methylparaben sodium 
N-Methylpyrrolidone 
Microcrystalline cellulose and carboxymethylcellulose sodium 
Microcrystalline cellulose and carrageenan 
Microcrystalline cellulose and guar gum 
Modified lanolin 
Monobasic potassium phosphate 
Montmorillonite 
Myristyl alcohol 
Neotrehalose 
Normal magnesium carbonate 
Octyl gallate 
Oleyl oleate 
Olive-pomace oil 
Palmitin 
Pharmaceutical glaze 
Phenoxypropanol 
Polacrilin 
Poly(methyl methacrylate) 
Potassium bisulfite 
Potassium myristate 
Potassium propionate 
Powdered fructose 
Propan-1-ol 
(S)-Propylene carbonate 
Propylparaben potassium 
Propylparaben sodium 
Purified bentonite 
Purified stearic acid 
Quaternium 18-hectorite 
Rapeseed oil 
Refined almond oil 
Refined olive-pomace oil 
Saccharin ammonium 
Saccharin calcium 
Self-emulsifying glyceryl monostearate 
Shellolic acid 
Sodium bisulfite 
Sodium borate anhydrous 
Sodium edetate 
Sodium erythorbate 
Sodium laurate 
Sodium myristate 
Sodium palmitate 
Sodium sorbate 
Sodium sulfite heptahydrate 
Soft water 
Sorbitol solution 70% 
Spermaceti wax 
Stearalkonium hectorite 
Sterile water for inhalation 
Sterile water for injection 
Sterile water for irrigation 
Sunset yellow FCF 
Synthetic paraffin 
DL-()-Tartaric acid 
Tartrazine 
Theobroma oil 
Tocopherols excipient 
Tribasic sodium phosphate 
Trimethyl-b-cyclodextrin 
Trimethyltetradecylammonium bromide 
Trisodium edetate 
Virgin olive oil 
Water for injection 
White petrolatum 
Zinc propionate 
Related Substances xv

Preface 
Pharmaceutical dosage forms contain both pharmacologically 
active compounds and excipients added to aid the formulation 
and manufacture of the subsequent dosage form for administration 
to patients. Indeed, the properties of the final dosage 
form (i.e. its bioavailability and stability) are, for the most part, 
highly dependent on the excipients chosen, their concentration 
and interaction with both the active compound and each other. 
No longer can excipients be regarded simply as inert or inactive 
ingredients, and a detailed knowledge not only of the physical 
and chemical properties but also of the safety, handling and 
regulatory status of these materials is essential for formulators 
throughout the world. In addition, the growth of novel forms of 
delivery has resulted in an increase in the number of the 
excipients being used and suppliers of excipients have developed 
novel excipient mixtures and new physical forms to 
improve their properties. The Handbook of Pharmaceutical 
Excipients has been conceived as a systematic, comprehensive 
resource of information on all of these topics 
The first edition of the Handbook was published in 1986 and 
contained 145 monographs. This was followed by the second 
edition in 1994 containing 203 monographs, the third edition 
in 2000 containing 210 monographs and the fourth edition in 
2003 containing 249 monographs. Since 2000, the data has 
also been available on CD-ROM, updated annually, and from 
2004 online. This new printed edition with its companion CDROM, 
Pharmaceutical Excipients 5, contains 300 monographs 
compiled by over 120 experts in pharmaceutical formulation or 
excipient manufacture from Australia, Europe, India and the 
USA. All the monographs have been reviewed and revised in the 
light of current knowledge. There has been a greater emphasis 
on including published data from primary sources although 
some data from laboratory projects included in previous 
editions have been retained where relevant. Variations in test 
methodology can have significant effects on the data generated 
(especially in the case of the compactability of an excipient), 
and thus cause confusion. As a consequence, the editors have 
been more selective in including data relating to the physical 
properties of an excipient. However, comparative data that 
show differences between either source or batch of a specific 
excipient have been retained as this was considered relevant to 
the behavior of a material in practice. The Suppliers Directory 
(Appendix I) has also been completely updated with many more 
international suppliers included. 
In a systematic and uniform manner, the Handbook of 
Pharmaceutical Excipients collects essential data on the 
physical properties of excipients such as: boiling point, bulk 
and tap density, compression characteristics, hygroscopicity, 
flowability, melting point, moisture content, moisture-absorption 
isotherms, particle size distribution, rheology, specific 
surface area, and solubility. Scanning electron microphotographs 
(SEMs) are also included for many of the excipients. The 
Handbook contains information from various international 
sources and personal observation and comments from monograph 
authors, steering committee members, and the editors. 
All of the monographs in the Handbook are thoroughly 
cross-referenced and indexed so that excipients may be 
identified by either a chemical, a nonproprietary, or a trade 
name. Most monographs list related substances to help the 
formulator to develop a list of possible materials for use in a 
new dosage form or product. Related substances are not 
directly substitutable for each other but, in general, they are 
excipients that have been used for similar purposes in various 
dosage forms. 
The Handbook of Pharmaceutical Excipients is a comprehensive, 
uniform guide to the uses, properties, and safety of 
pharmaceutical excipients, and is an essential reference source 
for those involved in the development, production, control, or 
regulation of pharmaceutical preparations. Since many pharmaceutical 
excipients are also used in other applications, the 
Handbook of Pharmaceutical Excipients will also be of value to 
persons with an interest in the formulation or production of 
confectionery, cosmetics, and food products.

Arrangement 
The information consists of monographs that are divided into 
22 sections to enable the reader to find the information of 
interest easily. Although it was originally intended that each 
monograph contain only information about a single excipient, 
it rapidly became clear that some substances or groups of 
substances should be discussed together. This gave rise to such 
monographs as Coloring Agents and Hydrocarbons. In 
addition, some materials have more than one monograph 
depending on the physical characteristics of the material, e.g. 
Starch versus Pregelatinized Starch. Regardless of the complexity 
of the monograph they are all divided into 22 sections as 
follows: 
1 Nonproprietary Names 
2 Synonyms 
3 Chemical Name and CAS Registry Number 
4 Empirical Formula and Molecular Weight 
5 Structural Formula 
6 Functional Category 
7 Applications in Pharmaceutical Formulation or 
Technology 
8 Description 
9 Pharmacopeial Specifications 
10 Typical Properties 
11 Stability and Storage Conditions 
12 Incompatibilities 
13 Method of Manufacture 
14 Safety 
15 Handling Precautions 
16 Regulatory Status 
17 Related Substances 
18 Comments 
19 Specific References 
20 General References 
21 Authors 
22 Date of Revision 
Descriptions of the sections appear below with information 
from an example monograph if needed. 
Section 1, Nonproprietary Names, lists the excipient names 
used in the current British Pharmacopoeia, European Pharmacopeia, 
Japanese Pharmacopeia, and the United States Pharmacopeia/
National Formulary. 
Section 2, Synonyms, lists other names for the excipient, 
including trade names used by suppliers (shown in italics). 
The inclusion of one suppliers trade name and the absence of 
others should in no way be interpreted as an endorsement of 
one suppliers product over the other. The large number of 
suppliers internationally makes it impossible to include all the 
trade names. 
Section 3, Chemical Name and CAS Registry Number, indicates 
the unique Chemical Abstract Services number for an 
excipient along with the chemical name, e.g., Acacia [9000- 
01-5]. 
Sections 4 and 5, Empirical Formula and Molecular Weight 
and Structural Formula, are self-explanatory. Many excipients 
are not pure chemical substances, in which case their composition 
is described either here or in Section 8. 
Section 6, Functional Category, lists the function(s) that an 
excipient is generally thought to perform, e.g., diluent, emulsifying 
agent, etc. 
Section 7, Applications in Pharmaceutical Formulation or Technology, 
describes the various applications of the excipient. 
Section 8, Description, includes details of the physical appearance 
of the excipient, e.g., white or yellow flakes, etc. 
Section 9, Pharmacopeial Specifications, briefly presents the 
compendial standards for the excipient. Information included 
is obtained from the British Pharmacopoeia (BP), European 
Pharmacopeia (PhEur), Japanese Pharmacopeia (JP), and the 
United States Pharmacopeia/National Formulary (USP/ 
USPNF). Information from the JP, USP and USPNF are 
included if the substance is in those compendia. Information 
from the PhEur is also included. If the excipient is not in the 
PhEur but is included in the BP, information is included from 
the BP. Pharmacopeias are continually updated with most 
now being produced as annual editions. However, although 
efforts were made to include up-to-date information at the 
time of publication of this edition, the reader is advised to 
consult the most current pharmacopeias or supplements. 
Section 10, Typical Properties, describes the physical properties 
of the excipient which are not shown in Section 9. All 
data are for measurements made at 208C unless otherwise 
indicated. Where the solubility of the excipient is described in 
words, the following terms describe the solubility ranges: 
Very soluble 1 part in less than 1 
Freely soluble 1 part in 110 
Soluble 1 part in 1030 
Sparingly soluble 1 part in 30100 
Slightly soluble 1 part in 1001000 
Very slightly soluble 1 part in 100010 000 
Practically insoluble 1 part in more than 10 000 
or insoluble 
Where practical, data typical of the excipient or comparative 
data representative of different grades or sources of a material 
are included, the data being obtained from either the primary or 
the manufacturers literature. In previous editions of the 
Handbook a laboratory project was undertaken to determine 
data for a variety of excipients and in some instances this data 
has been retained. For a description of the specific methods

used to generate the data readers should consult the appropriate 
previous edition(s) of the Handbook. 
Section 11, Stability and Storage Conditions, describes the 
conditions under which the bulk material as received from 
the supplier should be stored. In addition some monographs 
report on storage and stability of the dosage forms that contain 
the excipient. 
Section 12, Incompatibilities, describes the reported incompatibilities 
for the excipient either with other excipients or with 
active ingredients. If an incompatibility is not listed it does 
not mean it does not occur but simply that it has not been 
reported or is not well known. Every formulation should be 
tested for incompatibilities prior to use in a commercial product. 
Section 13, Method of Manufacture, describes the common 
methods of manufacture and additional processes that are 
used to give the excipient its physical characteristics. In some 
cases the possibility of impurities will be indicated in the 
method of manufacture. 
Section 14, Safety, describes briefly the types of formulations 
in which the excipient has been used and presents relevant 
data concerning possible hazards and adverse reactions that 
have been reported. Relevant animal toxicity data are also 
shown. 
Section 15, Handling Precautions, indicates possible hazards 
associated with handling the excipient and makes recommendations 
for suitable containment and protection methods. A 
familiarity with current good laboratory practice (GLP) and 
current good manufacturing practice (GMP) and standard 
chemical handling procedures is assumed. 
Section 16, Regulatory Status, describes the accepted uses in 
foods and licensed pharmaceuticals where known. However, 
the status of excipients varies from one nation to another, 
and appropriate regulatory bodies should be consulted for 
guidance. 
Section 17, Related Substances, lists excipients similar to the 
excipient discussed in the monograph. 
Section 18, Comments, includes additional information and 
observations relevant to the excipient. Where appropriate, the 
different grades of the excipient available are discussed. Comments 
are the opinion of the listed author(s) unless referenced 
or indicated otherwise. 
Section 19, Specific References, is a list of references cited 
within the monograph. 
Section 20, General References, lists references which have 
general information about this type of excipient or the types 
of dosage forms made with these excipients. 
Section 21, Authors, lists the current authors of the monograph 
in alphabetical order. Authors of previous versions of 
the monograph are shown in previous printed editions of the 
text. 
Section 22, Date of Revision, indicates the date on which 
changes were last made to the text of the monograph. 
xviii Arrangement

Acknowledgments 
A publication containing so much detail could not be produced 
without the help of a large number of pharmaceutical scientists 
based world-wide. The voluntary support of over 120 authors 
has been acknowledged as in previous editions, but the current 
editors would like to thank them all personally for their 
contribution. Grateful thanks also go to the members of the 
International Steering Committee who advised the editors and 
publishers on all aspects of the Handbook project. Steering 
Committee members also diligently reviewed all of the 
monographs before their publication. Many authors and 
Steering Committee members have been involved in previous 
editions of the Handbook. For others, this was their first edition 
although not, we hope, their last. Walter Chambliss and John 
Hogan retired from the International Steering Committee 
during the preparation of this edition and we extend our 
thanks for their support over many years. Thanks are also 
extended to excipient manufacturers and suppliers who 
provided helpful information on their products. 
Thanks are also gratefully extended to the staff of the 
Pharmaceutical Press and American Pharmacists Association 
who were involved in the production of the Handbook: Eric 
Connor, Tamsin Cousins, Simon Dunton, Laurent Galichet, 
Julian Graubart, Louise McIndoe, Karl Parsons, Paul Weller, 
and John Wilson. Once again, the diligent copy-editing and 
challenging questions asked by Len Cegielka helped the authors 
and editors, we hope, to express their thoughts clearly, 
concisely, and accurately. 
Raymond C Rowe, Paul J Sheskey and Sia.n C Owen 
August 2005 
Notice to Readers 
The Handbook of Pharmaceutical Excipients is a reference 
work containing a compilation of information on the uses and 
properties of pharmaceutical excipients, and the reader is 
assumed to possess the necessary knowledge to interpret the 
information that the Handbook contains. The Handbook of 
Pharmaceutical Excipients has no official status and there is no 
intent, implied or otherwise, that any of the information 
presented should constitute standards for the substances. The 
inclusion of an excipient, or a description of its use in a 
particular application, is not intended as an endorsement of 
that excipient or application. Similarly, reports of incompatibilities 
or adverse reactions to an excipient, in a particular 
application, may not necessarily prevent its use in other 
applications. Formulators should perform suitable experimental 
studies to satisfy themselves and regulatory bodies that a 
formulation is efficacious and safe to use. 
While considerable efforts were made to ensure the accuracy 
of the information presented in the Handbook, neither the 
publishers nor the compilers can accept liability for any errors 
or omissions. In particular, the inclusion of a supplier within the 
Suppliers Directory is not intended as an endorsement of that 
supplier or its products and, similarly, the unintentional 
omission of a supplier or product from the directory is not 
intended to reflect adversely on that supplier or its product. 
Although diligent effort was made to use as recent 
compendial information as possible, compendia are frequently 
revised and the reader is urged to consult current compendia, or 
supplements, for up-to-date information, particularly as efforts 
are currently in progress to harmonize standards for excipients. 
Data presented for a particular excipient may not be 
representative of other batches or samples. 
Relevant data and constructive criticism are welcome and 
may be used to assist in the preparation of any future editions 
or electronic versions of the Handbook. The reader is asked to 
send any comments to the Editor, Handbook of Pharmaceutical 
Excipients, Royal Pharmaceutical Society of Great Britain, 1 
Lambeth High Street, London SE1 7JN, UK, or Editor, 
Handbook of Pharmaceutical Excipients, American Pharmacists 
Association, 2215 Constitution Avenue,NW,Washington, 
DC 20037-2985, USA.

Bibliography 
A selection of publications and websites which contain useful information on pharmaceutical excipients is listed below: 
Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd 
edn. Endicott, NY: Synapse Information Resources, 2002. 
Aulton ME, ed. Pharmaceutics: the Science of Dosage Form 
Design, 2nd edn. Edinburgh: Churchill Livingstone, 2002. 
Banker GS, Rhodes CT, eds. Modern Pharmaceutics, 4th edn. 
New York: Marcel Dekker, 2002. 
British Pharmacopoeia 2004. London: The Stationery Office, 
2004. 
Bugay DE, Findlay WP. Pharmaceutical Excipients Characterization 
by IR, Raman, and NMR Spectroscopy. New York: 
Marcel Dekker, 1999. 
European Pharmacopoeia, 5th edn. and supplements. Strasbourg: 
Council of Europe, 2005. 
Florence AT, Salole EG, eds. Formulation Factors in Adverse 
Reactions. London: Butterworth, 1990. 
Food and Drug Administration. Inactive Ingredient Guide. 
http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm 
(accessed 11 July 2005). 
Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996. 
Health and Safety Executive. EH40/2002: Occupational 
Exposure Limits 2002. Sudbury: Health and Safety Executive, 
2001. 
Health Canada. Canadian List of Acceptable Non-medicinal 
Ingredients. (accessed 11 July 2005) 
Hoepfner E, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of 
Excipients for Pharmaceuticals, Cosmetics and Related 
Areas. Aulendorf, Germany: Editio Cantor, 2002. 
Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004. 
Japanese Pharmacopeia, 14th edn. and supplement. Tokyo: 
Yakuji Nippo, 2001. 
Kemper FH, Luepke N-P, Umbach W, eds. Blue List Cosmetic 
Ingredients. Aulendorf, Germany: Editio Cantor, 2000. 
Lewis RJ, ed. Saxs Dangerous Properties of Industrial 
Materials, 11th edn. New York: John Wiley, 2004. 
Lund W, ed. The Pharmaceutical Codex: Principles and 
Practice of Pharmaceutics, 12th edn. London: Pharmaceutical 
Press, 1994. 
National Library of Medicine. TOXNET. 
http://toxnet.nlm.nih.gov (accessed 11 July 2005) 
ONeil MJ, Smith A, Heckelman PE, eds.The Merck Index: an 
Encyclopedia of Chemicals, Drugs, and Biologicals, 13th 
edn. Whitehouse Station, NJ: Merck, 2001. 
Smolinske SC. Handbook of Food, Drug and Cosmetic 
Excipients. Boca Raton, FL: CRC Press, 1992. 
Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical 
Technology, 2nd edn. New York: Marcel Dekker, 2002. 
Sweetman SC, ed. Martindale: the Complete Drug Reference, 
34rd edn. London: Pharmaceutical Press, 2005. 
United States Pharmacopeia 28 and National Formulary 23. 
and supplement. Rockville, MD: United States Pharmacopeial 
Convention, 2005. 
University of the Sciences in Philadelphia. Remington: the 
Science and Practice of Pharmacy, 21st edn. Baltimore: 
Lippincott Williams and Wilkins, 2005. 
Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: a Handbook of Excipients. New York: Marcel 
Dekker, 1989. 
Weiner ML, Kotkoskie LA, eds. Excipient Toxicity and Safety. 
New York: Marcel Dekker, 2000. 
Abbreviations 
Some units, terms, and symbols are not included in this list as they are defined in the text. Common abbreviations have been omitted. 
The titles of journals are abbreviated according to the general style of the Index Medicus. 
 approximately. 
Ad Addendum. 
ADI acceptable daily intake. 
approx approximately. 
atm atmosphere. 
BAN British Approved Name. 
bp boiling point. 
BP British Pharmacopoeia. 
BS British Standard (specification). 
BSI British Standards Institution. 
cal calorie(s). 
CAS Chemical Abstract Service. 
CFC chlorofluorocarbon. 
cm centimeter(s). 
cm2 square centimeter(s). 
cm3 cubic centimeter(s). 
cmc critical micelle concentration. 
CNS central nervous system. 
cP centipoise(s). 
cSt centistoke(s). 
CTFA Cosmetic, Toiletry, and Fragrance Association. 
D&C designation applied in USA to dyes permitted for use 
in drugs and cosmetics. 
DoH Department of Health (UK).

DSC differential scanning calorimetry. 
EC European Community. 
e.g. exemplit gratia, for example. 
EINECS European Inventory of Existing Commercial 
Chemical Substances. 
et al et alii, and others. 
EU European Union. 
FAO Food and Agriculture Organization of the United 
Nations. 
FAO/ Food and Agriculture Organization of the United 
WHO Nations and the World Health Organization. 
FCC Food Chemicals Codex. 
FDA Food and Drug Administration of the USA. 
FD&C designation applied in USA to dyes permitted for use 
in foods, drugs, and cosmetics. 
FFBE Flat face beveled edge. 
g gram(s). 
GMP Good Manufacturing Practice. 
GRAS generally recognized as safe by the Food and Drug 
Administration of the USA. 
HC hydrocarbon. 
HCFC hydrochlorofluorocarbon. 
HFC hydrofluorocarbon. 
HIV human immunodeficiency virus. 
HLB hydrophiliclipophilic balance. 
HSE Health and Safety Executive (UK). 
i.e. id est, that is. 
IM intramuscular. 
INN International Nonproprietary Name. 
IP intraperitoneal. 
ISO International Organization for Standardization. 
IU International Units. 
IV intravenous. 
J joule(s). 
JP Japanese Pharmacopeia. 
JPE Japanese Pharmaceutical Excipients 
kcal kilocalorie(s). 
kg kilogram(s). 
kJ kilojoule(s). 
kPa kilopascal(s). 
L liter(s). 
LAL Limulus amoebocyte lysate. 
LC50 a concentration in air lethal to 50% of the specified 
animals on inhalation. 
LD50 a dose lethal to 50% of the specified animals or 
microorganisms. 
LdLo lowest lethal dose for the specified animals or 
microorganisms. 
m meter(s). 
m2 square meter(s). 
m3 cubic meter(s). 
M molar. 
max maximum. 
MCA Medicines Control Agency (UK). 
mg milligram(s). 
MIC minimum inhibitory concentration. 
min minute(s) or minimum. 
mL milliliter(s). 
mm millimeter(s). 
mM millimolar. 
mm2 square millimeter(s). 
mm3 cubic millimeter(s). 
mmHg millimeter(s) of mercury. 
mmol millimole(s). 
mN millinewton(s). 
mol mole(s). 
mp melting point. 
mPa millipascal(s). 
MPa megapascal(s). 
mg microgram(s). 
mm micrometer(s). 
N newton(s) or normal (concentration). 
nm nanometer(s). 
o/w oil-in-water. 
o/w/o oil-in-water-in-oil. 
Pa pascal(s). 
pH the negative logarithm of the hydrogen ion 
concentration. 
PhEur European Pharmacopeia. 
pKa the negative logarithm of the dissociation constant. 
pph parts per hundred. 
ppm parts per million. 
psia pounds per square inch absolute. 
RDA recommended dietary allowance (USA). 
rpm revolutions per minute. 
s second(s). 
SC subcutaneous. 
SEM scanning electron microscopy or scanning electron 
microphotograph. 
SI Statutory Instrument or SystU. me International 
dUnites (International System of Units). 
TPN total parental nutrition. 
TWA time weighted average. 
UK United Kingdom. 
US or United States of America. 
USA 
USAN United States Adopted Name. 
USP The United States Pharmacopeia. 
USPNF The United States Pharmacopeia National 
Formulary. 
UV ultraviolet. 
v/v volume in volume. 
v/w volume in weight. 
WHO World Health Organization. 
w/o water-in-oil. 
w/o/w water-in-oil-in-water. 
w/v weight in volume. 
w/w weight in weight. 
Abbreviations xxi

Units of Measurement 
The information below shows imperial to SI unit conversions 
for the units of measurement most commonly used in the 
Handbook. SI units are used throughout with, where appropriate, 
imperial units reported in parentheses. 
Area 
1 square inch (in2) = 6.4516  104 square meter (m2) 
1 square foot (ft2) = 9.29030  102 square meter (m2) 
1 square yard (yd2) = 8.36127  101 square meter (m2) 
Density 
1 pound per cubic foot (lb/ft3) = 16.0185 kilograms per cubic 
meter (kg/m3) 
Energy 
1 kilocalorie (kcal) = 4.1840  103 joules (J) 
Force 
1 dyne (dynes) = 1  105 newton (N) 
Length 
1 angstrom (a.) = 1010 meter (m) 
1 inch (in) = 2.54  102 meter (m) 
1 foot (ft) = 3.048  101 meter (m) 
1 yard (yd) = 9.144  101 meter (m) 
Pressure 
1 atmosphere (atm) = 0.101325 megapascal (MPa) 
1 millimeter of mercury (mmHg) = 133.322 pascals (Pa) 
1 pound per square inch (psi) = 6894.76 pascals (Pa) 
Surface tension 
1 dyne per centimeter (dyne/cm) = 1 millinewton per meter 
(mN/m) 
Temperature 
Celsius (8C) = (1.8  8C) . 32 Fahrenheit (8F) 
Fahrenheit (8F) = (0.556  8F) 17.8 Celsius (8C) 
Viscosity (dynamic) 
1 centipoise (cP) = 1 millipascal second (mPa s) 
1 poise (P) = 0.1 pascal second (Pa s) 
Viscosity (kinematic) 
1 centistoke (cSt) = 1 square millimeter per second (mm2/s) 
Volume 
1 cubic inch (in3) = 1.63871  105 cubic meter (m3) 
1 cubic foot (ft3) = 2.83168  102 cubic meter (m3) 
1 cubic yard (yd3) = 7.64555  101 cubic meter (m3) 
1 pint (UK) = 5.68261  104 cubic meter (m3) 
1 pint (US) = 4.73176  104 cubic meter (m3) 
1 gallon (UK) = 4.54609  103 cubic meter (m3) 
1 gallon (US) = 3.78541  103 cubic meter (m3)

Acacia 
1 Nonproprietary Names 
BP: Acacia 
JP: Acacia 
PhEur: Acaciae gummi 
USPNF: Acacia 
2 Synonyms 
Acacia gum; arabic gum; E414; gum acacia; gummi africanum; 
gum arabic; gummi arabicum; gummi mimosae; talha gum. 
3 Chemical Name and CAS Registry Number 
Acacia [9000-01-5] 
4 Empirical Formula and Molecular Weight 
Acacia is a complex, loose aggregate of sugars and hemicelluloses 
with a molecular weight of approximately 
240 000580 000. The aggregate consists essentially of an 
arabic acid nucleus to which are connected calcium, magnesium, 
and potassium along with the sugars arabinose, 
galactose, and rhamnose. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emulsifying agent; stabilizing agent; suspending agent; tablet 
binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Acacia is mainly used in oral and topical pharmaceutical 
formulations as a suspending and emulsifying agent, often in 
combination with tragacanth. It is also used in the preparation 
of pastilles and lozenges, and as a tablet binder, although if used 
incautiously it can produce tablets with a prolonged disintegration 
time. Acacia has also been evaluated as a bioadhesive;(
1) and has been used in novel tablet formulations,(2) and 
modified release tablets.(3) See Table I. 
Acacia is also used in cosmetics, confectionery, food 
products, and spray-dried flavors.(4) 
See also Section 18. 
Table I: Uses of acacia. 
Use Concentration (%) 
Emulsifying agent 1020 
Pastille base 1030 
Suspending agent 510 
Tablet binder 15 
8 Description 
Acacia is available as white or yellowish-white thin flakes, 
spheroidal tears, granules, powder, or spray-dried powder. It is 
odorless and has a bland taste. 
9 Pharmacopeial Specifications 
The PhEur 2005 provides monographs on acacia and spraydried 
acacia, while the USPNF 23 describes acacia in a single 
monograph that encompasses tears, flakes, granules, powder, 
and spray-dried powder. The JP 2001 also has monographs on 
acacia and powdered acacia. See Table II. 
Table II: Pharmacopeial specifications for acacia. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . . . 
Microbial limit  4104/g . 
Water 417.0% 415.0% 415.0% 
415.0%(a) 410.0%(b)  
Total ash 44.0% 44.0% 44.0% 
Acid-insoluble ash 40.5%  40.5% 
Insoluble residue 40.2% 40.5% 450mg 
Arsenic   43 ppm 
Lead   40.001% 
Heavy metals   40.004% 
Starch, dextrin, and agar . . . 
Tannin-bearing gums . . . 
Tragacanth  .  
Sterculia gum  .  
Glucose and fructose  .  
Solubility and reaction   . 
Organic volatile impurities   . 
(a) Powdered acacia. 
(b) Spray-dried acacia. 
10 Typical Properties 
Acidity/alkalinity: pH = 4.55.0 (5% w/v aqueous solution) 
Acid value: 2.5 
Hygroscopicity: at relative humidities of 2565%, the equilibrium 
moisture content of powdered acacia at 258C is 
813% w/w, but at relative humidities above about 70% it 
absorbs substantial amounts of water. 
Solubility: soluble 1 in 20 of glycerin, 1 in 20 of propylene 
glycol, 1 in 2.7 of water; practically insoluble in ethanol 
(95%). In water, acacia dissolves very slowly, although 
almost completely after two hours, in twice the mass of 
water leaving only a very small residue of powder. The 
solution is colorless or yellowish, viscous, adhesive, and 
translucent. Spray-dried acacia dissolves more rapidly, in 
about 20 minutes. 
Specific gravity: 1.351.49 
Viscosity (dynamic): 100 mPa s (100 cP) for a 30% w/v aqueous 
solution at 208C. The viscosity of aqueous acacia solutions 
varies depending upon the source of the material, processing,

storage conditions, pH, and the presence of salts. Viscosity 
increases slowly up to about 25% w/v concentration and 
exhibits Newtonian behavior. Above this concentration, 
viscosity increases rapidly (non-Newtonian rheology). 
Increasing temperature or prolonged heating of solutions 
results in a decrease of viscosity owing to depolymerization 
or particle agglomeration. See also Section 12. 
11 Stability and Storage Conditions 
Aqueous solutions are subject to bacterial or enzymatic 
degradation but may be preserved by initially boiling the 
solution for a short time to inactivate any enzymes present; 
microwave irradiation can also be used.(5) Aqueous solutions 
may also be preserved by the addition of an antimicrobial 
preservative such as 0.1% w/v benzoic acid, 0.1% w/v sodium 
benzoate, or a mixture of 0.17% w/v methylparaben and 
0.03% propylparaben. Powdered acacia should be stored in an 
airtight container in a cool, dry place. 
12 Incompatibilities 
Acacia is incompatible with a number of substances including 
amidopyrine, apomorphine, cresol, ethanol (95%), ferric salts, 
morphine, phenol, physostigmine, tannins, thymol, and vanillin.
An oxidizing enzyme present in acacia may affect preparations 
containing easily oxidizable substances. However, the 
enzyme may be inactivated by heating at 1008C for a short 
time; see Section 11. 
Many salts reduce the viscosity of aqueous acacia solutions, 
while trivalent salts may initiate coagulation. Aqueous solutions 
carry a negative charge and will form coacervates with 
gelatin and other substances. In the preparation of emulsions, 
solutions of acacia are incompatible with soaps. 
13 Method of Manufacture 
Acacia is the dried gummy exudate obtained from the stems 
and branches of Acacia senegal (Linne.) Willdenow or other 
related species of Acacia (Fam. Leguminosae) that grow mainly 
in the Sudan and Senegal regions of Africa. 
The bark of the tree is incised and the exudate allowed to dry 
on the bark. The dried exudate is then collected, processed to 
remove bark, sand, and other particulate matter, and graded. 
Various acacia grades differing in particle size and other 
physical properties are thus obtained. A spray-dried powder is 
also commercially available. 
14 Safety 
Acacia is used in cosmetics, foods, and oral and topical 
pharmaceutical formulations. Although it is generally regarded 
as an essentially nontoxic material, there have been a limited 
number of reports of hypersensitivity to acacia after inhalation 
or ingestion.(6,7) Severe anaphylactic reactions have occurred 
following the parenteral administration of acacia and it is now 
no longer used for this purpose.(6) 
The WHO has not set an acceptable daily intake for acacia 
as a food additive because the levels necessary to achieve a 
desired effect were not considered to represent a hazard to 
health.(8) 
LD50 (hamster, oral): >18 g/kg(9) 
LD50 (mouse, oral): >16 g/kg 
LD50 (rabbit, oral): 8.0 g/kg 
LD50 (rat, oral): >16 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Acacia can be irritant to the 
eyes and skin and upon inhalation. Gloves, eye protection, and 
a dust respirator are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use in Europe as a food additive. 
Included in the FDA Inactive Ingredients Guide (oral preparations 
and buccal or sublingual tablets). Included in the 

Canadian List of Acceptable Non-medicinal Ingredients. 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 
Ceratonia; guar gum; tragacanth. 
18 Comments 
Concentrated aqueous solutions are used to prepare pastilles 
since on drying they form solid rubbery or glasslike masses 
depending upon the concentration used. Foreign policy changes 
and politically unstable conditions in Sudan, which is the 
principal supplier of acacia, has created a need to find a suitable 
replacement.(10) Poloxamer 188 (1215% w/w) can be used to 
make an oil/water emulsion with similar rheological characteristics 
to acacia. Other natural by-products of foods can also be 
used.(11) Acacia is also used in the food industry as an 
emulsifier, stabilizer, and thickener. A specification for acacia 
is contained in the Food Chemicals Codex (FCC). 
The EINECS number for acacia is 232-519-5. 
19 Specific References 
1 Attama AA, Adiknu MV, Okoli ND. Studies on bioadhesive 
granules. STP Pharma Sci 2003; 13(3): 177181. 
2 Streubel A, Siepmann J, Bodmeier R. Floating matrix tablets based 
on low density foam powder. Eur J Pharm Sci 2003; 18: 3745. 
3 Bahardwaj TR, Kanwar M, Lai R, Gupta A. Natural gums and 
modified natural gums as sustained-release carriers. Drug Dev Ind 
Pharm 2000; 26(10): 10251038. 
4 Buffo R, Reineccius G. Optimization of gum acacia/modified 
starch/maltodextrin blends for spray drying of flavors. Perfumer& 
Flavorist 2000; 25: 4554. 
5 Richards RME, Al Shawa R. Investigation of the effect of 
microwave irradiation on acacia powder. J Pharm Pharmacol 
1980; 32: 45P. 
6 Maytum CK, Magath TB. Sensitivity to acacia. J Am Med Assoc 
1932; 99: 2251. 
7 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 711. 
8 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990; No. 
789. 
9 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 289. 
10 Scheindlin S. Acacia  a remarkable excipient: the past, present, 
and future of gum arabic. JAMA 2001; 41(5): 669671. 
11 I-Achi A, Greenwood R, Akin-Isijola A. Experimenting with a new 
emulsifying agent (tahini) in mineral oil. Int J Pharm Compound 
2000; 4(4): 315317. 
2 Acacia

20 General References 
Anderson DMW, Dea ICM. Recent advances in the chemistry of acacia 
gums. J Soc Cosmet Chem 1971; 22: 6176. 
Anderson DM, Douglas DM, Morrison NA, Wang WP. Specifications 
for gum arabic (Acacia Senegal): analytical data for samples 
collected between 1904 and 1989. Food Add Contam 1990; 7: 
303321. 
Aspinal GO. Gums and mucilages. Adv Carbohydr Chem Biochem 
1969; 24: 333379. 
Whistler RL. Industrial Gums. New York: Academic Press, 1959. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
20 August 2005. 
Acacia 3

Acesulfame Potassium 
1 Nonproprietary Names 
PhEur: Acesulfamum kalicum 
2 Synonyms 
Acesulfame K; E950; 6-methyl-3,4-dihydro-1,2,3-oxathiazin- 
4(3H)-one 2,2-dioxide potassium salt; Sunett; Sweet One. 
3 Chemical Name and CAS Registry Number 
6-Methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium 
salt [55589-62-3] 
4 Empirical Formula and Molecular Weight 
C4H4KNO4S 201.24 
5 Structural Formula 
6 Functional Category 
Sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Acesulfame potassium is used as an intense sweetening agent in 
cosmetics, foods, beverage products, table-top sweeteners, 
vitamin and pharmaceutical preparations, including powder 
mixes, tablets, and liquid products. It is widely used as a sugar 
substitute in compounded formulations,(1) and as a toothpaste 
sweetener.(2) 
The approximate sweetening power is 180200 times that 
of sucrose. It enhances flavor systems and can be used to mask 
some unpleasant taste characteristics. 
8 Description 
Acesulfame potassium occurs as a colorless to white-colored, 
odorless, crystalline powder with an intensely sweet taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for acesulfame potassium. 
Test PhEur 2005 
Characters . 
Identification . 
Appearance of solution . 
Acidity or alkalinity . 
Acetylacetamide . 
Impurity B and related substances 420 ppm 
Fluorides 43 ppm 
Heavy metals 45 ppm 
Loss on drying 41.0% 
Assay 99.0101.0% 
SEM: 1 
Excipient: Acesulfame potassium 
Magnification: 150 Voltage: 5kV 
10 Typical Properties 
Bonding index: 0.007 
Brittle fracture index: 0.08(3) 
Flowability: 19% (Carr compressibility index)(3) 
Density (bulk): 1.04 g/cm3(3) 
Density (tapped): 1.28 g/cm3(3) 
Elastic modulus: 4000MPa(3) 
Melting point: 2508C 
Solubility: see Table II. 
Specific volume: 0.538 cm3/g(4) 
Tensile strength: 0.5MPa(3) 
Viscoelastic index: 2.6(3)

11 Stability and Storage Conditions 
Acesulfame potassium possesses good stability. In the bulk 
form it shows no sign of decomposition at ambient temperature 
over many years. In aqueous solutions (pH 3.03.5 at 208C) no 
reduction in sweetness was observed over a period of 
approximately 2 years. Stability at elevated temperatures is 
good, although some decomposition was noted following 
storage at 408C for several months. Sterilization and pasteurization 
do not affect the taste of acesulfame potassium.(5) 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 

13 Method of Manufacture 
Acesulfame potassium is synthesized from acetoacetic acid tertbutyl 
ester and fluorosulfonyl isocyanate. The resulting 
compound is transformed to fluorosulfonyl acetoacetic acid 
amide, which is then cyclized in the presence of potassium 
hydroxide to form the oxathiazinone dioxide ring system. 
Because of the strong acidity of this compound, the potassium 
salt is produced directly. 
An alternative synthesis route for acesulfame potassium 
starts with the reaction between diketene and amidosulfonic 
acid. In the presence of dehydrating agents, and after 
neutralization with potassium hydroxide, acesulfame potassium 
is formed. 
14 Safety 
Acesulfame potassium is widely used in beverages, cosmetics, 
foods, and pharmaceutical formulations and is generally 
regarded as a relatively nontoxic and nonirritant material. 
Pharmacokinetic studies have shown that acesulfame potassium 
is not metabolized and is rapidly excreted unchanged in 
the urine. Long-term feeding studies in rats and dogs showed no 
evidence to suggest acesulfame potassium is mutagenic or 
carcinogenic.(6) 
The WHO has set an acceptable daily intake for acesulfame 
potassium of up to 15 mg/kg body-weight.(6) 
LD50 (rat, IP): 2.2 g/kg(5) 
LD50 (rat, oral): 6.98.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide for oral and 
sublingual preparations. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. Accepted for use in 
Europe as a food additive. It is also accepted for use in certain 
food products in the USA and several countries in Central and 
South America, the Middle East, Africa, Asia, and Australia. 
17 Related Substances 
Alitame. 
18 Comments 
The perceived intensity of sweeteners relative to sucrose 
depends upon their concentration, temperature of tasting, and 
pH, and on the flavor and texture of the product concerned. 
Intense sweetening agents will not replace the bulk, textural, 
or preservative characteristics of sugar, if sugar is removed from 
a formulation. 
Synergistic effects for combinations of sweeteners have been 
reported, e.g., acesulfame potassium with aspartame or sodium 
cyclamate. A ternary combination of sweeteners that includes 
acesulfame potassium and sodium saccharin has a greater 
decrease in sweetness upon repeated tasting than other 
combinations.(7) 
Note that free acesulfame acid is not suitable for use as a 
sweetener. 
A specification for acesulfame potassium is contained in the 
Food Chemicals Codex (FCC). 
19 Specific References 
1 Kloesel L. Sugar substitutes. Int J Pharm Compound 2000; 4(2): 
8687. 
2 Schmidt R, Janssen E, Haussler O, et al. Evaluating toothpaste 
sweetening. Cosmet Toilet 2000; 115: 4953. 
3 Mullarney MP, Hancock BC, Carlson GT, Ladipo DD. The 
powder flow and compact mechanical properties of sucrose and 
three high-intensity sweeteners used in chewable tablets. Int J 
Pharm 2003; 257: 227236. 
4 Birch GG, Haywood KA, Hanniffy GG, et al. Apparent specific 
volumes and tastes of cyclamates, other sulfamates, saccharins and 
acesulfame sweeteners. Food Chemistry 2004; 84: 429435. 
5 Lipinski G-WvR, Huddart BE. Acesulfame K. Chem Ind 1983; 11: 
427432. 
6 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1991; No. 806. 
7 Schiffman SS, Sattely-Miller EA, Graham BG, et al. Effect of 
repeated presentation on sweetness intensity of binary and tertiary 
mixtures of sweetness. Chem Senses 2003; 28: 219229. 
20 General References 
Anonymous. Artificial sweetners. Can Pharm J 1996; 129: 22. 
Lipinski G-WvR, Lu. ck E. Acesulfame K: a new sweetener for oral 
cosmetics. Manuf Chem 1981; 52(5): 37. 
Marie S. Sweeteners. In: Smith J, ed. Food Additives Users Handbook. 
Glasgow: Blackie, 1991: 4774. 
Nutrinova. Technical literature: Sunett in Pharmaceuticals, 1998. 
21 Authors 
JH Chu. 
22 Date of Revision 
12 August 2005. 
Table II: Solubility of acesulfame potassium. 
Solvent Solubility at 208C 
unless otherwise stated 
Ethanol 1 in 1000 
Ethanol (50%) 1 in 100 
Water 1 in 7.1 at 08C 
1 in 3.7 
1 in 0.77 at 1008C 
Acesulfame Potassium 5

Acetic Acid, Glacial 
1 Nonproprietary Names 
BP: Glacial acetic acid 
JP: Glacial acetic acid 
PhEur: Acidum aceticum glaciale 
USP: Glacial acetic acid 
2 Synonyms 
E260; ethanoic acid; ethylic acid; methane carboxylic acid; 
vinegar acid. 
See also Sections 17 and 18. 
3 Chemical Name and CAS Registry Number 
Ethanolic acid [64-19-7] 
4 Empirical Formula and Molecular Weight 
C2H4O2 60.05 
5 Structural Formula 
6 Functional Category 
Acidifying agent. 
7 Applications in Pharmaceutical Formulations 
or Technology 
Glacial and diluted acetic acid solutions are widely used as 
acidifying agents in a variety of pharmaceutical formulations 
and food preparations. Acetic acid is used in pharmaceutical 
products as a buffer system when combined with an acetate salt 
such as sodium acetate. Acetic acid is also claimed to have some 
antibacterial and antifungal properties. 
8 Description 
Glacial acetic acid occurs as a crystalline mass or a clear, 
colorless volatile solution with a pungent odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for glacial acetic acid. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . .  
Freezing point 514.58C 514.88C 515.68C 
Nonvolatile matter 41.0mg 40.01% 41.0mg 
Sulfate . . . 
Chloride . . . 
Heavy metals 410 ppm 45 ppm 45 ppm 
Iron  45 ppm  
Readily oxidizable 
impurities 
. . . 
Assay 599.0% 99.5100.5% 99.5100.5% 
10 Typical Properties 
Acidity/alkalinity: 
pH = 2.4 (1M aqueous solution); 
pH = 2.9 (0.1M aqueous solution); 
pH = 3.4 (0.01M aqueous solution). 
Boiling point: 1188C 
Dissociation constant: pKa = 4.76 
Flash point: 398C (closed cup); 578C (open cup). 
Melting point: 178C 
Refractive index: nD
20 = 1.3718 
Solubility: miscible with ethanol, ether, glycerin, water, and 
other fixed and volatile oils. 
Specific gravity: 1.045 
11 Stability and Storage Conditions 
Acetic acid should be stored in an airtight container in a cool, 
dry place. 
12 Incompatibilities 
Acetic acid reacts with alkaline substances. 
13 Method of Manufacture 
Acetic acid is usually made by one of three routes: acetaldehyde 
oxidation, involving direct air or oxygen oxidation of liquid 
acetaldehyde in the presence of manganese acetate, cobalt 
acetate, or copper acetate; liquid-phase oxidation of butane or 
naphtha; methanol carbonylation using a variety of techniques. 
14 Safety 
Acetic acid is widely used in pharmaceutical applications 
primarily to adjust the pH of formulations and is thus generally 
regarded as relatively nontoxic and nonirritant. However, 
glacial acetic acid or solutions containing over 50% w/w acetic 
acid in water or organic solvents are considered corrosive and 
can cause damage to skin, eyes, nose, and mouth. If swallowed 
glacial acetic acid causes severe gastric irritation similar to that 
caused by hydrochloric acid.(1)

Dilute acetic acid solutions containing up to 10% w/w of 
acetic acid have been used topically following jellyfish stings.(2) 
Dilute acetic acid solutions containing up to 5% w/w of acetic 
acid have also been applied topically to treat wounds and burns 
infected with Pseudomonas aeruginosa.(3) 
The lowest lethal oral dose of glacial acetic acid in humans is 
reported to be 1470 mg/kg.(4) The lowest lethal concentration 
on inhalation in humans is reported to be 816 ppm.(4) Humans, 
are, however, estimated to consume approximately 1 g/day of 
acetic acid from the diet. 
LD50 (mouse, IV): 0.525 g/kg(4) 
LD50 (rabbit, skin): 1.06 g/kg 
LD50 (rat, oral): 3.31 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Acetic acid, particularly 
glacial acetic acid, can cause burns on contact with the skin, 
eyes, and mucous membranes. Splashes should be washed with 
copious quantities of water. Protective clothing, gloves, and eye 
protection are recommended. 
In the UK, the occupational exposure limits for acetic acid 
are 25 mg/m3 (10 ppm) long-term (8-hour TWA) and 37 mg/m3 
(15 ppm) short-term (15-minutes).(5) 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (injections, nasal, ophthalmic, 
and oral preparations). Included in parenteral and 
nonparenteral preparations licensed in the UK. 
17 Related Substances 
Acetic acid; artificial vinegar; dilute acetic acid. 
Acetic acid 
Comments: a diluted solution of glacial acetic acid containing 
3037% w/w of acetic acid. See Section 18. 
Artificial vinegar 
Comments: a solution containing 4% w/w of acetic acid. 
Dilute acetic acid 
Comments: a weak solution of acetic acid which may contain 
between 610% w/w of acetic acid. See Section 18. 
18 Comments 
In addition to glacial acetic acid, many pharmacopeias contain 
monographs for diluted acetic acid solutions of various 
strengths. For example, the USPNF 23 has a monograph for 
acetic acid, which is defined as an acetic acid solution 
containing 36.037.0% w/w of acetic acid. Similarly, the BP 
2004 contains separate monographs for glacial acetic acid, 
acetic acid (33%), and acetic acid (6%). Acetic acid (33%) BP 
2004 contains 32.533.5% w/w of acetic acid. Acetic acid (6%) 
BP 2004 contains 5.76.3% w/w of acetic acid. The JP 2001 
also contains a monograph for acetic acid that specifies that it 
contains 30.032.0% w/w of acetic acid. 
A specification for glacial acetic acid is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for acetic acid is 200-580-7. 
19 Specific References 
1 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1645. 
2 Fenner PJ, Williamson JA. Worldwide deaths and severe envenomation 
from jellyfish stings. Med J Aust 1996; 165: 658661. 
3 Milner SM. Acetic acid to treat Pseudomonas aeruginosa in 
superficial wounds and burns. Lancet 1992; 340: 61. 
4 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1516. 
5 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002, Sudbury: Health and Safety Executive, 2002. 
20 General References 

21 Authors 
WG Chambliss. 
22 Date of Revision 
8 August 2005. 
Acetic Acid, Glacial 7

Acetone 
1 Nonproprietary Names 
BP: Acetone 
PhEur: Acetonum 
USPNF: Acetone 
2 Synonyms 
Dimethylformaldehyde; dimethyl ketone; b-ketopropane; pyroacetic 
ether. 
3 Chemical Name and CAS Registry Number 
2-Propanone [67-64-1] 
4 Empirical Formula and Molecular Weight 
C3H6O 58.08 
5 Structural Formula 
6 Functional Category 
Solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Acetone is used as a solvent or cosolvent in topical preparations, 
and as an aid in wet granulation.(1,2) It has also been used 
when formulating tablets with water-sensitive active ingredients, 
or to solvate poorly water-soluble binders in a wet 
granulation process. Acetone has also been used in the 
formulation of microspheres to enhance drug release.(3) Owing 
to its low boiling point, acetone has been used to extract 
thermolabile substances from crude drugs.(4) 
8 Description 
Acetone is a colorless volatile, flammable, transparent liquid, 
with a sweetish odor and pungent sweetish taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for acetone. 
Test PhEur 2005 
(Suppl. 5.1) 
USPNF 23 
Identification . . 
Characters .  
Appearance of solution .  
Acidity or alkalinity .  
Relative density 0.7900.793 40.789 
Related substances .  
Matter insoluble in water .  
Reducing substances . . 
Residue on evaporation 450 ppm 40.004% 
Water 43 g/L . 
Assay  599.0% 
10 Typical Properties 
Boiling point: 56.28C 
Flash point: 208C 
Melting point: 94.38C 
Refractive index: nD
20 = 1.359 
Solubility: soluble in water; freely soluble in ethanol (95%) 
Vapor pressure: 185mmHg at 208C 
11 Stability and Storage Conditions 
Acetone should be stored in a cool, dry, well-ventilated place 
out of direct sunlight. 
12 Incompatibilities 
Acetone reacts violently with oxidizing agents, chlorinated 
solvents, and alkali mixtures. It reacts vigorously with sulfur 
dichloride, potassium t-butoxide, and hexachloromelamine. 
Acetone should not be used as a solvent for iodine, as it forms a 
volatile compound that is extremely irritating to the eyes.(4) 
13 Method of Manufacture 
Acetone is obtained by fermentation as a by-product of n-butyl 
alcohol manufacture, or by chemical synthesis from isopropyl 
alcohol; from cumene as a by-product in phenol manufacture; 
or from propane as a by-product of oxidation-cracking. 
14 Safety 
Acetone is considered moderately toxic, and is a skin irritant 
and severe eye irritant. Skin irritation has been reported due to 
its defatting action, and prolonged inhalation may result in 
headaches. Inhalation of acetone can produce systemic effects 
such as conjunctival irritation, respiratory system effects, 
nausea, and vomiting.(5) 
LD50 (mouse, oral): 3.0 g/kg(5) 
LD50 (mouse, IP): 1.297 g/kg 
LD50 (rabbit, oral): 5.340 g/kg 
LD50 (rabbit, skin): 0.2 g/kg

LD50 (rat, IV): 5.5 g/kg 
LD50 (rat, oral): 5.8 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Acetone is a skin and eye 
irritant (see Section 14), therefore gloves, eye protection and a 
respirator are recommended. In the UK, the long-term (8-hour 
TWA) exposure limit for acetone is 1210 mg/m3 (500 ppm). 
The short-term (15-minute) exposure limit is 3620 mg/m3 
(1500 ppm).(6) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (inhalation 
solution; oral tablets; topical preparations). Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 

18 Comments 
A specification for acetone is included in the Japanese 
Pharmaceutical Excipients (JPE).(7) The EINECS number for 
acetone is 200-662-2. 
19 Specific References 
1 Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. 
Endicott, NY: Synapse Information Resources, 2002: 282. 
2 Tang ZG, Black RA, Curran JM, et al. Surface properties and 
biocompatibility of solvent-cast poly[e-caprolactone] films. Biomaterials 
2004; 25(19): 47414748. 
3 Ruan G, Feng SS. Preparation and characterization of poly(lactic 
acid)poly(ethylene glycol)poly(lactic acid) (PLA-PEG-PLA) 
microspheres for controlled release of paclitaxel. Biomaterials 
2003; 24(27): 50375044. 
4 Todd RG, Wade A, eds. The Pharmaceutical Codex, 11th edn. 
London: Pharmaceutical Press, 1979: 6. 
5 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2223. 
6 Health and Safety Executive: EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
7 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 3536. 
20 General References 

21 Authors 
AH Kibbe, SC Owen. 
22 Date of Revision 
23 August 2005. 
Acetone 9

Acetyltributyl Citrate 
1 Nonproprietary Names 
USPNF: Acetyltributyl citrate 
PhEur: Tributylis acetylcitras 
2 Synonyms 
Acetylbutyl citrate; acetylcitric acid, tributyl ester; ATBC; 
Citroflex A-4; tributyl acetylcitrate; tributyl O-acetylcitrate; 
tributyl citrate acetate. 
3 Chemical Name and CAS Registry Number 
1,2,3-Propanetricarboxylic acid, 2-acetyloxy, tributyl ester 
[77-90-7] 
4 Empirical Formula and Molecular Weight 
C20H34O8 402.5 
5 Structural Formula 
6 Functional Category 
Plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Acetyltributyl citrate is used to plasticize polymers in formulated 
pharmaceutical coatings,(15) including capsules, 
tablets, beads, and granules for taste masking, immediate 
release, sustained-release and enteric formulations. 
8 Description 
Acetyltributyl citrate is a clear, odorless, practically colorless, 
oily liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for acetyltributyl citrate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Appearance  . 
Characters  . 
Specific gravity 1.0451055  
Refractive index 1.44101.4425 1.4421.445 
Sulfated ash  40.10% 
Acidity . . 
Water 40.25% 40.25% 
Heavy metals 40.001% 40.001% 
Assay (anhydrous basis) 599.0% 99.0101.0% 
10 Typical Properties 
Acid value: 0.02 
Boiling point: 3268C (decomposes) 
Flash point: 2048C 
Pour point: 598C 
Solubility: miscible with acetone, ethanol, and vegetable oil; 
practically insoluble in water. 
Viscosity (dynamic): 33 mPa s (33 cP) at 258C 
11 Stability and Storage Conditions 
Acetyltributyl citrate should be stored in a well-closed 
container in a cool, dry location at temperatures not exceeding 
388C. When stored in accordance with these conditions, 
acetyltributyl citrate is a stable product. 
12 Incompatibilities 
Acetyltributyl citrate is incompatible with strong alkalis and 
oxidizing materials. 
13 Method of Manufacture 
Acetyltributyl citrate is prepared by the esterification of citric 
acid with butanol followed by acylation with acetic anhydride. 
14 Safety 
Acetyltributyl citrate is used in oral pharmaceutical formulations 
and films intended for direct food contact. It is also used in 
self-adhesive thin films used for topical delivery systems.(6) It is 
generally regarded as a relatively nontoxic and nonirritating 
material. However, ingestion of large quantities may be 
harmful. 
LD50 (cat, oral): >50 mL/kg(7) 
LD50 (mouse, IP): >4 g/kg 
LD50 (rat, oral): >31.5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Acetyltributyl citrate is

slightly irritating to the eyes and may be irritating to the 
respiratory system as a mist or at elevated temperatures. Gloves 
and eye protection are recommended for normal handling, and 
a respirator is recommended when using acetyltributyl citrate at 
elevated temperatures. 
16 Regulatory Status 
Included in FDA Inactive Ingredients Guide (oral capsules and 
tablets). Included in nonparenteral medicines licensed in the 
UK. Approved in the USA for direct food contact in food films. 
17 Related Substances 
Acetyltriethyl citrate; tributyl citrate; triethyl citrate. 
18 Comments 
Acetyltributyl citrate is used as a plasticizer in food contact 
films, although it has been known to migrate from food-grade 
PVC films into high-fat foods such as olive oil.(8) 
Polylactide plasticized with acetyltributyl citrate has been 
investigated as a biodegradable barrier for use in guided-tissue 
regeneration therapy.(9) 
The EINECS number for acetyltributyl citrate is 201-067-0. 
19 Specific References 
1 Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and 
insoluble plasticizer on the physical and mechanical properties of 
acrylic resin copolymers. Int J Pharm 1994; 103: 293301. 
2 Lehmann K. Chemistry and application properties of polymethacrylate 
coating systems. In: McGinity JW, ed. Aqueous Polymeric 
Coatings for Pharmaceutical Dosage Forms. New York: Marcel 
Dekker, 1989: 153245. 
3 Steurnagel CR. Latex emulsions for controlled drug delivery. In: 
McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical 
Dosage Forms. New York: Marcel Dekker, 1989: 161. 
4 Gutierrez-Rocca JC, McGinity JW. Influence of aging on the 
physical-mechanical properties of acrylic resin films cast from 
aqueous dispersions and organic solutions. Drug Dev Ind Pharm 
1993; 19(3): 315332. 
5 Repka MA, Gerding TG, Repka SL. Influence of plasticisers and 
drugs on the physical-mechanical properties of hydroxypropylcellulose 
films prepared by hot melt extrusion. Drug Dev Ind Pharm 
1999; 25(5): 625633. 
6 Lieb S, Szeimies RM, Lee G. Self-adhesive thin films for topical 
delivery of 5-aminolevulinic acid. Eur J Pharm Biopharm 2002; 
53(1): 99106. 
7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3512. 
8 Goulas AE, Riganakos KA, Ehlermann DA, et al. Effect of highdose 
electron beam irradiation on the migration of DOA and 
ATBC plasticizers from food-grade PVC and PVDC/PVC films, 
respectively, into olive oil. J Food Prot 1998; 61(6): 720724. 
9 Dorfer CE, Kim TS, Steinbrenner H, et al. Regenerative periodontal 
surgery in interproximal intrabony defects with biodegradable 
barriers. J Clin Peridontol 2000; 27(3): 162168. 
20 General References 

21 Authors 
SW Kennedy. 
22 Date of Revision 
15 August 2005. 
Acetyltributyl Citrate 11

Acetyltriethyl Citrate 
1 Nonproprietary Names 
USPNF: Acetyltriethyl citrate 
2 Synonyms 
ATEC; Citroflex A-2; triethyl acetylcitrate; triethyl O-acetylcitrate; 
triethyl citrate acetate. 
3 Chemical Name and CAS Registry Number 
1,2,3-Propanetricarboxylic acid, 2-acetyloxy, triethyl ester [77- 
89-4] 
4 Empirical Formula and Molecular Weight 
C14H22O8 318.3 
5 Structural Formula 
6 Functional Category 
Plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Acetyltriethyl citrate is used to plasticize polymers in formulated 
pharmaceutical coatings.(1) The coating applications 
include capsules, tablets, beads and granules for taste masking, 
immediate release, sustained-release and enteric formulations.(
25) It is also used in diffusion-controlled release drug 
delivery systems.(6) 
8 Description 
Acetyltriethyl citrate occurs as a clear, odorless, practically 
colorless oily liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for acetyltriethyl citrate. 
Test USPNF 23 
Identification . 
Specific gravity 1.1351.139 
Refractive index 1.4321.441 
Acidity . 
Water 40.3% 
Heavy metals 40.001% 
Assay (anhydrous basis) 599.0% 
10 Typical Properties 
Acid value: 0.02 
Boiling point: 2948C (decomposes) 
Flash point: 1888C 
Pour point: 438C 
Solubility: soluble 1 in 140 of water; miscible with acetone, 
ethanol, and propan-2-ol. 
Viscosity (dynamic): 54 mPa s (54 cP) at 258C. 
11 Stability and Storage Conditions 
Acetyltriethyl citrate should be stored in dry, closed containers 
at temperatures not exceeding 388C. When stored in accordance 
with these conditions, acetyltriethyl citrate is a stable 
product. 
12 Incompatibilities 
Acetyltriethyl citrate is incompatible with strong alkalis and 
oxidizing materials. 
13 Method of Manufacture 
Acetyltriethyl citrate is prepared by the esterification of citric 
acid with ethanol followed by acylation with acetic anhydride. 
14 Safety 
Acetyltriethyl citrate is used in oral pharmaceutical formulations 
and is generally regarded as a nontoxic and nonirritating 
material. However, ingestion of large quantities may be 
harmful. 
LD50 (cat, oral): 8.5 g/kg(7) 
LD50 (mouse, IP): 1.15 g/kg 
LD50 (rat, oral): 7 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Acetyltriethyl citrate may be 
irritating to the eyes or the respiratory system as a mist or at 
elevated temperatures. Gloves and eye protection are recommended 
for normal handling and a respirator is recommended 
if used at elevated temperatures.

16 Regulatory Status 
Approved in the USA for direct food contact in food films. 
17 Related Substances 
Acetyltributyl citrate; tributyl citrate; triethyl citrate. 
18 Comments 
The EINECS number for acetyltriethyl citrate is 201-066-5. 
19 Specific References 
1 Jensen JL, Appel LE, Clair JH, Zentner GM. Variables that affect 
the mechanism of drug release from osmotic pumps coated with 
acrylate/methacrylate copolymer latexes. J Pharm Sci 1995; 84: 
530533. 
2 Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and 
insoluble plasticizer on the physical and mechanical properties of 
acrylic resin copolymers. Int J Pharm 1994; 103: 293301. 
3 Lehmann K. Chemistry and application properties of polymethacrylate 
coating systems. In: McGinity JW, ed. Aqueous Polymeric 
Coatings for Pharmaceutical Dosage Forms. New York: Marcel 
Dekker, 1989: 153245. 
4 Steurnagel CR. Latex emulsions for controlled drug delivery. In: 
McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical 
Dosage Forms. New York: Marcel Dekker, 1989: 161. 
5 Gutierrez-Rocca JC, McGinity JW. Influence of aging on the 
physical-mechanical properties of acrylic resin films cast from 
aqueous dispersions and organic solutions. Drug Dev Ind Pharm 
1993; 19(3): 315332. 
6 Siepmann J, Lecomte F, Bodmeier R. Diffusion-controlled drug 
delivery systems: calculation of the required composition to 
achieve desired release profiles. J Control Release 1999; 60(23): 
379389. 
7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 5859. 
20 General References 

21 Authors 
SW Kennedy. 
22 Date of Revision 
15 August 2005. 
Acetyltriethyl Citrate 13

Agar 
1 Nonproprietary Names 
JP: Agar 
PhEur: Agar 
USPNF: Agar 
2 Synonyms 
Agar-agar; Bengal isinglass; Ceylon isinglass; Chinese isinglass; 
E406; gelosa; gelose; Japan agar; Japan isinglass; layor carang. 
3 Chemical Name and CAS Registry Number 
Agar [9002-18-0] 
4 Empirical Formula and Molecular Weight 
See Section 5. 
5 Structural Formula 
Agar is a dried, hydrophilic, colloidal polysaccharide complex 
extracted from the agarocytes of algae of the Rhodophyceae. 
The structure is believed to be a complex range of polysaccharide 
chains having alternating a-(1!3) and b-(1!4) linkages. 
There are three extremes of structure noted: namely neutral 
agarose; pyruvated agarose having little sulfation; and a 
sulfated galactan. Agar can be separated into a natural gelling 
fraction, agarose, and a sulfated nongelling fraction, agaropectin. 
6 Functional Category 
Emulsifying agent; stabilizing agent; suppository base; suspending 
agent; sustained-release agent; tablet binder; thickening 
agent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Agar is widely used in food applications as a stabilizing agent. 
In pharmaceutical applications, agar is used in a handful of oral 
tablet and topical formulations. It has also been investigated in 
a number of experimental pharmaceutical applications including 
as a sustained-release agent in gels, beads, microspheres, 
and tablets.(14) It has also been reported to work as a 
disintegrant in tablets.(5) Agar has been used in a floating 
controlled-release tablet; the buoyancy in part being attributed 
to air entrapped in the agar gel network.(6) It can be used as a 
viscosity-increasing agent in aqueous systems. Agar can also be 
used as a base for nonmelting, and nondisintegrating suppositories.(
7) Agar has an application as a suspending agent in 
pharmaceutical suspensions.(8) 
8 Description 
Agar occurs as transparent, odorless, tasteless strips or as a 
coarse or fine powder. It may be weak yellowish-orange, 
yellowish-gray to pale-yellow colored, or colorless. Agar is 
tough when damp, brittle when dry. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for agar. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . .  
Swelling index  .  
Arsenic   43 ppm 
Lead   40.001% 
Sulfuric acid .   
Sulfurous acid and 
starch 
.   
Gelatin  . . 
Heavy metals   40.004% 
Insoluble matter 415.0mg  415.0mg 
Water absorption 475 mL  475 mL 
Loss on drying 422.0% 420.0% 420.0% 
Microbial 
contamination 
 41000/g(a) . 
Total ash 44.5% 45.0% 46.5% 
Acid-insoluble ash 40.5% 41.0% 40.5% 
Foreign organic matter   41.0% 
Limit of foreign starch   . 
Organic volatile 
impurities 
  . 
(a) Total viable aerobic count, determined by plate-count. 
10 Typical Properties 
Solubility: soluble in boiling water to form a viscous solution; 
practically insoluble in ethanol (95%), and cold water. A 
1% w/v aqueous solution forms a stiff jelly on cooling. 
11 Stability and Storage Conditions 
Agar solutions are most stable at pH 410. 
Agar should be stored in a cool, dry, place. Containers of 
this material may be hazardous when empty since they retain 
product residues (dust, solids). 
12 Incompatibilities 
Agar is incompatible with strong oxidizing agents. Agar is 
dehydrated and precipitated from solution by ethanol (95%). 
Tannic acid causes precipitation; electrolytes cause partial 
dehydration and decrease in viscosity of sols.(9)

13 Method of Manufacture 
Agar is obtained by freeze-drying a mucilage derived from 
Gelidium amansii Lamouroux, other species of the same family 
(Gelidiaceae), or other red algae (Rhodophyta). 
14 Safety 
Agar is widely used in food applications and has been used in 
oral and topical pharmaceutical applications. It is generally 
regarded as relatively nontoxic and nonirritant when used as an 
excipient. 
LD50 (hamster, oral): 6.1 g/kg(10) 
LD50 (mouse, oral): 16.0 g/kg 
LD50 (rabbit, oral): 5.8 g/kg 
LD50 (rat, oral): 11.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. When heated to 
decomposition, agar emits acrid smoke and fumes. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral tablets). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. Included in nonparenteral medicines licensed in the 
UK. 
17 Related Substances 

18 Comments 
The EINECS number for agar is 232-658-1. 
19 Specific References 
1 Bhardwaj TJ, Kanwar M, Lal R, Gupta A. Natural gums and 
modified natural gums as sustained release carriers. Drug Dev Ind 
Pharm 2000; 26(10): 10251038. 
2 Sakr FM, El-Said Y, El-Helw A. Design and evaluation of a dry 
solidification technique for preparing pharmaceutical beads. STP 
Pharma Sci 1995; 5(4): 291295. 
3 Boraie NA, Naggar VF. Sustained release of theophylline and 
aminophylline from agar tablets. Acta Pharm Jugosl 1984; 
34(OctDec): 247256. 
4 Nakano M, Nakamura Y, Takikawa K, et al. Sustained release of 
sulfamethizole from agar beads. J Pharm Pharmacol 1979; 31: 
869872. 
5 Fassihi AR. Characteristics of hydrogel as disintegrant in solid 
dose technology. J Pharm Pharmacol 1989; 54: 5962. 
6 Desai S, Boston S. A floating controlled-release drug delivery 
system: in vitroin vivo evaluation. Pharm Res 1993; 10: 1321 
1325. 
7 Singh KK, Deshpande SG, Baichwal MR. Studies on suppository 
bases: design and evaluation of sodium CMC and agar bases. 
Indian Drugs 1994; 31(April): 149154. 
8 Kahela P, Hurmerinta T, Elfving R. Effect of suspending agents on 
the bioavailability of erythromycin ethylsuccinate mixtures. Drug 
Dev Ind Pharm 1978; 4(3): 261274. 
9 Gennaro AR, ed. Remington: The Science and Practice of 
Pharmacy, 20th edn. Baltimore: Lippincott Williams & Wilkins, 
2000: 1030. 
10 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 9091. 
20 General References 

21 Authors 
VK Gupta. 
22 Date of Revision 
10 May 2005. 
Agar 15

Albumin 
1 Nonproprietary Names 
BP: Human albumin solution 
PhEur: Albumini humani solutio 
USP: Albumin human 
2 Synonyms 
Albuconn; albumin human solution; Albuminar; Albumisol; 
Albuspan; Albutein; Buminate; human serum albumin; normal 
human serum albumin; Plasbumin; plasma albumin; Pro- 
Bumin; Proserum. 
3 Chemical Name and CAS Registry Number 
Serum albumin [9048-49-1] 
4 Empirical Formula and Molecular Weight 
Human serum albumin has a molecular weight of about 66 500 
and is a single polypeptide chain consisting of 585 amino acids. 
Characteristic features are a single tryptophan residue, a 
relatively low content of methionine (6 residues), and a large 
number of cysteine (17) and of charged amino acid residues of 
aspartic acid (36), glutamic acid (61), lysine (59), and arginine 
(23). 
5 Structural Formula 
Primary structure: human albumin is a single polypeptide chain 
of 585 amino acids and contains seven disulfide bridges. 
Secondary structure: human albumin is known to have a 
secondary structure that is about 55% a-helix. The 
remaining 45% is believed to be divided among turns, 
disordered, and b structures.(1) 
Albumin is the only major plasma protein that does not 
contain carbohydrate constituents. Assays of crystalline 
albumin show less than one sugar residue per molecule. 
6 Functional Category 
Stabilizing agent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Albumin is primarily used as an excipient in parenteral 
pharmaceutical formulations, where it is used as a stabilizing 
agent for formulations containing proteins and enzymes.(2) 
Albumin has also been used to prepare microspheres and 
microcapsules for experimental drug-delivery systems.(3) 
As a stabilizing agent, albumin has been employed in protein 
formulations at concentrations as low as 0.003%, although 
concentrations of 15% are commonly used. Albumin has also 
been used as a cosolvent(4) for parenteral drugs, as a 
cryoprotectant during lyophilization, and to prevent adsorption 
of other proteins to surfaces. 
Therapeutically, albumin solutions have been used parenterally 
for plasma volume replacement and to treat severe acute 
albumin loss. However, the benefits of using albumin in such 
applications in critically ill patients has been questioned.(5) 
8 Description 
The USP 28 describes albumin human as a sterile nonpyrogenic 
preparation of serum albumin obtained from healthy human 
donors; see Section 13. It is available as a solution containing 4, 
5, 20, or 25 g of serum albumin in 100mL of solution, with not 
less than 96% of the total protein content as albumin. The 
solution contains no added antimicrobial preservative but may 
contain sodium acetyltryptophanate with or without sodium 
caprylate as a stablizing agent. 
The PhEur 2005 similarly describes albumin solution as an 
aqueous solution of protein obtained from human plasma; see 
Section 13. It is available as a concentrated solution containing 
150250 g/L of total protein or as an isotonic solution 
containing 3550 g/L of total protein. Not less than 95% of 
the total protein content is albumin. A suitable stabilizer against 
the effects of heat, such as sodium caprylate (sodium octanoate) 
or N-acetyltryptophan or a combination of these two at a 
suitable concentration, may be added, but no antimicrobial 
preservative is added. 
Aqueous albumin solutions are slightly viscous and range in 
color from almost colorless to amber depending upon the 
protein concentration. In the solid state, albumin appears as 
brownish amorphous lumps, scales, or powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for albumin. 
Test PhEur 2005 USP 28 
Identification .  
Characters .  
pH (10 g/L solution) 6.77.3 . 
Polymers and aggregates .  
Potassium 40.05 mmol/g  
Sodium 4160 mmol/L 130160 mEq/L 
Heme . . 
Aluminum 4200 mg/L  
Sterility . . 
Hepatitis B surface antigen  . 
Pyrogens . . 
Total protein 95105% 596% 
for 4 g in 100 mL  93.75106.25% 
for 5 to 25 g in 100 mL  94.0106.0% 
Protein composition .  
Prekallikrein activator 435 IU/mL  
10 Typical Properties 
Acidity/alkalinity: pH = 6.77.3 for a 1% w/v solution, in 
0.9% w/v sodium chloride solution, at 208C.

Osmolarity: a 45% w/v aqueous solution is isoosmotic with 
serum. 
Solubility: freely soluble in dilute salt solutions and water. 
Aqueous solutions containing 40% w/v albumin can be 
readily prepared at pH 7.4. The high net charge of the 
peptide contributes to its solubility in aqueous media. The 
seven disulfide bridges contribute to its chemical and spatial 
conformation. At physiological pH, albumin has a net 
electrostatic charge of about 17. Aqueous albumin solutions 
are slightly viscous and range in color from almost 
colorless to amber depending on the protein concentration. 
11 Stability and Storage Conditions 
Albumin is a protein and is therefore susceptible to chemical 
degradation and denaturation by exposure to extremes of pH, 
high salt concentrations, heat, enzymes, organic solvents, and 
other chemical agents. 
Albumin solutions should be protected from light and stored 
at a temperature of 2258C or as indicated on the label. 
12 Incompatibilities 
See Section 11. 
13 Method of Manufacture 
Albumin human (USP 28) Albumin human is a sterile nonpyrogenic 
preparation of serum albumin that is obtained by 
fractionating material (source blood, plasma, serum, or placentas) 
from healthy human donors. The source material is 
tested for the absence of hepatitis B surface antigen. It is 
made by a process that yields a product safe for intravenous 
use. 
Albumin solution, human (PhEur 2005) Human albumin solution 
is an aqueous solution of protein obtained from plasma. 
Separation of the albumin is carried out under controlled conditions 
so that the final product contains not less than 95% 
albumin. Human albumin solution is prepared as a concentrated 
solution containing 150250 g/L of total protein or as 
an isotonic solution containing 3550 g/L of total protein. A 
suitable stabilizer against the effects of heat such as sodium 
caprylate (sodium octanoate) or N-acetyltryptophan or a 
combination of these two at a suitable concentration, may be 
added, but no antimicrobial preservative is added at any stage 
during preparation. The solution is passed through a bacteria-
retentive filter and distributed aseptically into sterile 
containers, which are then closed so as to prevent contamination. 
The solution in its final container is heated to 60  1.08C and maintained at this temperature for not less than 10 
hours. The containers are then incubated at 30328C for not 
less than 14 days or at 20258C for not less than 4 weeks 
and examined visually for evidence of microbial contamination. 
14 Safety 
Albumin occurs naturally in the body, comprising about 60% 
of all the plasma proteins. As an excipient, albumin is used 
primarily in parenteral formulations and is generally regarded 
as an essentially nontoxic and nonirritant material. Adverse 
reactions to albumin infusion rarely occur but include nausea, 
vomiting, increased salivation, chills, and febrile reactions. 
Urticaria and skin rash have been reported. Allergic reactions, 
including anaphylactic shock, can occur. Albumin infusions are 
contraindicated in patients with severe anemia or cardiac 
failure. Albumin solutions with aluminum content of less than 
200 mg/L should be used in dialysis patients and premature 
infants.(6) 
LD50 (monkey, IV): >12.5 g/kg(7) 
LD50 (rat, IV): >12.5 g/kg 
15 Handling Precautions 
Observe handling precautions appropriate for a biologically 
derived blood product. 
16 Regulatory Acceptance 
Included in the FDA Inactive Ingredients Guide (oral, tablets, 
film-coatings; IV injections). Included in parenteral products 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Albumins derived from animal sources are also commercially 
available, e.g., bovine serum albumin. 
18 Comments 
A 100mL aqueous solution of albumin containing 25 g of 
serum albumin is osmotically equivalent to 500mL of normal 
human plasma. The EINECS number for albumin is 310-127-6. 
19 Specific References 
1 Bramanti E, Benedetti E. Determination of the secondary structure 
of isomeric forms of human serum albumin by a particular 
frequency deconvolution procedure applied to Fourier transform 
IR analysis. Biopolymers 1996; 38(5): 639653. 
2 Wang JUC, Hanson MA. Parenteral formulations of proteins and 
peptides: stability and stabilizers. J Parenter Sci Technol 1988; 
42(S): S1S26. 
3 Arshady R. Albumin microspheres and microcapsules: methodology 
of manufacturing techniques. J Control Release 1990; 14: 
111131. 
4 Olson WP, Faith MR. Human serum albumin as a cosolvent for 
parenteral drugs. J Parenter Sci Technol 1988; 42: 8285. 
5 Cochrane Injuries Group Albumin Reviewers. Human albumin 
administration in critically ill patients: systematic review of 
randomised controlled trials. Br Med J 1998; 317: 235240. 
6 Quagliaro DA, Geraci VA, Dwan RE, et al. Aluminum in albumin 
for injection. J Parenter Sci Technol 1988; 42: 187190. 
7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1970. 
20 General References 
Kragh-Hansen U. Structure and ligand properties of human serum 
albumin. Danish Med Bull 1990; 37(1): 5784. 
Putnam FW, ed. The Plasma Proteins, Structure, Function and Genetic 
Control. London: Academic Press, 1975. 
21 Authors 
RT Guest. 
22 Date of Revision 
23 August 2005. 
Albumin 17

Alcohol 
1 Nonproprietary Names 
BP: Ethanol (96%) 
JP: Ethanol 
PhEur: Ethanolum (96 per centum) 
USP: Alcohol 
2 Synonyms 
Ethyl alcohol; ethyl hydroxide; grain alcohol; methyl carbinol. 
3 Chemical Name and CAS Registry Number 
Ethanol [64-17-5] 
4 Empirical Formula and Molecular Weight 
C2H6O 46.07 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; disinfectant; skin penetrant; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethanol and aqueous ethanol solutions of various concentrations 
(see Sections 8 and 17) are widely used in pharmaceutical 
formulations and cosmetics; see Table I. Although ethanol is 
primarily used as a solvent, it is also employed in solutions as an 
antimicrobial preservative.(1,2) Topical ethanol solutions are 
also used as penetration enhancers(36) and as disinfectants. 
Ethanol has also been used in transdermal preparations in 
combination with Labrasol as a co-surfactant.(7) 
Table I: Uses of alcohol. 
Use Concentration (% v/v) 
Antimicrobial preservative 510 
Disinfectant 6090 
Extracting solvent in galenical manufacture Up to 85 
Solvent in film coating Variable 
Solvent in injectable solutions Variable 
Solvent in oral liquids Variable 
Solvent in topical products 6090 
8 Description 
In the BP 2004, the term ethanol used without other 
qualification refers to ethanol containing 599.5% v/v of 
C2H6O. The term alcohol, without other qualification, refers 
to ethanol 95.196.9% v/v. Where other strengths are intended, 
the term alcohol or ethanol is used, followed by the 
statement of the strength. 
In the PhEur 2005, anhydrous ethanol contains not less than 
99.5% v/v of C2H6O at 208C. The term ethanol (96%) is used 
to describe the material containing water and 95.196.9% v/v 
of C2H6O at 208C. 
In the USP 28, the term dehydrated alcohol refers to 
ethanol 599.5% v/v. The term alcohol without other 
qualification refers to ethanol 94.996.0% v/v. 
In the JP 2001, ethanol (alcohol) contains 95.195.6% v/v 
(by specific gravity) of C2H6O at 158C. 
In the Handbook of Pharmaceutical Excipients, the term 
alcohol is used for either ethanol 95% v/v or ethanol 96% v/v. 
Alcohol is a clear, colorless, mobile, and volatile liquid with 
a slight, characteristic odor and burning taste. 
See also Section 17. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Antimicrobial activity: ethanol is bactericidal in aqueous 
mixtures at concentrations between 60% and 95% v/v; 
the optimum concentration is generally considered to be 
70% v/v. Antimicrobial activity is enhanced in the presence 
of edetic acid or edetate salts.(1) Ethanol is inactivated in the 
presence of nonionic surfactants and is ineffective against 
bacterial spores. 
Boiling point: 78.158C 
Flammability: readily flammable, burning with a blue, smokeless 
flame. 
Flash point: 148C (closed cup) 
Solubility: miscible with chloroform, ether, glycerin, and water 
(with rise of temperature and contraction of volume). 
Specific gravity: 0.81190.8139 at 208C 
Note: the above typical properties are for alcohol (ethanol 95% 
or 96% v/v). See Section 17 for typical properties of 
dehydrated alcohol. 
11 Stability and Storage Conditions 
Aqueous ethanol solutions may be sterilized by autoclaving or 
by filtration and should be stored in airtight containers, in a 
cool place. 
12 Incompatibilities 
In acidic conditions, ethanol solutions may react vigorously 
with oxidizing materials. Mixtures with alkali may darken in 
color owing to a reaction with residual amounts of aldehyde. 
Organic salts or acacia may be precipitated from aqueous 
solutions or dispersions. Ethanol solutions are also incompatible 
with aluminum containers and may interact with some 
drugs.

13 Method of Manufacture 
Ethanol is manufactured by the controlled enzymatic fermentation 
of starch, sugar, or other carbohydrates. A fermented 
liquid is produced containing about 15% ethanol; ethanol 95% 
v/v is then obtained by fractional distillation. Ethanol may also 
be prepared by a number of synthetic methods. 
14 Safety 
Ethanol and aqueous ethanol solutions are widely used in a 
variety of pharmaceutical formulations and cosmetics. It is also 
consumed in alcoholic beverages. 
Ethanol is rapidly absorbed from the gastrointestinal tract 
and the vapor may be absorbed through the lungs; it is 
metabolized, mainly in the liver, to acetaldehyde, which is 
further oxidized to acetate. 
Ethanol is a central nervous system depressant and ingestion 
of low to moderate quantities can lead to symptoms of 
intoxication including muscle incoordination, visual impairment, 
slurred speech, etc. Ingestion of higher concentrations 
may cause depression of medullary action, lethargy, amnesia, 
hypothermia, hypoglycemia, stupor, coma, respiratory depression, 
and cardiovascular collapse. The lethal human bloodalcohol 
concentration is generally estimated to be 400500 mg/ 
100 mL. 
Although symptoms of ethanol intoxication are usually 
encountered following deliberate consumption of ethanolcontaining 
beverages, many pharmaceutical products contain 
ethanol as a solvent, which, if ingested in sufficiently large 
quantities, may cause adverse symptoms of intoxication. In the 
USA, the maximum quantity of alcohol included in OTC 
medicines is 10% v/v for products labeled for use by people of 
12 years of age and older, 5%v/v for products intended for use 
by children aged 612 years of age, and 0.5% v/v for products 
for use by children under 6 years of age.(8) 
Parenteral products containing up to 50% of alcohol 
(ethanol 95 or 96% v/v) have been formulated. However, 
such concentrations can produce pain on intramuscular 
injection and lower concentrations such as 510% v/v are 
preferred. Subcutaneous injection of alcohol (ethanol 95% v/v) 
similarly causes considerable pain followed by anesthesia. If 
injections are made close to nerves, neuritis and nerve 
degeneration may occur. This effect is used therapeutically to 
cause anesthesia in cases of severe pain, although the practice of 
using alcohol in nerve blocks is controversial. Doses of 1mL of 
absolute alcohol have been used for this purpose.(9) 
Preparations containing more than 50% v/v alcohol may 
cause skin irritation when applied topically. 
LD50 (mouse, IP): 0.93 g/kg(10) 
LD50 (mouse, IV): 1.97 g/kg 
LD50 (mouse, oral): 3.45 g/kg 
LD50 (mouse, SC): 8.29 g/kg 
LD50 (rat, IP): 3.75 g/kg 
LD50 (rat, IV): 1.44 g/kg 
LD50 (rat, oral): 7.06 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Ethanol and aqueous ethanol 
solutions should be handled in a well-ventilated environment. 
In the UK, the long-term 8-hour TWA exposure limit for 
ethanol is 1920 mg/m3 (1000 ppm).(11) Ethanol may be irritant 
to the eyes and mucous membranes and eye protection and 
gloves are recommended. Ethanol is flammable and should be 
heated with care. Fixed storage tanks should be electrically 
grounded to avoid ignition from electrostatic discharges when 
ethanol is transferred. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (dental 
preparations; inhalations; IM, IV, and SC injections; nasal 
and ophthalmic preparations; oral capsules, solutions, suspensions, 
syrups, and tablets; rectal, topical, and transdermal 
preparations). Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. Included in nonparenteral and 
parenteral medicines licensed in the UK. 
17 Related Substances 
Dehydrated alcohol; denatured alcohol; dilute alcohol; isopropyl 
alcohol. 
Dehydrated alcohol 
Synonyms: absolute alcohol; anhydrous ethanol; ethanol. 
Autoignition temperature: 3658C 
Boiling point: 78.58C 
Explosive limits: 3.519.0% v/v in air 
Flash point: 128C (closed cup) 
Melting point: 1128C 
Moisture content: absorbs water rapidly from the air. 
Table II: Pharmacopeial specifications for alcohol. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . .  
Specific gravity 0.8140.816 0.8050.812 0.8120.816 
Acidity or alkalinity . . . 
Clarity of solution . .  
Nonvolatile residue 41 mg/40 mL 425 ppm 41 mg/40 mL 
Water-insoluble 
substances 
  . 
Volatile impurities . .  
Aldehydes . 410 ppm v/v . 
Amyl alcohol, etc.   . 
Absorbance  .  
at 240 nm  40.40  
at 250260 nm  40.30  
at 270340 nm  40.10  
Fusel oil constituents .   
Acetone and 
propan-2-ol 
  . 
Methanol  4200 ppm . 
Benzene  42 ppm  
Acetaldehyde and 
acetal 
 410 ppm  
Reducing 
substances 
.   
Organic volatile 
impurities 
  . 
Chloride .   
Heavy metals 41.2 ppm   
Assay 95.195.6% 95.196.9% 92.393.8% 
by weight 
94.996.0% 
by volume 
Alcohol 19

Refractive index: nD
20 = 1.361 
Specific gravity: 0.79040.7935 at 208C 
Surface tension: 22.75 mN/m at 208C (ethanol/vapor) 
Vapor density (relative): 1.59 (air = 1) 
Vapor pressure: 5.8 Pa at 208C 
Viscosity (dynamic): 1.22 mPa s (1.22 cP) at 208C 
Comments: dehydrated alcohol is ethanol 599.5% v/v. See 
Section 8. 
Denatured alcohol 
Synonyms: industrial methylated spirit; surgical spirit. 
Comments: denatured alcohol is alcohol intended for external 
use only. It has been rendered unfit for human consumption 
by the addition of a denaturing agent such as methanol or 
methyl isobutyl ketone. 
Dilute alcohol 
Synonyms: dilute ethanol. 
Specific gravity: see Table III. 
Table III: Specific gravity of alcohol. 
Strength of alcohol (% v/v) Specific gravity at 208C 
90 0.82890.8319 
80 0.85990.8621 
70 0.88600.8883 
60 0.91030.9114 
50 0.93140.9326 
45 0.94070.9417 
25 0.96940.9703 
20 0.97480.9759 
Comments: the term dilute alcohol refers to a mixture of 
ethanol and water of stated concentration. The BP 2004 lists 
eight strengths of dilute alcohol (dilute ethanol) containing 
90%, 80%, 70%, 60%, 50%, 45%, 25%, and 20% v/v 
respectively of ethanol. 
18 Comments 
Possession and use of nondenatured alcohols are usually 
subject to close control by excise authorities. 
A specification for alcohol is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for alcohol is 200-578-6. 
19 Specific References 
1 Chiori CO, Ghobashy AA. A potentiating effect of EDTA on the 
bactericidal activity of lower concentrations of ethanol. Int J 
Pharm 1983; 17: 121128. 
2 Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation 
of preservative efficacy. IV. The determination of antimicrobial 
characteristics of some pharmaceutical compounds in aqueous 
solutions. Int J Pharm 1989; 54: 5156. 
3 Liu P, Higuchi WI, Song W, et al. Quantitative evaluation of 
ethanol effects on diffusion and metabolism of b-estradiol in 
hairless mouse skin. Pharm Res 1991; 8(7): 865872. 
4 Verma DD, Fahr A. Synergistic penetration enhancement of 
ethanol and phospholipids on the topical delivery of cyclosporin 
A. J Controlled Release 2004; 97(1): 5566. 
5 Gwak SS, Oh IS, Chun IK. Transdermal delivery of ondansetron 
hydrochloride: effects of vehicles and penetration enhancers. Drug 
Dev Ind Pharm 2004; 30(2): 187194. 
6 Williams AC, Barry BW. Penetration enhancers. Adv Drug 
Delivery Rev 2004; 56(5): 603618. 
7 Kwean JH, Chi SC, Park ES. Transdermal delivery of diclofenac 
using microemulsions. Arch Pharmacol Res 2004; 27(3): 351356. 
8 Jass HE. Regulatory review. Cosmet Toilet 1995; 110(5): 2122. 
9 Lloyd JW. Use of anaesthesia: the anaesthetist and the pain clinic. 
Br Med J 1980; 281: 432434. 
10 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 16271628. 
11 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Lund W, ed. The Pharmaceutical Codex: Principles and Practice of 
Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 
694695. 
Spiegel AJ, Noseworthy MN. Use of nonaqueous solvents in parenteral 
products. J Pharm Sci 1963; 52: 917927. 
Wade A, ed. Pharmaceutical Handbook, 19th edn. London: Pharmaceutical 
Press, 1980: 227230. 
21 Authors 
SC Owen. 
22 Date of Revision 
10 February 2005. 
20 Alcohol

Alginic Acid 
1 Nonproprietary Names 
BP: Alginic acid 
PhEur: Acidum alginicum 
USPNF: Alginic acid 
2 Synonyms 
E400; Kelacid; L-gulo-D-mannoglycuronan; polymannuronic 
acid; Protacid; Satialgine H8. 
3 Chemical Name and CAS Registry Number 
Alginic acid [9005-32-7] 
4 Empirical Formula and Molecular Weight 
Alginic acid is a linear glycuronan polymer consisting of a 
mixture of b-(1!4)-D-mannosyluronic acid and a-(1!4)-Lgulosyluronic 
acid residues, of general formula (C6H8O)n. The 
molecular weight is typically 20 000240 000. 
5 Structural Formula 
The PhEur 2005 describes alginic acid as a mixture of 
polyuronic acids [(C6H8O6)n] composed of residues of 
D-mannuronic and L-glucuronic acid, and is obtained mainly 
from algae belonging to the Phaeophyceae. A small proportion 
of the carboxyl groups may be neutralized. 
See also Section 4. 
6 Functional Category 
Stabilizing agent; suspending agent; sustained release adjuvant; 
tablet binder; tablet disintegrant; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Alginic acid is used in a variety of oral and topical 
pharmaceutical formulations. In tablet and capsule formulations, 
alginic acid is used as both a binder and disintegrating 
agent at concentrations of 15% w/w.(1,2) Alginic acid is widely 
used as a thickening and suspending agent in a variety of pastes, 
creams, and gels; and as a stabilizing agent for oil-in-water 
emulsions. Alginic acid has also been investigated for use in an 
ocular formulation of carteolol.(3) 
Therapeutically, alginic acid has been used as an antacid.(4) 
In combination with an H2-receptor antagonist, it has also been 
utilized for the management of gastroesophageal reflux.(5) 
Chemically modified alginic acid derivatives have been 
researched for their anti-inflammatory, antiviral, and antitumoral 
activities.(6) 
In the area of controlled release, the preparation of 
indomethacin sustained-release microparticles from alginic 
acid (alginate)gelatin hydrocolloid coacervate systems has 
been investigated.(7) In addition, as controlled-release systems 
for liposome-associated macromolecules, microspheres have 
been produced encapsulating liposomes coated with alginic 
acid and poly-L-lysine membranes.(8) Alginate gel beads 
capable of floating in the gastric cavity have been prepared, 
the release properties of which were reported to be applicable 
for sustained release of drugs, and for tareting the gastric 
mucosa.(9) Alginic acid has also been used to improve the 
stability of levosimendan.(10) Mechanical properties, water 
uptake, and permeability properties of a sodium salt of alginic 
acid have been characterized for controlled-release applications.(
11) In addition, sodium alginate has been incorporated 
into an ophthalmic drug delivery system for pilocarpine 
nitrate.(12) It has also been reported that associated chains of 
alginic acid complexed with cations can bind to cell surfaces 
and exert pharmacological effects which depend on the cell type 
and the complexed cation. These complexes can be used to treat 
rheumatic disorders, diseases associated with atopic diathesis 
and liver diseases.(13) Furthermore, an alginic oligosaccharide, 
obtained from a natural edible polysaccharide, has been shown 
to suppress Th2 responses and IgE production by inducing 
IL-12 production, was found to be a useful approach for 
preventing allergic disorders.(14) 
SEM: 1 
Excipient: Alginic acid 
Magnification: 100 Voltage: 25 kV 
8 Description 
Alginic acid is a tasteless, practically odorless, white to 
yellowish-white, fibrous powder. 
9 Pharmacopeial Specifications 
See Table I.

SEM: 2 
Excipient: Alginic acid 
Magnification: 500 Voltage: 25 kV 
Table I: Pharmacopeial specifications for alginic acid 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Microbial limits 4102/g 4200/g 
pH (3% dispersion)  1.53.5 
Loss on drying 415.0% 415.0% 
Ash  44.0% 
Sulfated ash 48.0%  
Arsenic  43 ppm 
Chloride 41.0%  
Lead  40.001% 
Heavy metals 420 ppm 40.004% 
Acid value (dried basis)  5230 
Assay (of COOH groups) 19.025.0%  
10 Typical Properties 
Acidity/alkalinity: pH = 1.53.5 for a 3% w/v aqueous 
dispersion. 
Crosslinking: addition of a calcium salt, such as calcium citrate 
or calcium chloride, causes crosslinking of the alginic acid 
polymer resulting in an apparent increase in molecular 
weight. Films crosslinked with triphosphate (tripolyphosphate) 
and calcium chloride were found to be insoluble but 
permeable to water vapor. Drug permeability varies with pH 
and the extent of crosslinking.(11) 
Density (true): 1.601 g/cm3 
Moisture content: 7.01% 
Solubility: soluble in alkali hydroxides, producing viscous 
solutions; very slightly soluble or practically insoluble in 
ethanol (95%) and other organic solvents. Alginic acid 
swells in water but does not dissolve; it is capable of 
absorbing 200300 times its own weight of water. 
Viscosity (dynamic): various grades of alginic acid are 
commercially available that vary in their molecular weight 
and hence viscosity. Viscosity increases considerably with 
increasing concentration; typically a 0.5% w/w aqueous 
dispersion will have a viscosity of approximately 20 mPa s, 
while a 2.0% w/w aqueous dispersion will have a viscosity 
of approximately 2000 mPa s. The viscosity of dispersions 
decreases with increasing temperature. As a general rule, a 
18C increase in temperature results in a 2.5% reduction in 
viscosity. At low concentrations, the viscosity of an alginic 
acid dispersion may be increased by the addition of a 
calcium salt, such as calcium citrate. See also Sections 11 
and 18. 
11 Stability and Storage Conditions 
Alginic acid hydrolyzes slowly at warm temperatures producing 
a material with a lower molecular weight and lower 
dispersion viscosity. 
Alginic acid dispersions are susceptible to microbial spoilage 
on storage, which may result in some depolymerization and 
hence a decrease in viscosity. Dispersions should therefore be 
preserved with an antimicrobial preservative such as benzoic 
acid; potassium sorbate; sodium benzoate; sorbic acid; or 
paraben. Concentrations of 0.10.2% are usually used. 
Alginic acid dispersions may be sterilized by autoclaving or 
filtration through a 0.22 mm filter. Autoclaving may result in a 
decrease in viscosity which can vary depending upon the nature 
of any other substances present.(15) 
Alginic acid should be stored in a well-closed container in a 
cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents, alginic acid forms 
insoluble salts in the presence of alkaline earth metals and 
group III metals with the exception of magnesium. 
13 Method of Manufacture 
Alginic acid is a hydrophilic colloid carbohydrate that occurs 
naturally in the cell walls and intercellular spaces of various 
species of brown seaweed (Phaeophyceae). The seaweed occurs 
widely throughout the world and is harvested, crushed, and 
treated with dilute alkali to extract the alginic acid. 
14 Safety 
Alginic acid is widely used in food products and topical and 
oral pharmaceutical formulations. It is generally regarded as a 
nontoxic and nonirritant material, although excessive oral 
consumption may be harmful. Inhalation of alginate dust may 
be irritant and has been associated with industrially related 
asthma in workers involved in alginate production. However, it 
appears that the cases of asthma were linked to exposure to 
unprocessed seaweed dust rather than pure alginate dust.(16) An 
acceptable daily intake of alginic acid and its ammonium, 
calcium, potassium, and sodium salts was not set by the WHO 
because the quantities used, and the background levels in food, 
did not represent a hazard to health.(17) 
LD50 (rat, IP): 1.6 g/kg(18) 
22 Alginic Acid

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Alginic acid may be irritant 
to the eyes or respiratory system if inhaled as dust; see Section 
14. Eye protection, gloves, and a dust respirator are recommended. 
Alginic acid should be handled in a well-ventilated 
environment. 
16 Regulatory Status 
GRAS listed. Accepted in Europe for use as a food additive. 
Included in the FDA Inactive Ingredients Guide (ophthalmic 
preparations, oral capsules, and tablets). Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 
Ammonium alginate; calcium alginate; potassium alginate; 
propylene glycol alginate; sodium alginate. 
18 Comments 
Alginic acid dispersions are best prepared by pouring the alginic 
acid slowly and steadily into vigorously stirred water. Dispersions 
should be stirred for approximately 30 minutes. Premixing 
the alginic acid with another powder, such as sugar, or a 
water-miscible liquid such as ethanol (95%) or glycerin, aids 
dispersion. 
When using alginic acid in tablet formulations, the alginic 
acid is best incorporated or blended using a dry granulation 
process. 
A specification for alginic acid is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for alginic acid is 232-680-1. 
19 Specific References 
1 Shotton E, Leonard GS. Effect of intragranular and extragranular 
disintegrating agents on particle size of disintegrated tablets. J 
Pharm Sci 1976; 65: 11701174. 
2 Esezobo S. Disintegrants: effects of interacting variables on the 
tensile strengths and disintegration times of sulfaguanidine tablets. 
Int J Pharm 1989; 56: 207211. 
3 Tissie G, Sebastian C, Elena PP, Driot JY, Trinquand C. Alginic 
acid effect on carteolol ocular pharmacokinetics in the pigmented 
rabbit. J Ocul Pharmacol Ther 2002; 18(1): 6573. 
4 Vatier J, Vallot T, Farinotti R. Antacid drugs: multiple but too often 
unknown pharmacological properties. J Pharm Clin 1996; 15(1): 
4151. 
5 Stanciu C, Bennett JR. Alginate/antacid in the reduction of gastrooesophageal 
reflux. Lancet 1974; i: 109111. 
6 Boisson-Vidal C, Haroun F, Ellouali M, et al. Biological activities 
of polysaccharides from marine algae. Drugs Future 1995; 
20(Dec): 12471249. 
7 Joseph I, Venkataram S. Indomethacin sustained release from 
alginate-gelatin or pectin-gelatin coacervates. Int J Pharm 1995; 
125: 161168. 
8 Machluf M, Regev O, Peled Y, et al. Characterization of 
microencapsulated liposome systems for the controlled delivery 
of liposome-associated macromolecules. J Control Release 1997; 
43: 3545. 
9 Murata Y, Sasaki N, Miyamoto E, Kawashima S. Use of floating 
alginate gel beads for stomach-specific drug delivery. Eur J Pharm 
Biopharm 2000; 50(2): 221226. 
10 Larma I, Harjula M. Stable compositions comprising levosimendan 
and alginic acid. Patent No: WO9955337; 1999. 
11 Remunan-Lopez C, Bodmeier R. Mechanical, water uptake and 
permeability properties of crosslinked chitosan glutamate and 
alginate films. J Control Release 1997; 44: 215225. 
12 Cohen S, Lobel E, Treygoda A, Peled Y. Novel in situ-forming 
opthalmic drug delivery system from alginates undergoing gelation 
in the eye. J Control Release 1997; 44: 201208. 
13 Gradl T. Use of alginic acid and/or its derivatives and salts for 
combating or preventing diseases. Patent No: DE19723155; 1998. 
14 Tadashi Y, Aki H, Hanae W, Koji T, Makoto H. Alginic acid 
oligosaccharide suppresses Th2 development and IgE production 
by inducing IL-12 production. Int Arch Allergy Imm 2004; 133(3): 
239247. 
15 Vandenbossche GMR, Remon J-P. Influence of the sterilization 
process on alginate dispersions. J Pharm Pharmacol 1993; 45: 
484486. 
16 Henderson AK, Ranger AF, Lloyd J, et al. Pulmonary hypersensitivity 
in the alginate industry. Scott Med J 1984; 29(2): 9095. 
17 FAO/WHO. Evaluation of certain food additives and naturally 
occurring toxicants. Thirty-ninth report of the joint FAO/WHO 
expert committee on food additives. World Health Organ Tech 
Rep Ser 1993; No. 837. 
18 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 101102. 
20 General References 
Marshall PV, Pope DG, Carstensen JT. Methods for the assessment of 
the stability of tablet disintegrants. J Pharm Sci 1991; 80: 899903. 
21 Authors 
JW McGinity, MA Repka. 
22 Date of Revision 
23 August 2005. 
Alginic Acid 23

Aliphatic Polyesters 
1 Nonproprietary Names 
See Table I. 
2 Synonyms 
See Table I. 
3 Chemical Name and CAS Registry Number 
See Table I. 
4 Empirical Formula and Molecular Weight 
Aliphatic polyesters are synthetic homopolymers or copolymers 
of lactic acid, glycolic acid, and e-hydroxycaproic acid. 
Typically, the molecular weights of homopolymers and 
copolymers range from 2000 to >100 000. 
5 Structural Formula 
6 Functional Category 
Bioabsorbable; biocompatible; biodegradable material. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aliphatic polyesters are a group of synthesized, nontoxic, 
biodegradable polymers. In an aqueous environment, they 
undergo hydrolytic degradation, through cleavage of the ester 
linkages, into nontoxic hydroxycarboxylic acids. Aliphatic 
polyesters are eventually metabolized to carbon dioxide and 
water, via the citric acid cycle. Owing to their reputation as safe 
materials and their biodegradability, aliphatic polyesters are 
primarily used as biocompatible and biodegradable polymers 
for formulation of many types of implantable and injectable 
drug-delivery systems for both human and veterinary use. 
Examples of implantable drug delivery systems include rods, 
cylinders, tubing, films,(1) fibers,(2) pellets, and beads.(3) 
Examples of injectable drug-delivery systems include microcapsules,(
4) microspheres,(5) nanoparticles, and liquid injectable 
controlled-release systems. The rate of biodegradation and 
drug-release characteristics from these systems formulated with 
the aliphatic polyesters can be controlled by changing the 
physicochemical properties of the polymers, such as crystallinity, 
hydrophobicity, monomer stereochemistry, copolymer 
ratio, and polymer molecular weight. 
8 Description 
Aliphatic polyesters are a group of synthesized homopolymers 
or copolymers. They are nontoxic and can easily be fabricated 
into a variety of novel devices, such as rods, screws, nails, and 
cylinders. The polymers are commercially available in varying 
molecular weights as both homopolymers and copolymers. 
Molecular weights of polyesters range from 2000 to greater 
than 100 000. 
Co-monomer ratios of lactic acid and glycolic acid for 
poly(DL-lactide-co-glycolide) range from 85 : 15 to 50 : 50. 
Table I shows the chemical and trade names of different 
commercially available aliphatic polyesters. 
9 Pharmacopeial Specifications 

10 Typical Properties 
For typical physical and mechanical properties of the aliphatic 
polyesters, see Table II. 
Polymer composition and crystallinity play important roles 
in the solubility of these aliphatic polyesters. The crystalline 
homopolymers of glycolic acid are soluble only in strong 
solvents, such as hexafluoroisopropanol. The crystalline 
homopolymers of lactic acid also do not have good solubility 
in most organic solvents. However, amorphous polymers of DLlactic 
acid and copolymers of lactic acid and glycolic acid with a 
low glycolic acid content are soluble in many organic solvents 
(Table II). Aliphatic polyesters are slightly soluble or insoluble 
in water, methanol, ethylene glycol, heptane, and hexane.

Table I: Chemical names and CAS registry numbers of the aliphatic polyesters. 
Generic name Composition (%) Synonyms Trade name Manufacturer CAS name CAS number 
Lactide Glycolide Caprolactone 
Poly(D-lactide) 100 0 0 D-PLA Purasorb PD PURAC (3R-cis)-3,6-Dimethyl-1,4-dioxane-2,5-dione 
homopolymer 
[25038-75-9] 
Poly(L-lactide) 100 0 0 L-PLA Lactel L-PLA BPI Propanoic acid, 2-hydroxy-, homopolymer [26161-42-2] 
Medisorb 100 L Alkermes 
Purasorb PL PURAC 
Resomer L 206, 207, 209, 210, 
214 
BI 
Poly(DL-lactide) 100 0 0 DL-PLA Lactel DL-PLA BPI Propanoic acid, 2-hydroxy-, homopolymer [34346-01-5] 
Medisorb 100 DL Alkermes 
Pursasorb PDL PURAC 
Resomer R 202, 202H, 203, 206, 
207, 208 
BI 
Poly(glycolide) 0 100 0 PGA Lactel PGA BPI Acetic acid, hydroxy-, homopolymer [34346-01-5] 
Medisorb 100 PGA Alkermes 
Purasorb PG PURAC 
Resomer G 205 BI 
Poly(L-lactide-co-glycolide) 75 25 0 L-PLGA (75 : 25) Pursasorb PLG PURAC 1,4-Dioxane-2,5-dione, polymer with (3S-cis)- 
3,6-dimethyl-1,4-dioxane-2,5-dione 
[30846-39-0] 
Poly(L-lactide-co-glycolide) 50 50 0 L-PLGA (50 : 50) Purasorb PLG PURAC 1,4-Dioxane-2,5-dione,polymer with (3S-cis)- 
3,6-dimethyl-1,4-dioxane-2,5-dione 
[30846-39-0] 
Poly(DL-lactide-coglycolide) 
85 15 0 Polyglactin;DL-PLGA 
(85:15) 
Lactel 8515 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with 
hydroxyacetic acid 
[26780-50-7] 
Medisorb 8515 DL Alkermes 
Resomer RG 858 BI 
Poly(DL-lactide-coglycolide) 
75 25 0 Polyglactin;DL-PLGA 
(75 : 25) 
Lactel 7525 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with 
hydroxyacetic acid 
[26780-50-7] 
Pursasorb PDLG PURAC 
Resomer RG 752, 755, 756 BI 
Poly(DL-lactide-coglycolide) 
65 35 0 Polyglactin;DL-PLGA 
(65 : 35) 
Lactel 6535 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with 
hydroxyacetic acid 
[26780-50-7] 
Poly(DL-lactide-coglycolide) 
50 50 0 Polyglactin;DL-PLGA 
(50 : 50) 
Lactel 5050 DL-PLGA BPI Propanoic acid, 2-hydroxypolymer with 
hydroxyacetic acid 
[26780-50-7] 
Medisorb 5050 DL Alkermes 
Purasorb PDLG PURAC 
Resomer RG 502, 502H, 503, 
503H, 504, 504H, 505, 506 
BI 
Poly-e-caprolactone 0 0 100 PCL Lactel PCL BPI 2-Oxepanone, homopolymer [24980-41-4] 
Poly(DL-lactide-cocaprolactone) 
75 0 25 DL-PLCL (75 : 25) Lactel 7525 DL-PLCL BPI 1,4-Dioxane-2,5-dione,3,6-dimethyl-, 
polymer with 2-oxepanone 
[70524-20-8] 
Poly(DL-lactide-cocaprolactone) 
25 0 75 DL-PLCL (25 : 75) Lactel 2575 DL-PLCL BPI 1,4-Dioxane-2,5-dione,3,6-dimethyl-, 
polymer with 2-oxepanone 
[70524-20-8] 
Alkermes, Alkermes Inc.; BI, Boehringer Ingelheim; BPI, Birmingham Polymers Inc.; PURAC, PURAC America. 
Aliphatic Polyesters 25

Table II: Typical physical and mechanical properties of the aliphatic polyesters.(a) 
50/50 DL-PLG 65/35 DL-PLG 75/25 DL-PLG 85/15 DL-PLG DL-PLA L-PLA PGA PCL 
Molecular weight 40 000100 000 40 000100 000 40 000100 000 40 000100 000 40 000100 000 >100 000 >100 000 80150 000 
Inherent viscosity (mPa s) 0.50.8(b) 0.50.8(b) 0.50.8(c) 0.50.8(c) 0.50.8(c) 0.91.2(c) 1.11.4(b) 0.71.3(c) 
Melting point (8C) Amorphous Amorphous Amorphous Amorphous Amorphous 173178 225230 5863 
Glass transition (8C) 4550 4550 5055 5055 5560 6065 3540 65 to 60 
Color White to light gold White to light gold White to light gold White to light gold White White Light tan White 
Solubility(d) MeCl2, THF, EtOAc, 
C3H6O, CHCl3 
MeCl2, THF, EtOAc, 
C3H6O, CHCl3 
MeCl2, THF, EtOAc, 
C3H6O, CHCl3 
MeCl2, THF, EtOAc, 
C3H6O, CHCl3, 
MeCl2, THF, EtOAc, 
C3H6O, CHCl3 
MeCl2, CHCl3 HFIP, HFASH MeCl2, CHCl3, 
C3H6O 
Specific gravity 1.34 1.30 1.30 1.27 1.25 1.24 1.53 1.11 
Tensile strength (psi) 60008000 60008000 60008000 60008000 40006000 800012 000 10 000. 30005000 
Elongation (%) 310 310 310 310 310 510 1520 300500 
Modulus (psi) 24  105 24  105 24  105 24  105 24  105 46  105 1  106 35  104 
Note: DL-PLG: DL-poly(lactic-co-glycolic acid); DL-PLA: DL-polylactic acid; L-PLA: L-polylactic acid; PGA: polyglycolic acid; PCL: poly-e-caprolactone. 
(a) Specifications obtained from Birmingham Polymers, Inc. 
(b) (HFIP) hexafluoroisopropanol. 
(c) (CHCl3) chloroform. 
(d) Partial listing only: MeCl2, methylene chloride; THF, tetrahydrofuran; EtOAc, ethyl acetate; HFIP, hexafluoroisopropanol; HFASH, hexafluoroacetone sesquihydrate; C3H6O, acetone. 
26 Aliphatic Polyesters

11 Stability and Storage Conditions 
The aliphatic polyesters are easily susceptible to hydrolysis in 
the presence of moisture. Hence, they should be properly 
stored, preferably refrigerated at below 08C. It is necessary to 
allow the polymers to reach room temperature before opening 
the container. After the original package has been opened, it is 
recommended to re-purge the package with high-purity dry 
nitrogen prior to resealing. 
12 Incompatibilities 

13 Method of Manufacture 
Generally, aliphatic polyesters can be synthesized via polycondensation 
of hydroxycarboxylic acids and catalytic ringopening 
polymerization of lactones. Ring-opening polymerization 
is preferred because polyesters with high molecular weights 
can be produced. Moreover, the dehydration of hydroxycarboxylic 
acids to form lactones does not have to be carried to a 
high degree of completion. Lactones can easily be purified 
owing to the differences of their physical and chemical 
properties from those of the corresponding hydroxycarboxylic 
acid. 
14 Safety 
Poly(lactide), poly(glycolide), poly(lactide-co-glycolide), and 
polycaprolactone are used in parenteral pharmaceutical formulations 
and are regarded as biodegradable, biocompatible, 
and bioabsorbable materials. Their biodegradation products 
are nontoxic, noncarcinogenic, and nonteratogenic. In general, 
these polyesters exhibit very little hazard. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Contact with eyes, skin, and 
clothing, and breathing the dust of the polymers should be 
avoided. Aliphatic polyesters produce acid materials such as 
hydroxyacetic and/or lactic acid in the presence of moisture; 
thus, contact with materials that will react with acids, especially 
in moist conditions, should be avoided. 
16 Regulatory Status 
GRAS listed. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Lactic acid. 
18 Comments 
Due to their ability to form complexes with heavy metal ions, 
aliphatic polyesters are added to skin-protective ointments.(6) 
19 Specific References 
1 Jackanicz TM, Nash HA, Wise DL, Gregory JB. Polylactic acid as a 
biodegradable carrier for contraceptive steroids. Contraception 
1973; 8: 227233. 
2 Eenink MJD, Feijen J, Olijslager J, et al. In: Anderson JM, Kim SW, 
eds. Advances in Drug Delivery Systems. Amsterdam: Elsevier: 
1987: 225247. 
3 Schwope AD,Wise DL, Howes JF. Lactic/glycolic acid polymers as 
narcotic antagonist delivery system. Life Sci 1975; 17: 18771886. 
4 Juni K, Ogata J, Nakano M, et al. Preparation and evaluation in 
vitro and in vivo of polylactic acid microspheres containing 
doxorubicin. Chem Pharm Bull 1985; 33(1): 313318. 
5 Sanders LM, Burns R, Bitale K, Hoffman P. Clinical performance 
of nafarelin controlled release injectable: influence of formulation 
parameters on release kinetics and duration of efficacy. Proc Int 
Symp Control Rel Bioact Mater 1988; 15: 6263. 
6 Hoeffner EM, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of 
Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th 
edn. Munich, Germany: Editio Cantor Verlag Aulendorf, 2002: 
1270. 
20 General References 
Barrows T. Degradable implant materials: a review of synthetic 
absorbable polymers and their applications. Clin Mater 1986; 1: 
233257. 
Chu CC. An in-vitro study of the effect of buffer on the degradation of 
poly (glycolide) sutures. J Biomed Mater Res 1981; 15: 1927. 
Chu CC. The effect of pH on the in vitro degradation of poly (glycolide 
lactide) copolymer absorbable sutures. J Biomed Mater Res 1982; 
16: 117124. 
Danckwerts M, Fassihi A. Implantable controlled release drug delivery 
systems: a review. Drug Dev Ind Pharm 1991; 17(11): 14651502. 
Gilding DK, Reed AM. Biodegradable polymers for use in surgerypolyglycolic/
poly(lactic acid) homo- and copolymers: 1. Polymer 
1979; 20: 14591464. 
Kissel T, Li YX, Volland C. Properties of block- and randomcopolymers 
of lactic acid and glycolic acid. Proc Int Symp Control 
Rel Bioact Mater 1993; 20: 127128. 
Kitchell JP, Wise DL. Poly(lactic/glycolic acid) biodegradable drugpolymer 
matrix systems. Methods Enzymol 1985; 112: 436448. 
Kulkarni RK, Moore EG, Hegyeli AF, Leonard F. Biodegradable 
poly(lactic acid) polymers. J Biomed Mater Res 1971; 5: 169181. 
Lewis H. Controlled release of bioactive agents from lactide/glycolide 
polymers. In: Chasin M, Langer R, eds. Biodegradable Polymers as 
Drug Delivery Systems. New York: Marcel Dekker, 1990: 141. 
Li SM, Garreau H, Vert M. Structureproperty relationships in the case 
of the degradation of massive aliphatic poly-(a-hydroxy acids) in 
aqueous media, Part 1: Poly(dl-lactic acid). J Mater Sci Mater Med 
1990; 1: 130139. 
Nguyen TH, Higuchi T, Himmelstein J. Erosion characteristics of 
catalyzed poly(orthoester) matrices. J Controlled Release 1987; 5: 
112. 
Pitt CG, Gratzl MM, Jeffcoat AR, et al. Sustained drug delivery systems 
II: factors affecting release rates from poly (e-caprolactone) and 
related biodegradable polyesters. J Pharm Sci 1979; 68(12): 1534 
1538. 
Reed AM, Gilding DK. Biodegradable polymers for use in surgerypoly(
glycolic)/poly(lactic acid) homo and copolymers: 2. In vitro 
degradation. Polymer 1981; 22: 494498. 
Shah SS, Cha Y, Pitt CG. Poly(glycolic acid-co-dl lactic acid): diffusion 
or degradation controlled drug delivery? J Controlled Release 1992; 
18: 261270. 
Vert M, Li S, Garreau H. New insights on the degradation of 
bioresorbable polymeric devices based on lactic and glycolic acids. 
Clin Mater 1992; 10: 38. 
Visscher GE, Robison RL, Maulding HV, et al. Biodegradation and 
tissue reaction to 50 : 50 poly(dl-lactide-co-glycolide) microcapsules. 
J Biomed Mater Res 1985; 19: 349365. 
Williams DF. Mechanisms of biodegradation of implantable polymers. 
Clin Mater 1992; 10: 912. 
21 Authors 
RK Chang, AJ Shukla, Y Sun. 
22 Date of Revision 
26 August 2005. 
Aliphatic Polyesters 27

Alitame 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Aclame; L-aspartyl-D-alanine-N-(2,2,4,4-tetramethylthietan-3- 
yl)amide; 3-(L-aspartyl-D-alaninamido)-2,2,4,4-tetramethylthietane. 
3 Chemical Name and CAS Registry Number 
L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide 
anhydrous [80863-62-3] 
L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide 
hydrate [99016-42-9] 
4 Empirical Formula and Molecular Weight 
C14H25N3O4S 331.44 (for anhydrous) 
C14H25N3O4S21=2H2O 376.50 (for hydrate) 
5 Structural Formula 
6 Functional Category 
Sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Alitame is an intense sweetening agent developed in the early 
1980s and is approximately 2000 times sweeter than sucrose. It 
has an insignificant energy contribution of 6 kJ (1.4 kcal) per 
gram of alitame. 
Alitame is currently primarily used in a wide range of foods 
and beverages at a maximum level of 40300 mg/kg.(1) 
8 Description 
Alitame is a white nonhygroscopic crystalline powder; odorless 
or having a slight characteristic odor. 
9 Pharmacopeial Specifications 

10 Typical Properties 
Acidity/alkalinity: pH = 56 (5% w/v aqueous solution) 
Isoelectric point: pH 5.6 
Melting point: 1361478C 
Solubility: see Table I. 
Table I: Solubility of alitame. 
Solvent Solubility at 208C 
unless otherwise stated 
Chloroform 1 in 5000 at 258C 
Ethanol 1 in 1.6 at 258C 
n-Heptane Practically insoluble 
Methanol 1 in 2.4 at 258C 
Propylene glycol 1 in 1.9 at 258C 
Water 1 in 8.3 at 58C 
1 in 7.6 at 258C 
1 in 3.3 at 408C 
1 in 2.0 at 508C 
Specific rotation [a]D
25: .408 to .508 (1% w/v aqueous 
solution) 
11 Stability and Storage Conditions 
Alitame is stable in dry, room temperature conditions but 
undergoes degradation at elevated temperatures or when in 
solution at low pH. Alitame can degrade in a one-stage process 
to aspartic acid and alanine amide (under harsh conditions) or 
in a slow two-stage process by first degrading to its b-aspartic 
isomer and then to aspartic acid and alanine amide. At pH 58, 
alitame solutions at 238C have a half-life of approximately 4 
years. At pH 2 and 238C the half-life is 1 year. 
Alitame should be stored in a well-closed container in a cool, 
dry place. 
12 Incompatibilities 
Alitame may be incompatible with oxidizing and reducing 
substances or strong acids and bases. 
13 Method of Manufacture 
Alitame may be synthesized by a number of routes.(2,3) For 
example, 3-(D-alaninamido)-2,2,4,4-tetramethylthietane is dissolved 
in water and L-aspartic acid N-thiocarboxyanhydride is 
then added in portions with vigorous stirring, maintaining the 
pH of 8.59.5. The pH is then adjusted to 5.5 and ptoluenesulfonic 
acid monohydrate is added over a period of 
one hour. The precipitated crystalline p-toluenesulfonate salt is 
collected by filtration. To obtain alitame from its salt, a mixture 
of Amberlite LA-1 (liquid anion exchange resin), dichloromethane, 
deionized water, and the salt is stirred for one hour, 
resulting in two clear layers. The aqueous layer is treated with 
carbon, clarified by filtration, and cooled to crystallize alitame. 
Alternatively, tetramethylthietane amine is condensed with 
an N-protected form of D-alanine to give alanyl amide. This is 
then coupled to a protected analogue of L-aspartic acid to give a 
crude form of alitame. The crude product is then purified.

14 Safety 
Alitame is a relatively new intense sweetening agent used 
primarily in foods and confectionary. It is generally regarded as 
a relatively nontoxic and nonirritant material. 
Chronic animal studies in mice, rats, and dogs carried out 
for a minimum of 18 months at concentrations >100 mg/kg per 
day exhibited no toxic or carcinogenic effects. In people, no 
evidence of untoward effects were observed following ingestion 
of 15 mg/kg per day for two weeks. 
Following oral administration 722% of alitame is unabsorbed 
and excreted in the feces. The remaining amount is 
hydrolyzed to aspartic acid and alanine amide. The aspartic 
acid is metabolized normally and the alanine amide excreted in 
the urine as a sulfoxide isomer, as the sulfone, or conjugated 
with glucuronic acid. 
TheWHOhas set an acceptable daily intake of alitame at up 
to 0.1 mg/kg body-weight.(4) 
LD50 (mouse, oral): >5 g/kg 
LD50 (rabbit, skin): >2 g/kg 
LD50 (rat, oral): >5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Alitame should be stored in tightly closed 
containers, and protected from exposure to direct sunlight and 
higher than normal room temperatures. 
16 Regulatory Status 
Alitame is approved for use in food applications in a number of 
countries worldwide including Australia, Chile, China, Mexico, 
and New Zealand. 
17 Related Substances 
Acesulfame potassium; aspartame; saccharin; saccharin 
sodium; sodium cyclamate. 
18 Comments 

19 Specific References 
1 FAO/WHO. Evaluation of certain food additives and contaminants. 
Fifty-ninth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 2002; No. 
913. 
2 Sklavounos C. Process for preparation, isolation and purification 
of dipeptide sweeteners. United States Patent No. 4,375,430; 1 
Mar, 1983. 
3 Brennan TM, Hendrick ME. Branched amides of L-aspartyl-Damino 
acid dipeptides. United States Patent No. 4,411,925; 25 
Oct, 1983. 
4 FAO/WHO. Evaluation of certain food additives and contaminants. 
Forty-sixth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1997; 
No.868. 
20 General References 
Anonymous. Use of nutritive and nonnutritive sweetenersposition of 
ADA. J Am Diet Assoc 1998; 98: 580587. 
Hendrick ME. Alitame. In: Nabors L, Gelardi R, eds. Alternative 
Sweeteners. New York: Marcel Dekker, 1991: 2938. 
Hendrick ME. In: Grenby TH, ed. Advances in Sweeteners. Glasgow: 
Blackie, 1996: 226239. 
21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
Alitame 29

Almond Oil 
1 Nonproprietary Names 
BP: Almond oil 
PhEur: Amygdalae oleum virginum 
USPNF: Almond oil 
2 Synonyms 
Almond oil, bitter; artificial almond oil; bitter almond oil; 
expressed almond oil; huile damande; oleo de ame.ndoas; olio 
di mandorla; sweet almond oil; virgin almond oil. 
3 Chemical Name and CAS Registry Number 
Almond oil [8007-69-0] 
4 Empirical Formula and Molecular Weight 
Almond oil consists chiefly of glycerides of oleic acid, with 
smaller amounts of linoleic and palmitic acids. The PhEur 2005 
describes almond oil as the fatty oil obtained by cold expression 
from the ripe seeds of Prunus dulcis (Miller) DA Webb var. 
dulcis or Prunus dulcis (Miller) DA Webb var. amara (DC) 
Buchheim or a mixture of both varieties. A suitable antioxidant 
may be added. 
The USPNF 23 describes almond oil as the fixed oil obtained 
by expression from the kernels of varieties of Prunus amygdalus 
Batsch (Fam. Rosaceae). 
5 Structural Formula 
See above. 
6 Functional Category 
Emollient; oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Almond oil is used therapeutically as an emollient(1) and to 
soften ear wax. As a pharmaceutical excipient it is employed as 
a vehicle in parenteral preparations,(2) such as oily phenol 
injection. It is also used in nasal spray,(3) and topical 
preparations.(4)Almond oil is also consumed as a food 
substance, see Section 18. 
8 Description 
A clear, colorless, or pale-yellow colored oil with a bland, nutty 
taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for almond oil. 
Test PhEur 2005 USPNF 23 
Identification . . 
Absorbance .  
Acid value 42.0  
Characters .  
Cottonseed oil  . 
Foreign kernel oils  . 
Foreign oils  . 
Iodine value  95105 
Mineral oil and fatty oils  . 
Peroxide value 415.0  
Saponification value  190200 
Sesame oil  . 
Specific gravity  0.9100.915 
Unsaponifiable matter 40.7%  
Free fatty acids . . 
Saturated fatty acids < C16 40.1%  
Arachidic acid 40.2%  
Behenic acid 40.2%  
Eicosenoic acid 40.3%  
Erucic acid 40.1%  
Linoleic acid 20.030.0%  
Linolenic acid 40.4%  
Margaric acid 40.2%  
Oleic acid 62.086.0%  
Palmitic acid 4.09.0%  
Palmitoleic acid 40.6%  
Stearic acid 43.0%  
Sterols .  
5-Avenasterol 510.0%  
7-Avenasterol 43.0%  
Brassicasterol 40.3%  
Cholesterol 40.7%  
Campesterol 44.0%  
Stigmasterol 43.0%  
b-Sitosterol 73.087.0%  
7-Stigmasterol 43.0%  
10 Typical Properties 
Flash point: 3208C 
Melting point: 188C 
Refractive index: nD
40 = 1.46301.4650 
Smoke point: 2208C 
Solubility: miscible with chloroform, and ether; slightly soluble 
in ethanol (95%). 
11 Stability and Storage Conditions 
Almond oil should be stored in a well-closed container in a 
cool, dry place away from direct sunlight and odors. It may be 
sterilized by heating at 1508C for 1 hour. Almond oil does not 
easily turn rancid.

12 Incompatibilities 

13 Method of Manufacture 
Almond oil is expressed from the seeds of the bitter or sweet 
almond, Prunus dulcis (Prunus amygdalus; Amygdalus communis) 
var. amara or var. dulcis (Rosaceae).(5) See also Section 
4. 
14 Safety 
Almond oil is widely consumed as a food and is used both 
therapeutically and as an excipient in topical and parenteral 
pharmaceutical formulations, where it is generally regarded as 
a nontoxic and nonirritant material. However, there has been a 
single case reported of a 5-month-old child developing allergic 
dermatitis attributed to the application of almond oil for 2 
months to the cheeks and buttocks.(6) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in nonparenteral and parenteral medicines licensed in 
the UK. Widely used as an edible oil. 
17 Related Substances 
Canola oil; corn oil; cottonseed oil; peanut oil; refined almond 
oil; sesame oil; soybean oil. 
Refined almond oil 
Synonyms: amygdalae oleum raffinatum. 
Comments: refined almond oil is defined in some pharmacopeias 
such as the PhEur 2005. Refined almond oil is a clear, 
pale yellow colored oil with virtually no taste or odor. It is 
obtained by expression of almond seeds followed by 
subsequent refining. It may contain a suitable antioxidant. 
18 Comments 
A 100 g quantity of almond oil has a nutritional energy value of 
3700 kJ (900 kcal) and contains 100 g of fat of which 28% is 
polyunsaturated, 64% is monounsaturated and 8% is saturated 
fat. 
Studies have suggested that almond consumption is 
associated with health benefits, including a decreased risk of 
colon cancer.(7) 
A specification for bitter almond oil is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Pesko LJ. Peanut recipe softens brittle, split nails. Am Drug 1997; 
214(Dec): 48. 
2 Van Hoogmoed LM, Agnew DW, Whitcomb M, et al. Ultrasonographic 
and histologic evaluation of medial and middle patellar 
ligaments in exercised horses following injection with ethanolamine 
oleate and 2% iodine in almond oil. Am J Vet Res 2002; 
63(5): 738743. 
3 Cicinelli E, Savino F, Cagnazzo I, et al. Progesterone administration 
by nasal spray in menopausal women: comparison between 
two different spray formulations. Gynecol Endocrinol 1992; 6(4): 
247251. 
4 Christen P, Kloeti F, Gander B. Stability of prednisolone and 
prednisolone acetate in various vehicles used in semi-solid topical 
preparations. J Clin Pharm Ther 1990; 15(5): 325329. 
5 Evans WC. Trease and Evans Pharmacognosy, 14th edn. London: 
WB Saunders, 1996: 184. 
6 Guillet G, Guillet M-H. Percutaneous sensitization to almond in 
infancy and study of ointments in 27 children with food allergy. 
Allerg Immunol 2000; 32(8): 309311. 
7 Davis PA, Iwahashi CK. Whole almonds and almond fractions 
reduce aberrant crypt foci in a rat model of colon carcinogenesis. 
Cancer Lett 2001; 165(1): 2733. 
20 General References 
Allen LV. Oleaginous vehicles. Int J Pharm Compound 2000; 4(6): 470 
472. 
Anonymous. Iodine 2% in oil injection. Int J Pharm Compound 2001; 
5(2): 131. 
Brown JH, Arquette DJ, Kleiman R, et al. Oxidative stability of 
botanical emollients. Cosmet Toilet 1997; 112(Jul): 8790, 92, 94, 
9698. 
Shaath NA, Benveniste B. Natural oil of bitter almond. Perfum Flavor 
1991; 16(NovDec): 17, 1924. 
21 Authors 
SA Shah, D Thassu. 
22 Date of Revision 
15 August 2005. 
Almond Oil 31

Alpha Tocopherol 
1 Nonproprietary Names 
BP: Alpha tocopherol 
JP: Tocopherol 
PhEur: RRR-a-Tocopherolum 
USP: Vitamin E 
See also Sections 3, 9, and 17. 
2 Synonyms 
Copherol F1300; ()-3,4-dihydro-2,5,7,8-tetramethyl-2- 
(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol; E307; Eastman 
Vitamin E TPGS; synthetic alpha tocopherol; all-rac-atocopherol; 
dl-a-tocopherol; 5,7,8-trimethyltocol. 
3 Chemical Name and CAS Registry Number 
()-(2RS,40RS,80RS)-2,5,7,8-Tetramethyl-2-(40,80,120-trimethyltridecyl)-
6-chromanol [10191-41-0] 
Note that alpha tocopherol has three chiral centers, giving 
rise to eight isomeric forms. The naturally occurring form is 
known as d-alpha tocopherol or (2R,40R,80R)-alpha-tocopherol. 
The synthetic form, dl-alpha tocopherol or simply 
alpha tocopherol, occurs as a racemic mixture containing 
equimolar quantities of all the isomers. 
Similar considerations apply to beta, delta, and gamma 
tocopherol and tocopherol esters. 
See Section 17 for further information. 
4 Empirical Formula and Molecular Weight 
C29H50O2 430.72 
5 Structural Formula 
Alpha tocopherol: R1 = R2 = R3 = CH3 
Beta tocopherol: R1 = R3 = CH3; R2 = H 
Delta tocopherol: R1 = CH3; R2 = R3 = H 
Gamma tocopherol: R1 = R2 = CH3; R3 = H 
* Indicates chiral centers. 
6 Functional Category 
Antioxidant; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Alpha tocopherol is primarily recognized as a source of vitamin 
E, and the commercially available materials and specifications 
reflect this purpose. While alpha tocopherol also exhibits 
antioxidant properties, the beta, delta, and gamma tocopherols 
are considered to be more effective as antioxidants. 
Alpha-tocopherol is a highly lipophilic compound, and is an 
excellent solvent for many poorly soluble drugs.(14) Of 
widespread regulatory acceptability, tocopherols are of value 
in oil- or fat-based pharmaceutical products and are normally 
used in the concentration range 0.0010.05% v/v. There is 
frequently an optimum concentration; thus the autoxidation of 
linoleic acid and methyl linolenate is reduced at low concentrations 
of alpha tocopherol, and is accelerated by higher 
concentrations. Antioxidant effectiveness can be increased by 
the addition of oil-soluble synergists such as lecithin and 
ascorbyl palmitate.(4) 
D-a-Tocopherol has also been used as a non-ionic surfactant 
in oral and injectable formulations.(3) 
8 Description 
Alpha tocopherol is a natural product. The PhEur 2005 (Suppl. 
5.1) describes a-tocopherol as a clear, colorless or yellowishbrown, 
viscous, oily liquid. See also Section 17. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for alpha tocopherol. 
Test JP 2001 PhEur 2005 
(Suppl. 5.1) 
USP 28 
Identification . . . 
Characters  .  
Acidity   . 
Acid value  42  
Optical rotation  0.018 to .0.018 . 
Heavy metals 420 ppm 420 ppm  
Sulfated ash  40.1%  
Organic volatile 
impurities 
  . 
Absorbance . .  
at 255 nm  5.58.0  
at 292 nm 71.076.0 72.076.0  
Refractive index 1.5031.507   
Specific gravity 0.9470.955   
Clarity and color 
of solution 
.   
Assay 96.0102.0% 96.0101.5% 96.0 
102.0% 
Note that the USP 28 describes vitamin E as comprising d- or 
dl-alpha tocopherol, d- or dl-alpha tocopheryl acetate, or d- or 
dl-alpha tocopheryl acid succinate. However, the PhEur 2005 
describes alpha tocopherol and alpha tocopheryl acetate in 
separate monographs. 
The diversity of the tocopherols described in the various 
pharmacopeial monographs makes the comparison of specifications 
more complicated; see Section 17.

10 Typical Properties 
Boiling point: 2358C 
Density: 0.9470.951 g/cm3 
Flash point: 2408C 
Ignition point: 3408C 
Refractive index: nD
20 = 1.5031.507 
Solubility: practically insoluble in water; freely soluble in 
acetone, ethanol, ether, and vegetable oils. 
11 Stability and Storage Conditions 
Tocopherols are oxidized slowly by atmospheric oxygen and 
rapidly by ferric and silver salts. Oxidation products include 
tocopheroxide, tocopherylquinone, and tocopherylhydroquinone, 
as well as dimers and trimers. Tocopherol esters are more 
stable to oxidation than the free tocopherols but are in 
consequence less effective antioxidants. See also Section 17. 
Tocopherols should be stored under an inert gas, in an 
airtight container in a cool, dry place and protected from light. 
12 Incompatibilities 
Tocopherols are incompatible with peroxides and metal ions, 
especially iron, copper, and silver. Tocopherols may be 
absorbed into plastic.(5) 
13 Method of Manufacture 
Naturally occurring tocopherols are obtained by the extraction 
or molecular distillation of steam distillates of vegetable oils; 
for example, alpha tocopherol occurs in concentrations of 
0.10.3% in corn, rapeseed, soybean, sunflower, and wheat 
germ oils.(6) Beta and gamma tocopherol are usually found in 
natural sources along with alpha tocopherol. Racemic synthetic 
tocopherols may be prepared by the condensation of the 
appropriate methylated hydroquinone with racemic isophytol.(
7) 
14 Safety 
Tocopherols (vitamin E) occur in many food substances that are 
consumed as part of the normal diet. The daily nutritional 
requirement has not been clearly defined but is estimated to be 
3.020.0 mg. Absorption from the gastrointestinal tract is 
dependent upon normal pancreatic function and the presence of 
bile. Tocopherols are widely distributed throughout the body, 
with some ingested tocopherol metabolized in the liver; 
excretion of metabolites is via the urine or bile. Individuals 
with vitamin E deficiency are usually treated by oral administration 
of tocopherols, although intramuscular and intravenous 
administration may sometimes be used. 
Tocopherols are well tolerated, although excessive oral 
intake may cause headache, fatigue, weakness, digestive 
disturbance, and nausea. Prolonged and intensive skin contact 
may lead to erythema and contact dermatitis. 
The use of tocopherols as antioxidants in pharmaceuticals 
and food products is unlikely to pose any hazard to human 
health since the daily intake from such uses is small compared 
to the intake of naturally occurring tocopherols in the diet. 
The WHO has set an acceptable daily intake of tocopherol 
used as an antioxidant at 0.152.0 mg/kg body-weight.(8) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Gloves and eye protection are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted in Europe as a food additive. Included in 
the FDA Inactive Ingredients Guide (IV injections, powder, 
lyophilized powder for liposomal suspension; oral capsules, 
tablets, and topical preparations). Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. Included in 
nonparenteral medicines licensed in the UK. 
17 Related Substances 
d-Alpha tocopherol; d-Alpha tocopheryl acetate; dl-Alpha 
tocopheryl acetate; d-Alpha tocopheryl acid succinate; dl- 
Alpha tocopheryl acid succinate; beta tocopherol; delta 
tocopherol; gamma tocopherol; tocopherols excipient. 
d-Alpha tocopherol 
Empirical formula: C29H50O2 
Molecular weight: 430.72 
CAS number: [59-02-9] 
Synonyms: natural alpha tocopherol; (.)-(2R,40R,80R)- 
2,5,7,8-tetramethyl-2-(40,80,120-trimethyltridecyl)-6-chromanol; 
d-a-tocopherol; vitamin E. 
Appearance: a practically odorless, clear, yellow, or greenishyellow 
viscous oil. 
Melting point: 2.53.58C 
Solubility: practically insoluble in water; soluble in ethanol 
(95%). Miscible with acetone, chloroform, ether, and 
vegetable oils. 
Specific gravity: 0.95 
Comments: d-alpha tocopherol is the naturally occurring form 
of alpha tocopherol. 
d-Alpha tocopheryl acetate 
Empirical formula: C31H52O3 
Molecular weight: 472.73 
CAS number: [58-95-7] 
Synonyms: (.)-(2R,40R,80R)-2,5,7,8-tetramethyl-2-(40,80,120- 
trimethyltridecyl)-6-chromanyl acetate; d-a-tocopheryl acetate; 
vitamin E. 
Appearance: a practically odorless, clear, yellow, or greenishyellow 
colored viscous oil that may solidify in the cold. 
Melting point: 288C 
Solubility: practically insoluble in water; soluble in ethanol 
(95%). Miscible with acetone, chloroform, ether, and 
vegetable oils. 
Specific rotation [a]D
25: .0.258 (10% w/v solution in chloroform) 
Comments: unstable to alkalis. 
dl-Alpha tocopheryl acetate 
Empirical formula: C31H52O3 
Molecular weight: 472.73 
CAS number: [7695-91-2] 
Synonyms: ()-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-
2H-1-benzopyran-6-ol acetate; ()- 
(2RS,40RS,80RS)-2,5,7,8-tetramethyl-2-(40,80,120-trimethyltridecyl)-
6-chromanyl acetate; ()-a-tocopherol acetate; atocopheroli 
acetas; all-rac-a-tocopheryl acetate; dl-a-tocopheryl 
acetate; vitamin E. 
Alpha Tocopherol 33

Appearance: a practically odorless, clear, yellow, or greenishyellow 
viscous oil. 
Density: 0.953 g/cm3 
Melting point: 27.58C 
Refractive index: nD
20 = 1.49501.4972 
Solubility: practically insoluble in water; freely soluble in 
acetone, chloroform, ethanol, ether, and vegetable oils; 
soluble in ethanol (95%). 
Comments: unstable to alkali. However, unlike alpha tocopherol, 
the acetate is much less susceptible to the effects of 
air, light, or ultraviolet light. Alpha tocopherol acetate 
concentrate, a powdered form of alpha tocopherol acetate, 
is described in the PhEur 2005. The concentrate may be 
prepared by either dispersing alpha tocopherol acetate in a 
suitable carrier such as acacia or gelatin, or by adsorbing 
alpha tocopherol acetate on silicic acid. 
d-Alpha tocopheryl acid succinate 
Empirical formula: C33H54O5 
Molecular weight: 530.8 
CAS number: [4345-03-3] 
Synonyms: (.)-a-tocopherol hydrogen succinate; d-a-tocopheryl 
acid succinate; vitamin E. 
Appearance: a practically odorless white powder. 
Melting point: 76778C 
Solubility: practically insoluble in water; slightly soluble in 
alkaline solutions; soluble in acetone, ethanol (95%), ether, 
and vegetable oils; very soluble in chloroform. 
Comments: unstable to alkalis. 
dl-Alpha tocopheryl acid succinate 
Empirical formula: C33H54O5 
Molecular weight: 530.8 
CAS number: [17407-37-3] 
Synonyms: ()-a-tocopherol hydrogen succinate; dl-a-tocopheryl 
acid succinate; dl-a-tocopherol succinate; vitamin E. 
Appearance: a practically odorless, white crystalline powder. 
Solubility: practically insoluble in water; slightly soluble in 
alkaline solutions; soluble in acetone, ethanol (95%), ether, 
and vegetable oils; very soluble in chloroform. 
Comments: unstable to alkalis. 
Beta tocopherol 
Empirical formula: C28H48O2 
Molecular weight: 416.66 
CAS number: [148-03-8] 
Synonyms: cumotocopherol; ()-3,4-dihydro-2,5,8-trimethyl- 

2-(4,8,12-trimethyltridecyl)-2H-1-b-benzopyran-6-ol; 5,8- 
dimethyltocol; neotocopherol; dl-b-tocopherol; vitamin E; 
p-xylotocopherol. 
Appearance: a pale yellow-colored viscous oil. 
Solubility: practically insoluble in water; freely soluble in 
acetone, chloroform, ethanol (95%), ether, and vegetable 
oils. 
Specific rotation [a]D
20: .6.378 
Comments: less active biologically than alpha tocopherol. 
Obtained along with alpha tocopherol and gamma tocopherol 
from natural sources. Beta tocopherol is very stable 
to heat and alkalis and is slowly oxidized by atmospheric 
oxygen. 
Delta tocopherol 
Empirical formula: C27H46O2 
Molecular weight: 402.64 
CAS number: [119-13-1] 
Synonyms: ()-3,4-dihydro-2,8-dimethyl-2-(4,8,12-trimethyltridecyl)-
2H-1-benzopyran-6-ol; E309; 8-methyltocol; dl-dtocopherol; 
vitamin E. 
Appearance: a pale yellow-colored viscous oil. 
Solubility: practically insoluble in water; freely soluble in 
acetone, chloroform, ethanol (95%), ether, and vegetable 
oils. 
Comments: occurs naturally as 30% of the tocopherol content 
of soybean oil. Delta tocopherol is said to be the most potent 
antioxidant of the tocopherols. 
Gamma tocopherol 
Empirical formula: C28H48O2 
Molecular weight: 416.66 
CAS number: [7616-22-0] 
Synonyms: ()-3,4-dihydro-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)-
2H-1-benzopyran-6-ol; 7,8-dimethyltocol; 
E308; dl-g-tocopherol; vitamin E; o-xylotocopherol. 
Appearance: a pale yellow-colored viscous oil. 
Melting point: 308C 
Solubility: practically insoluble in water; freely soluble in 
acetone, chloroform, ethanol (95%), ether, and vegetable 
oils. 
Specific rotation [a]D
20: 2.48 (in ethanol (95%)) 
Comments: occurs in natural sources along with alpha and beta 
tocopherol. Gamma tocopherol is biologically less active 
than alpha tocopherol. Very stable to heat and alkalis; 
slowly oxidized by atmospheric oxygen and gradually 
darkens on exposure to light. 
Tocopherols excipient 
Synonyms: Embanox tocopherol. 
Appearance: a pale yellow-colored viscous oil. 
Comments: tocopherols excipient is described in the USPNF 23 
as a vegetable oil solution containing not less than 50.0% of 
total tocopherols, of which not less than 80.0% consists of 
varying amounts of beta, delta, and gamma tocopherols. 
18 Comments 
Note that most commercially available tocopherols are used as 
sources of vitamin E, rather than as antioxidants in pharmaceutical 
formulations. 
Various mixtures of tocopherols, and mixtures of tocopherols 
with other excipients, are commercially available and 
individual manufacturers should be consulted for specific 
information on their products. The EINECS number for atocopherol 
is 215-798-8. The EINECs number for d-atocopherol 
is 200-412-2; and the EINECS number for dl-atocopherol 
is 233-466-0. 
19 Specific References 
1 Nielsen PB, Mu. llertz A, Norling T, Kristensen HG. The effect of atocopherol 
on the in vitro solubilisation of lipophilic drugs. Int J 
Pharm 2001; 222: 217224. 
2 Constantinides PP, Tustian A, Kessler DR. Tocol emulsions for 
drug solubilization and parenteral delivery. Adv Drug Delivery 
2004; 56(9): 12431255. 
3 Strickley RG. Solubilizing excipients in oral and injectable 
formulations. Pharm Res 2004; 21(2): 201230. 
34 Alpha Tocopherol

4 Johnson DM, Gu LC. Autoxidation and antioxidants. In: 
Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical 
Technology, volume 1. New York: Marcel Dekker, 1988: 415450. 
5 Allwood MC. Compatibility and stability of TPN mixtures in big 
bags. J Clin Hosp Pharm 1984; 9: 181198. 
6 Buck DF. Antioxidants. In: Smith J, ed. Food Additive Users 
Handbook. Glasgow: Blackie, 1991: 146. 
7 Rudy BC, Senkowski BZ. dl-Alpha-tocopheryl acetate. In: Florey 
K, ed. Analytical Profiles of Drug Substances, volume 3. New 
York: Academic Press, 1974: 111126. 
8 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirtieth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1987; No. 
751. 
20 General References 
US National Research Council Food and Nutrition Board. Recommended 
Dietary Allowances, 10th edn. Washington DC: National 
Academy Press, 1989: 99105. 
21 Authors 
SC Owen. 
22 Date of Revision 
4 August 2005. 
Alpha Tocopherol 35

Aluminum Hydroxide Adjuvant 
1 Nonproprietary Names 
PhEur: Aluminii hydroxidum hydricum ad adsorptionem 
2 Synonyms 
Alhydrogel; aluminium hydroxide adjuvant; aluminium oxyhydroxide; 
poorly crystalline boehmite; pseudoboehmite; 
Rehydragel. 
3 Chemical Name and CAS Registry Number 
Aluminum oxyhydroxide [21645-51-2] 
4 Empirical Formula and Molecular Weight 
AlO(OH) 59.99 
5 Structural Formula 
Structural hydroxyl groups form hydrogen bonds between 
AlO(OH) octahedral sheets, where hydroxyl groups are 
exposed at the surface. The surface hydroxyl groups produce 
a pH-dependent surface charge by accepting a proton to 
produce a positive site, or donating a proton to produce a 
negative site. The pH-dependent surface charge is characterized 
by the point of zero charge, which is equivalent to the isoelectric 
point in protein chemistry. The surface hydroxyl groups may 
also undergo ligand exchange with fluoride, phosphate, 
carbonate, sulfate, or borate anions. 
6 Functional Category 
Adsorbent; vaccine adjuvant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aluminum hydroxide adjuvant is used in parenteral human and 
veterinary vaccines.(1) It activates TH2 immune responses, 
including IgG and IgE antibody responses. It is also used for the 
isolation of certain serum components such as blood clotting 
factors.(2) 
8 Description 
Aluminum hydroxide adjuvant is a white hydrogel that 
sediments slowly and forms a clear supernatant. 
9 Pharmacopeial Specifications 
See Table I. Note that the USP 28 includes a monograph for 
aluminum hydroxide gel, which is a form of aluminum 
hydroxide that is used as an antacid, in which there is a partial 
substitution of carbonate for hydroxide. 
See Section 17. 
Table I: Pharmacopeial specifications for aluminum hydroxide 
adjuvant. 
Test PhEur 2005 
Identification . 
Characters . 
Solution . 
pH 5.58.5 
Adsorption power . 
Sedimentation . 
Chlorides 40.33% 
Nitrates 4100 ppm 
Sulfates 40.5% 
Ammonium 450 ppm 
Arsenic 41 ppm 
Iron 410 ppm 
Heavy metals 420 ppm 
Bacterial endotoxins . 
Assay 90.0110.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.58.5 
Particle size distribution: primary particles are fibrous with 
average dimensions of 4.5  2.2  10 nm. The primary 
particles form aggregates of 110 mm. 
Point of zero charge: pH = 11.4 
Protein binding capacity: >0.5 mg BSA/mg equivalent Al2O3 
Solubility: soluble in alkali hydroxides and mineral acids. Heat 
may be required to dissolve the aluminum hydroxide 
adjuvant. 
Specific surface area: 500m2/g.(3) 
X-ray diffractogram: exhibits characteristic x-ray diffraction 
pattern having diffraction bands at 6.46, 3.18, 2.35, 1.86, 
1.44 and 1.31A .
. 
11 Stability and Storage Conditions 
Aluminum hydroxide adjuvant is stable for at least two years 
when stored at 4308C in well-sealed inert containers. It must 
not be allowed to freeze as the hydrated colloid structure will be 
irreversibly damaged. 
12 Incompatibilities 
When exposed to phosphate, carbonate, sulfate, or borate 
anions, the point of zero charge for aluminum hydroxide 
adjuvant decreases. 
13 Method of Manufacture 
Aluminum hydroxide adjuvant is prepared by the precipitation 
of a soluble aluminum salt by an alkali hydroxide, or the 
precipitation of an alkali aluminate by acid.

14 Safety 
Aluminum hydroxide adjuvant is intended for use in parenteral 
vaccines and is generally regarded as nontoxic. It may cause 
mild irritation, dryness, and dermatitis on skin contact. On eye 
contact, aluminum hydroxide adjuvant may also cause redness, 
conjunctivitis, and short-term mild irritation. Ingestion of large 
amounts may cause gastrointestinal irritation with nausea, 
vomiting, and constipation. Inhalation of the dried product 
may cause respiratory irritation and cough. Type I hypersensitivity 
reactions following parenteral administration have been 
reported.(4) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use in human and veterinary 
parenteral vaccines in Europe and the USA. The limits for use 
in human vaccines are 0.85 mg aluminum/dose (FDA) and 
1.25 mg aluminum/dose (WHO). There are no established 
limits for use in veterinary vaccines. Reported in the EPATSCA 
Inventory. 
17 Related Substances 
Aluminum phosphate adjuvant. 
18 Comments 
Different grades of aluminum hydroxide adjuvant with various 
concentrations, protein binding capacities, and points of zero 
charge are available. 
The impurity limits at 2% equivalent Al2O3 are Cl < 0.5%; 
SO4 < 0.5%; PO4 < 0.1%; NO3 < 0.1%; NH4 < 0.1%; Fe < 
20 ppm; As < 0.6 ppm; and heavy metals < 20 ppm. 
The aluminum hydroxide gel referred to in the USP 28 is 
used in cosmetics as an emollient, filler, humectant, a mild 
astringent, and viscosity controlling agent. In pharmaceutical 
preparations it is used as an adsorbent, and as a protein 
binder.(5) It is also used therapeutically as an antacid, and as an 
abrasive in dentrifrices. It is not, however, used as a vaccine 
adjuvant. 
19 Specific References 
1 Shirodkar S, Hutchinson RL, Perry DL, et al. Aluminum 
compounds used as adjuvants in vaccines. Pharm Res 1990; 7: 
12821288. 
2 Prowse CV, Griffin B, Pepper DS, et al. Changes in factor VIII 
complex activities during the production of a clinical intermediate 
purity factor VIII concentrate. Thromb Haemost 1981; 46: 597 
601. 
3 Johnston CT, Wang JL, Hem SL. Measuring the surface area of 
aluminum hydroxide adjuvant. J Pharm Sci 2002; 91: 17021706. 
4 Goldenthal KL, Cavagnaro JA, Alving G, Vogel FR. Safety 
evaluation of vaccine adjuvants. AIDS Res Hum Retroviruses 
1993: 9 (Suppl. 1): 547551. 
5 Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. 
Endicott, NY: Synapse Information Resources, 2002: 298. 
20 General References 
Gupta RK, Rost BE, Relyveld E, Siber GR. Adjuvant properties of 
aluminum and calcium compounds. In: Powell MF, Newman MJ, 
eds. Vaccine Design. New York: Plenum, 1995: 229248. 
Hem SL, White JL. Structure and properties of aluminum-containing 
adjuvants. In: Powel MF, Newman MJ, eds. Vaccine Design. New 
York: Plenum, 1995: 249276. 
Lindblad EB. Aluminum adjuvants  in retrospect and prospect. 
Vaccine 2004; 22: 36583668. 
Lindblad EB. Aluminum adjuvants. In: Stewart-Tull DES, ed. The 
Theory and Practical Application of Adjuvants. New York: Wiley, 
1995: 2135. 
Vogel FR, Powell MF. A compendium of vaccine adjuvants and 
excipients. In: Powell MF, Newman MJ, eds. Vaccine Design. New 
York: Plenum, 1995: 229248. 
Vogel FR, Hem SL. Immunogenic adjuvants. In: Plotkin SA, Orestein 
WA, eds. Vaccines, 4th edn. New York: W.B. Saunders, 2004: 72 
76. 
White JL, Hem SL. Characterization of aluminum-containing adjuvants. 
In: Brown F, Corbel M, Griffiths E, eds. Physico-Chemical 
Procedures for the Characterization of Vaccines, IABS Symposia 
Series, Development in Biologicals. New York: Karger, 2000; 103: 
217228. 
21 Authors 
SL Hem, PB Klepak, EB Lindblad. 
22 Date of Revision 
2 September 2005. 
Aluminum Hydroxide Adjuvant 37

Aluminum Oxide 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Activated alumina; activated aluminum oxide; alpha aluminum 
oxide; alumina; alumina, activated; alumina, calcined; alumina, 
tabular; aluminum oxide alumite; aluminum trioxide. 
3 Chemical Name and CAS Registry Number 
Aluminum oxide [1344-28-1] 
4 Empirical Formula and Molecular Weight 
Al2O3 101.96 
5 Structural Formula 
Aluminum oxide occurs naturally as the minerals bauxite, 
bayerite, boehmite, corundum, diaspore, and gibbsite. 
6 Functional Category 
Adsorbent; dispersing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aluminum oxide is used mainly in tablet formulations.(1) It is 
used for decoloring powders and is particularly widely used in 
antibiotic formulations. It is also used in suppositories, 
pessaries, and urethral inserts. Hydrated aluminum oxide (see 
Section 18) is used in mordant dyeing to make lake pigments, in 
cosmetics, and therapeutically as an antacid. 
8 Description 
Aluminum oxide occurs as a white crystalline powder. 
Aluminum oxide occurs as two crystalline forms. a-aluminum 
oxide is composed of colorless hexagonal crystals, and galuminum 
oxide is composed of minute colorless cubic crystals 
that are transformed to the a-form at high temperatures. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Boiling point: 29778C 
Density (bulk): 0.91.1 g/cm3 
Flammability: nonflammable. 
Hardness (Mohs): 8.8 
Hygroscopicity: very hygroscopic. 
Melting point: 20508C 
Solubility: slowly soluble in aqueous alkaline solutions; 
practically insoluble in nonpolar organic solvents, diethyl 
ether, ethanol (95%), and water. 
Specific gravity: 2.8 (becomes 4.0 at 8008C) 
Vapor pressure: 133.3 Pa at 21588C 
11 Stability and Storage Conditions 
Aluminum oxide should be stored in a well-closed container in 
a cool, dry, place. It is very hygroscopic. 
12 Incompatibilities 
Aluminum oxide should be kept well away from water. It is 
incompatible with strong oxidizers and chlorinated rubber. 
Aluminum oxide also reacts with chlorine trifluoride, ethylene 
oxide, sodium nitrate, and vinyl acetate. Exothermic reactions 
above 2008C with halocarbon vapors produce toxic hydrogen 
chloride and phosgene fumes. 
13 Method of Manufacture 
Most of the aluminum oxide produced commercially is 
obtained by the calcination of aluminum hydroxide. 
14 Safety 
Aluminum oxide is generally regarded as relatively nontoxic 
and nonirritant when used as an excipient. Inhalation of finely 
divided particles may cause lung damage (Shavers disease). 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled.(2) In the UK, the 
occupational exposure limits for aluminum oxide are 
10 mg/m3 long-term (8-hour TWA) for total inhalable dust 
and 4 mg/m3 for respirable dust.(3) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral tablets 
and topical sponge). Included in nonparenteral medicines 
licensed in the UK. 
17 Related Substances 

18 Comments 
A specification for aluminum oxide is included in Japanese 
Pharmaceutical Excipients 2004 (JPE), see Table I. A specification 
for light aluminum oxide is also included. The PhEur 2005 
includes a specification for hydrated aluminum oxide that 
contains the equivalent of 47.060.0% of Al2O3. The EINECS 
number for aluminum oxide is 215-691-6.

Table I: JPE specification for aluminum oxide.(4) 
Test JPE 2004 
Identification . 
Water-soluble substances . 
Heavy metals 430 ppm 
Lead 430 ppm 
Arsenic 45 ppm 
Loss on drying 41.5% 
Loss on ignition 42.5% 
Assay 596.0% 
19 Specific References 
1 Rupprecht H. Processing of potent substances with inorganic 
supports by imbedding and coating. Acta Pharm Technol 1980; 
26: 1327. 
2 National Poisons Information Service (1997). Aluminium oxide. 
http://www.intox.org/databank/documents/chemical/alumoxde/ 
ukpid33.htm (accessed 25 April 2005). 
3 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
4 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 6768. 
20 General References 

21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
Aluminum Oxide 39

Aluminum Phosphate Adjuvant 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Aluminum hydroxyphosphate; aluminium hydroxyphosphate; 
Adju-Phos; Rehydraphos. 
3 Chemical Name and CAS Registry Number 
Aluminum phosphate [7784-30-7] 
4 Empirical Formula and Molecular Weight 
Al(OH)x(PO4)y 
The molecular weight is dependent on the degree of 
substitution of phosphate groups for hydroxyl groups. 
5 Structural Formula 
Aluminum phosphate adjuvant occurs as a precipitate of 
amorphous aluminum hydroxide in which some sites contain 
phosphate groups instead of hydroxyl. Both hydroxyl and 
phosphate groups are exposed at the surface. The hydroxyl 
groups produce a pH-dependent surface charge by accepting a 
proton to produce a positive site, or donating a proton to 
produce a negative site. The pH-dependent surface charge is 
characterized by the point of zero charge, which is equivalent to 
the isoelectric point in protein chemistry. The surface hydroxyl 
groups may also undergo ligand exchange with fluoride, 
phosphate, carbonate, sulfate, or borate groups. 
Aluminum phosphate adjuvant is not a stoichiometric 
compound. Rather, the degree of phosphate group substitution 
for hydroxyl groups depends on the precipitation recipe and 
conditions. 
6 Functional Category 
Adsorbent; vaccine adjuvant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aluminum phosphate adjuvant is used in parenteral human and 
veterinary vaccines.(1) It activates TH2 immune responses, 
including IgG and IgE antibody responses. 
8 Description 
Aluminum phosphate adjuvant is a white hydrogel that 
sediments slowly and forms a clear supernatant. 
9 Pharmacopeial Specifications 
 
10 Typical Properties 
Acidity/alkalinity: 6.08.0 
Al : P atomic ratio: 1.11.15 : 1.0 
Aluminum (%): 0.50.75 
Particle size distribution: primary particles are platy with an 
average diameter of 50 nm. The primary particles form 
aggregates of 110 mm. 
Point of zero charge: pH = 4.65.6, depending on the Al : P 
atomic ratio. 
Protein binding capacity: >0.6 mg lysozyme/mg equivalent 
Al2O3 
Solubility: soluble in mineral acids and alkali hydroxides. 
X-ray diffractogram: amorphous to x-rays. 
11 Stability and Storage Conditions 
Aluminum phosphate adjuvant is stable for at least six months 
when stored at 4308C in well-sealed inert containers. It must 
not be allowed to freeze as the hydrated colloid structure will be 
irreversibly damaged. 
12 Incompatibilities 
The point of zero charge is related directly to the Al : P atomic 
ratio. Therefore, the substitution of additional phosphate 
groups for hydroxyl groups will lower the point of zero charge. 
Substitution of carbonate, sulfate, or borate ions for hydroxyl 
groups will also affect the point of zero charge. 
13 Method of Manufacture 
Aluminum phosphate adjuvant is formed by the reaction of a 
solution of aluminum chloride and phosphoric acid with alkali 
hydroxide. 
14 Safety 
Aluminum phosphate adjuvant is intended for use in parenteral 
vaccines and is generally regarded as safe. It may cause mild 
irritation, dryness, and dermatitis on skin contact. It may also 
cause redness, conjunctivitis, and short-term mild irritation on 
eye contact. Ingestion of large amounts of aluminum phosphate 
adjuvant may cause respiratory irritation with nausea, vomiting, 
and constipation. Inhalation is unlikely, although the dried 
product may cause respiratory irritation and cough. Type I 
hypersensitivity reactions following parenteral administration 
have also been reported.(2) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use in human and veterinary 
vaccines in Europe and the USA. The limits for use in human

vaccines are 0.85 mg aluminum/dose (FDA) and 1.25 mg 
aluminum/dose (WHO). There are no established limits for 
use in veterinary vaccines. Reported in the EPA TSCA 
Inventory. 
17 Related Substances 
Aluminum hydroxide adjuvant. 
18 Comments 
The USP 28 monograph for aluminum phosphate (ALPO4) gel 
describes aluminum phosphate, which is used as an antacid, not 
as a vaccine adjuvant. 
19 Specific References 
1 Shirodkar S, Hutchinson RL, Perry DL, et al. Aluminum 
compounds used as adjuvants in vaccines. Pharm Res 1990; 7: 
12821288. 
2 Goldenthal KL, Cavagnaro JA, Alving G, Vogel FR. Safety 
evaluation of vaccine adjuvants. AIDS Res Hum Retroviruses 
1993: 9 (Suppl. 1): 547551. 
20 General References 
Hem SL, White JL. Structure and properties of aluminum-containing 
adjuvants. In: Powell MF, Newman MJ, eds. Vaccine Design. New 
York: Plenum, 1995: 249276. 
Gupta RK, Rost BE, Relyveld E, Siber GR. Adjuvant properties of 
aluminum and calcium compounds. In: Powell MF, Newman MJ, 
eds. Vaccine Design. New York: Plenum, 1995: 229248. 
Lindblad EB. Aluminum adjuvants  in retrospect and prospect. 
Vaccine 2004; 22: 36583668. 
Lindblad EB. Aluminum adjuvants. In: Stewart-Tull DES, ed. The 
Theory and Practical Application of Adjuvants. New York: Wiley, 
1995: 2135. 
Vogel FR, Hem SL. Immunogenic adjuvants. In: Plotkin SA, Orenstein 
WA, eds. Vaccines, 4th edn. New York: W.B. Saunders, 2003. 
Vogel FR, Powell MF. A compendium of vaccine adjuvants and 
excipients. In: Powell MF, Newman MJ, eds. Vaccine Design. New 
York: Plenum, 1995: 142. 
White JL, Hem SL. Characterization of aluminum-containing adjuvants. 
In: Brown F, Corbel M, Griffiths E, eds. Physico-Chemical 
Procedures for the Characterization of Vaccines, IABS Symposia 
Series, Developments in Biologicals. New York: Karger, 2000, 103: 
217228. 
21 Authors 
SL Hem, PB Klepak, EB Lindblad. 
22 Date of Revision 
2 September 2005. 
Aluminum Phosphate Adjuvant 41

Aluminum Stearate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Octadecanoic acid aluminum salt; stearic acid aluminum salt. 
3 Chemical Name and CAS Registry Number 
Aluminum tristearate [637-12-7] 
4 Empirical Formula and Molecular Weight 
C54H105AlO6 877.39 
5 Structural Formula 
[CH3(CH2)16COO]3Al 
6 Functional Category 
Emollient; emulsion stabilizer; gelling agent; opacifier; stabilizing 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aluminum stearate is mainly used in microencapsulation(13) 
and in the manufacture of ointments. It is also used in cosmetics 
such as mascara, moisturizers, and sunscreens. 
It should be noted that aluminum stearate can also refer to 
the distearate (CAS number [300-92-5]) and the monostearate 
(CAS number [7047-84-9]) in addition to the tristearate. The 
distearate exhibits the same excipient properties as the 
tristearate and is used in similar pharmaceutical applications. 
However, the monostearate is more widely used in cosmetics as 
a colorant. 
8 Description 
Aluminum stearate occurs as a white, fine, bulky powder with a 
slight odor of fatty acid. It is a hard material. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Melting point: 1171208C 
Solubility: practically insoluble in water. Soluble in ethanol 
(95%), benzene, turpentine oil, and mineral oils when 
freshly prepared. 
Specific gravity: 1.01 
11 Stability and Storage Conditions 
Aluminum stearate should be stored in a well-closed container 
in a cool, dry, place. It is stable under ordinary conditions of use 
and storage. 
12 Incompatibilities 

13 Method of Manufacture 
Aluminum stearate is prepared by reacting aluminum with 
stearic acid. 
14 Safety 
Aluminum stearate is generally regarded as relatively nontoxic 
and nonirritant when used as an excipient. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. When heated to 
decomposition, aluminum stearate emits acrid smoke and 
irritating vapors. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets, topical creams and ointments). Included in 
nonparenteral medicines licensed in the UK. 
17 Related Substances 
Aluminum distearate; aluminum monostearate. 
Aluminum distearate 
Empirical formula: C36H71O5Al 
Molecular weight: 610.9 
CAS number: [300-92-5] 
Synonyms: hydroxyaluminum distearate; aluminum stearate; 
aluminum monobasic stearate 
Description: aluminum distearate occurs as a fine white to offwhite 
colored powder with a slight odor of fatty acid. 
Melting point: 150165 8C 
Specific gravity: 1.01 
Solubility: soluble in benzene, and in ethanol (95%); practically 
insoluble in water. 
Comments: the EINECS number for aluminum distearate is 
206-101-8. 
Aluminum monostearate 
Empirical formula: C18H37O4Al 
Molecular weight: 344.5 
CAS number: [7047-84-9] 
Synonyms: dihydroxyaluminum monostearate; aluminum stearate; 
aluminum, dihydroxy (octadecanoato-O-); stearic acid 
aluminum dihydroxide salt.

Melting point: 2202258C 
Specific gravity: 1.14 
Solubility: soluble in benzene, and in ethanol (95%); practically 
insoluble in water. 
Comments: the EINECS number for aluminum monostearate is 
230-325-5. 
18 Comments 
A specification for aluminum stearate, described as consisting 
mainly of the distearate, is included in the Japanese Pharmaceutical 
Excipients 2004 (JPE), see Table I. The EINECS 
number for aluminum tristearate is 211-279-5. 
Table I: JPE specifications for aluminum stearate.(4) 
Test JPE 2004 
Identification . 
Acid value of fatty acid . 
Free fatty acid . 
Soluble salt . 
Heavy metals 420 ppm 
Lead 420 ppm 
Arsenic 42 ppm 
Loss on drying 42.0% 
Assay (of Al) 4.06.0% 
19 Specific References 
1 Horoz BB, Kilicarslan M, Yuksel N, et al. Effect of different 
dispersing agents on the characteristics of Eudragit microspheres 
prepared by a solvent evaporation method. J Microencapsul 2004; 
21: 191202. 
2 Wu PC, Huang YB, Chang JI, et al. Preparation and evaluation of 
sustained release microspheres of potassium chloride prepared 
with ethylcellulose. Int J Pharm 2003; 260: 115121. 
3 Wu PC, Huang YB, Chang JS, et al. Design and evaluation of 
sustained release microspheres of potassium chloride prepared by 
Eudragit. Eur J Pharm Sci 2003; 19: 115122. 
4 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 7475. 
20 General References 

21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
Aluminum Stearate 43

Ammonia Solution 
1 Nonproprietary Names 
BP: Ammonia solution, concentrated 
PhEur: Ammoniae solution concentrata 
USPNF: Strong ammonia solution 
2 Synonyms 
Ammoniaca; ammoniacum; aqua ammonia; concentrated 
ammonia solution; spirit of hartshorn; stronger ammonia 
water. 
3 Chemical Name and CAS Registry Number 
Ammonia [7664-41-7] 
4 Empirical Formula and Molecular Weight 
NH3 17.03 
5 Structural Formula 
NH3 
6 Functional Category 
Alkalizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ammonia solution is typically not used undiluted in pharmaceutical 
applications. Generally, it is used as a buffering agent 
or to adjust the pH of solutions. Most commonly, ammonia 
solution (the concentrated form) is used to produce more dilute 
ammonia solutions. 
Therapeutically, dilute ammonia solution is used as a reflex 
stimulant in smelling salts, as a rubefacient, and as a 
counterirritant to neutralize insect bites or stings.(1) 
8 Description 
Strong ammonia solution occurs as a clear, colorless liquid 
having an exceedingly pungent, characteristic odor. The PhEur 
2005 states that concentrated ammonia solution contains not 
less than 25.0% and not more than 30.0% w/w of ammonia 
(NH3). The USPNF 23 states that strong ammonia solution 
contains not less than 27.0% and not more than 31.0% w/w of 
ammonia (NH3). 
See also Section 17. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ammonia solution. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Appearance of solution .  
Oxidizable substances . . 
Pyridine and related substances 42 ppm  
Carbonates 460 ppm  
Chlorides 41 ppm  
Sulfates 45 ppm  
Iron 40.25 ppm  
Heavy metals 41 ppm 40.0013% 
Residue on evaporation 40.02 g/L  
Limit of nonvolatile residue  40.05% 
Assay (of NH3) 25.030.0% 27.031.0% 
10 Typical Properties 
Solubility: miscible with ethanol (95%) and water. 
Specific gravity: 0.8920.910 
11 Stability and Storage Conditions 
On exposure to the air, ammonia solution rapidly loses 
ammonia. Ammonia solution should be stored in a well-closed 
container, protected from the air, in a cool, dry place. The 
storage temperature should not exceed 208C. 
12 Incompatibilities 
Ammonia solution reacts vigorously with sulfuric acid or other 
strong mineral acids and the reaction generates considerable 
heat; the mixture boils. 
13 Method of Manufacture 
Ammonia is obtained commercially chiefly by synthesis from its 
constituent elements, nitrogen and hydrogen, which are 
combined under high pressure and temperature in the presence 
of a catalyst. Ammonia solution is produced by dissolving 
ammonia gas in water. 
14 Safety 
Ingestion of strong solutions of ammonia is very harmful and 
causes severe pain in the mouth, throat, and gastrointestinal 
tract as well as severe local edema with cough, vomiting, and 
shock. Burns to the esophagus and stomach may result in 
perforation. Inhalation of the vapor causes sneezing, coughing, 
and, in high concentration, pulmonary edema. Asphyxia has 
been reported. The vapor is irritant to the eyes. Strong solutions 
are harmful when applied to the conjunctiva and mucous 
membranes. Topical application of even dilute ammonia 
solutions, used to treat insect bites, has caused burns, 
particularly when used with a subsequent dressing.(24)

When used as an excipient, ammonia solution is generally 
present in a formulation in a highly diluted form. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Care should be used in 
handling strong or concentrated ammonia solutions because of 
the caustic nature of the solution and the irritating properties of 
its vapor. Before containers are opened, they should be well 
cooled. The closure should be covered with a cloth or similar 
material while opening. Ammonia solution should not be tasted 
and inhalation of the vapor should be avoided. Ammonia 
solution should be handled in a fume cupboard. Eye protection, 
gloves, and a respirator are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral suspensions, 
topical preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dilute ammonia solution. 
Dilute ammonia solution 
Synonyms: ammonia water. 
Specific gravity: 0.950.96 
Comments: several pharmacopeias include monographs for 
dilute ammonia solution. The JP 2001, for example, states 
that ammonia water contains not less than 9.5% and not 
more than 10.5% w/v of ammonia (NH3). 
18 Comments 
Where ammonia solution is prescribed therapeutically, dilute 
ammonia solution should be dispensed or supplied. 
The EINECS number for ammonia solution is 231-635-3. 
19 Specific References 
1 Frohman IG. Treatment of physalia stings. J Am Med Assoc 1996; 
197: 733. 
2 Beare JD, Wilson RS, Marsh RJ. Ammonia burns of the eye: an old 
weapon in new hands. Br Med J 1988; 296: 590. 
3 Payne MP, Delic JI. Ammonia. In: Toxicity Review 24. London: 
HMSO, 1991: 112. 
4 Leduc D, Gris P, Lheureux P, et al. Acute and long term respiratory 
damage following inhalation of ammonia. Thorax 1992; 47: 755 
757. 
20 General References 

21 Authors 
PJ Sheskey. 
22 Date of Revision 
12 August 2005. 
Ammonia Solution 45

Ammonium Alginate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Alginic acid, ammonium salt; ammonium polymannuronate; 
E404; Keltose. 
3 Chemical Name and CAS Registry Number 
Ammonium alginate [9005-34-9] 
4 Empirical Formula and Molecular Weight 
(C6H11NO6)n 193.16 (calculated) 
217 (actual, average) 
Ammonium alginate is the ammonium salt of alginic acid. 
5 Structural Formula 
The number and sequence of the mannuronate and 
glucuronate residues shown above vary in the naturally 
occurring alginate. The associated water molecules are not 
shown. 
6 Functional Category 
Diluent; emulsifier; film-former; humectant; stabilizer; thickener; 
thickening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ammonium alginate is widely used in foods as a stabilizer, 
thickener and emulsifier. It is also used in pharmaceutical 
preparations as a color-diluent, emulsifier, film-former, and 
humectant. 
8 Description 
Ammonium alginate occurs as white to yellowish brown 
filamentous, grainy, granular, or powdered forms. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Solubility: dissolves slowly in water to form a viscous solution; 
insoluble in ethanol and in ether. 
Moisture content: not more than 15% at 1058C for 4 hours. 
11 Stability and Storage Conditions 
Ammonium alginate is a hygroscopic material, although it is 
stable if stored at low relative humidities and cool temperatures. 
12 Incompatibilities 
Incompatible with oxidizing agents and strong acids and 
alkalis. 
13 Method of Manufacture 

14 Safety 
Ammonium alginate is widely used in cosmetics and food 
products, and also in pharmaceutical formulations such as 
tablets. It is generally regarded as a nontoxic and nonirritant 
material, although excessive oral consumption may be harmful. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. Eye protection, gloves, 
and a dust respirator are recommended. 
16 Regulatory Status 
GRAS listed. Accepted in Europe for use as a food additive. 
Included in the FDA Inactive Ingredients Guide (oral, tablets). 
17 Related Substances 
Alginic acid; calcium alginate; potassium alginate; propylene 
glycol alginate; sodium alginate. 
18 Comments 
Alginates are commonly used in wound dressings.(1) Chitosan 
and alginates have been used together to produce sponges for 
use as wound dressings, or matrices for tissue engineering.(2) 
Alginate microspheres have been produced by internal gelation 
using emulsification methods.(3) 
Although not included in any pharmacopeias, a specification 
for ammonium alginate is contained in the Food Chemicals 
Codex (FCC), see Table I.

Table I: FCC specification for ammonium alginate.(4) 
Test FCC 1996(4) 
Identification . 
Arsenic 43 mg/kg 
Ash 44.0% after drying 
Heavy metals (as Pb) 40.002% 
Lead 45 mg/kg 
Loss on drying 415.0% 
Assay 18.021.0% of CO2, corresponding to 
88.7103.6% ammonium alginate 
19 Specific References 
1 Morgan D. Woundswhat should a dressing formulary include? 
Hosp Pharm 2002; 9(9): 261266. 
2 Lai HL, Abu Khalil A, Craig DQ. The preparation and 
characterization of drug-loaded alginate and chitosan sponges. 
Int J Pharm 2003; 251(12): 175181. 
3 Chan LW, Lee HY, Heng PW. Production of alginate microspheres 
by internal gelation using an emulsification method. Int J Pharm 
2002; 242(12): 259262. 
4 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 24. 
20 General References 

21 Authors 
D Thassu, S Shah. 
22 Date of Revision 
15 August 2005. 
Ammonium Alginate 47

Ascorbic Acid 
1 Nonproprietary Names 
BP: Ascorbic acid 
JP: Ascorbic acid 
PhEur: Acidum ascorbicum 
USP: Ascorbic acid 
2 Synonyms 
C-97; cevitamic acid; 2,3-didehydro-L-threo-hexono-1,4-lactone; 
E300; 3-oxo-L-gulofuranolactone, enol form; vitamin C. 
3 Chemical Name and CAS Registry Number 
L-(.)-Ascorbic acid [50-81-7] 
4 Empirical Formula and Molecular Weight 
C6H8O6 176.13 
5 Structural Formula 
6 Functional Category 
Antioxidant; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ascorbic acid is used as an antioxidant in aqueous pharmaceutical 
formulations at a concentration of 0.010.1% w/v. 
Ascorbic acid has been used to adjust the pH of solutions for 
injection, and as an adjunct for oral liquids. It is also widely 
used in foods as an antioxidant. Ascorbic acid has also proven 
useful as a stabilizing agent in mixed micelles containing 
tetrazepam.(1) 
8 Description 
Ascorbic acid occurs as a white to light-yellow-colored, 
nonhygroscopic, odorless, crystalline powder or colorless 
crystals with a sharp, acidic taste. It gradually darkens in color 
upon exposure to light. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ascorbic acid. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters  .  
Specific rotation . 20.58 to . 20.58 to . 20.58 to 
(10% w/v solution) . 21.58 . 21.58 . 21.58 
Residue on ignition 40.10%  40.1% 
pH 2.22.5 2.12.6  
Sulfated ash  40.1%  
Copper  45 ppm  
Heavy metals 420 ppm 410 ppm 40.002% 
Loss on drying 40.20%   
Iron  42 ppm  
Oxalic acid  .  
Appearance of 
solution 
. .  
Organic volatile 
impurities 
  . 
Assay 599.0% 99.0100.5% 99.0100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.12.6 (5% w/v aqueous solution) 
Density (bulk): 
0.70.9 g/cm3 for crystalline material; 
0.50.7 g/cm3 for powder. 
Density (particle): 1.65 g/cm3 
Density (tapped): 
1.01.2 g/cm3 for crystalline material; 
0.91.1 g/cm3 for powder. 
Density (true): 1.688 g/cm3 
Dissociation constant: 
pKa1 = 4.17; 
pKa2 = 11.57. 
Melting point: 1908C (with decomposition) 
Moisture content: 0.1% w/w 
Solubility: see Table II. 
Table II: Solubility of ascorbic acid. 
Solvent Solubility at 208C 
Chloroform Practically insoluble 
Ethanol 1 in 50 
Ethanol (95%) 1 in 25 
Ether Practically insoluble 
Fixed oils Practically insoluble 
Glycerin 1 in 1000 
Propylene glycol 1 in 20 
Water 1 in 3.5

SEM: 1 
Excipient: Ascorbic acid USP (fine powder) 
Manufacturer: Pfizer Ltd 
Lot No.: 9A-3/G92040-CO 146 
Magnification: 120 Voltage: 20 kV 
SEM: 2 
Excipient: Ascorbic acid USP (fine powder) 
Manufacturer: Pfizer Ltd 
Lot No.: 9A-3/G92040-CO 146 
Magnification: 600 Voltage: 20 kV 
SEM: 3 
Excipient: Ascorbic acid USP (fine granular) 
Manufacturer: Pfizer Ltd 
Lot No.: 9A-2/G01280-CO 148 
Magnification: 120 Voltage: 20 kV 
11 Stability and Storage Conditions 
In powder form, ascorbic acid is relatively stable in air. In the 
absence of oxygen and other oxidizing agents it is also heat 
stable. Ascorbic acid is unstable in solution, especially alkaline 
solution, readily undergoing oxidation on exposure to the 
air.(2,3) The oxidation process is accelerated by light and heat 
and is catalyzed by traces of copper and iron. Ascorbic acid 
solutions exhibit maximum stability at about pH 5.4. Solutions 
may be sterilized by filtration. 
The bulk material should be stored in a well-closed 
nonmetallic container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Incompatible with alkalis, heavy metal ions, especially copper 
and iron, oxidizing materials, methenamine, phenylephrine 
hydrochloride, pyrilamine maleate, salicylamide, sodium 
nitrite, sodium salicylate, theobromine salicylate, and picotamide.(
4,5) Additionally, ascorbic acid has been found to 
interfere with certain colorimetric assays by reducing the 
intensity of the color produced.(6) 
13 Method of Manufacture 
Ascorbic acid is prepared synthetically or extracted from 
various vegetable sources in which it occurs naturally, such as 
rose hips, blackcurrants, the juice of citrus fruits, and the ripe 
fruit of Capsicum annuum L. A common synthetic procedure 
involves the hydrogenation of D-glucose to D-sorbitol, followed 
by oxidation using Acetobacter suboxydans to form L-sorbose. 
A carboxyl group is then added at C1 by air oxidation of the 
diacetone derivative of L-sorbose and the resulting diacetone-2- 
keto-L-gulonic acid is converted to L-ascorbic acid by heating 
with hydrochloric acid. 
Ascorbic Acid 49

14 Safety 
Ascorbic acid is an essential part of the human diet, with 40 mg 
being the recommended daily dose in the UK(7) and 60 mg in the 
US.(8) However, these figures are controversial, with some 
advocating doses of 150 or 250 mg daily. Megadoses of 10 g 
daily have also been suggested to prevent illness although such 
large doses are now generally considered to be potentially 
harmful.(911) 
The body can absorb about 500 mg of ascorbic acid daily 
with any excess immediately excreted by the kidneys. Large 
doses may cause diarrhea or other gastrointestinal disturbances. 
Damage to the teeth has also been reported.(12) 
However, no adverse effects have been reported at the levels 
employed as an antioxidant in foods and pharmaceuticals. The 
WHO has set an acceptable daily intake of ascorbic acid, 
potassium ascorbate, and sodium ascorbate, as antioxidants in 
food, at up to 15 mg/kg body-weight in addition to that 
naturally present in food.(13) 
LD50 (mouse, IV): 0.52 g/kg(14) 
LD50 (mouse, oral): 3.37 g/kg 
LD50 (rat, oral): 11.9 g/kg 
15 Handling Precautions 
Ascorbic acid may be harmful if ingested in large quantities and 
may be irritating to the eyes. Observe normal precautions 
appropriate to the circumstances and quantity of material 
handled. Eye protection and rubber or plastic gloves are 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (inhalations, 
injections, oral capsules, suspensions, tablets, topical preparations, 
and suppositories). Included in medicines licensed in the 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Ascorbyl palmitate; erythorbic acid; sodium ascorbate. 
18 Comments 
Many dosage forms for ascorbic acid have been developed for 
its administration to patients, including microencapsulation.(15) 
A specification for ascorbic acid is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for ascorbic acid is 200-066-2. 
19 Specific References 
1 Hammad MA, Muller BW. Solubility and stability of tetrazepam in 
mixed micelles. Eur J Pharm Sci 1998; 7: 4955. 
2 Hajratwala BR. Stability of ascorbic acid. STP Pharma 1985; 1: 
281286. 
3 Touitou E, Gilhar D, Alhaique F, et al. Ascorbic acid in aqueous 
solution: bathochromic shift in dilution and degradation. Int J 
Pharm 1992; 78: 8587. 
4 Botha SA, Lo. tter AP, du Preez JFL. DSC screening for drugdrug 
interactions in polypharmaceuticals intended for the alleviation of 
the symptoms of colds and flu. Drug Dev Ind Pharm 1987; 13: 
345354. 
5 Mura P, Bettinetti GP, Faucci MT, et al. Differential scanning 
calorimetry in compatibility testing of picotamide with pharmaceutical 
excipients. Thermochim Acta 1998; 321: 5965. 
6 Krishnan G, Talwar SK, Sharma SC, Sharma RG. Estimation of 
phenylephrine hydrochloride in multi-component pharmaceutical 
preparations. Eastern Pharmacist 1990; 33: 143145. 
7 Department of Health. Dietary reference values for food energy 
and nutrients for the United Kingdom: report of the panel on 
dietary reference values of the committee on medical aspects of 
food policy. Report on Health and Social Subjects 41. London: 
HMSO, 1991. 
8 Subcommittee on the tenth edition of the RDAs, Food and 
Nutrition Board, Commission on Life Sciences. National Research 
Council. Recommended Dietary Allowances, 10th edn. Washington, 
DC: National Academy Press, 1989. 
9 Ovesen L. Vitamin therapy in the absence of obvious deficiency: 
what is the evidence? Drugs 1984; 27: 148170. 
10 Bates CJ. Is there a maximum safe dose of vitamin C (ascorbic 
acid)? Br Med J 1992; 305: 32. 
11 Mason P. Vitamin C. Dietary Supplements, 2nd edn. London: 
Pharmaceutical Press, 2001: 227233. 
12 Giunta JL. Dental erosion resulting from chewable vitamin C 
tablets. J Am Dent Assoc 1983; 107: 253256. 
13 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
14 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 309310. 
15 Esposito E, Cervellayi F, Menegatti E, et al. Spray-dried Eudragit 
microparticles as encapsulation devices for vitamin C. Int J Pharm 
2002; 242: 329334. 
20 General References 
Abramovici B, Molard F, Seguin B, Gromenil JC. Comparative study of 
the tabletability of different grades of vitamin C [in French]. STP 
Pharma 1987; 3: 1622. 
Allwood MC. Factors influencing the stability of ascorbic acid in total 
parenteral nutrition infusions. J Clin Hosp Pharm 1984; 9: 7585. 
Bhagavan HN,Wolkoff BI. Correlation between the disintegration time 
and the bioavailability of vitamin C tablets. Pharm Res 1993; 10: 
239242. 
Davies MB, Austin J, Partridge DA. Vitamin CIts Chemistry and 
Biochemistry. London: Royal Society of Chemistry, 1991. 
Hu F, Wang H, Wu X. Effects of different adhesives on the stability of 
vitamin C buccal tablets. Zhejiang Yike Daxue Xuebao 1997; 26: 
108110. 
Krishna G, Mao J, Almassian B. Development of a parenteral 
formulation of an investigational anticancer drug, 3-aminopyridine-
2-carboxaldehyde thiosemicarbazone. Pharm Dev Technol 
1999; 4: 7180. 
Nebuloni M, Pifferi G, Munna E. Thermal analysis in preformulation 
studies of a lyophilized form of an antibiotic. Boll Chim Farm 1996; 
135: 94100. 
Pinsuwan S, Alvarez-Nunez FA, et al. Degradation kinetics of 4- 
dedimethylamino sancycline, a new anti-tumor agent, in aqueous 
solutions. Int J Pharm 1999; 181: 3140. 
Saleh SI, Stamm A. Evaluation of some directly compressible L-ascorbic 
acid forms. STP Pharma 1988; 4: 1014. 
Saleh SI, Stamm A. Contribution to the preparation of a directly 
compressible L-ascorbic acid granular form: comparison of granules 
prepared by three granulation methods and evaluation of their 
corresponding tablets. STP Pharma 1988; 4: 182187. 
Seta Y, Higuchi F, Otsuka T, et al. Preparation and pharmacological 
evaluation of Captopril sustained-release dosage forms using oily 
semisolid matrix. Int J Pharm 1988; 41: 255262. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
12 August 2005. 
50 Ascorbic Acid

Ascorbyl Palmitate 
1 Nonproprietary Names 
BP: Ascorbyl palmitate 
PhEur: Ascorbylis palmitas 
USPNF: Ascorbyl palmitate 
2 Synonyms 
L-Ascorbic acid 6-palmitate; E304; 3-oxo-L-gulofuranolactone 
6-palmitate; vitamin C palmitate. 
3 Chemical Name and CAS Registry Number 
L-Ascorbic acid 6-hexadecanoate [137-66-6] 
4 Empirical Formula and Molecular Weight 
C22H38O7 414.54 
5 Structural Formula 
6 Functional Category 
Antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ascorbyl palmitate is primarily used either alone or in 
combination with alpha tocopherol as a stabilizer for oils in 
oral pharmaceutical formulations and food products; generally 
0.05% w/v is used. It may also be used in oral and topical 
preparations as an antioxidant for drugs unstable to oxygen. 
The combination of ascorbyl palmitate with alpha tocopherol 
shows marked synergism, which increases the effect of the 
components and allows the amount used to be reduced. 
The solubility of ascorbyl palmitate in alcohol permits it to 
be used in nonaqueous and aqueous systems and emulsions. 
8 Description 
Ascorbyl palmitate is a practically odorless, white to yellowish 
powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ascorbyl palmitate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Appearance of solution .  
Melting range  1071178C 
Specific rotation (10% w/v in 
methanol) 
.218 to .248 .218 to .248 
Loss on drying 41.0% 42.0% 
Residue on ignition  40.1% 
Sulfated ash 40.1%  
Heavy metals 410 ppm 40.001% 
Organic volatile impurities  . 
Assay (dried basis) 98.0100.5% 95.0100.5% 
10 Typical Properties 
Solubility: see Table II. 
Table II: Solubility of ascorbyl palmitate. 
Solvent Solubility at 208C unless otherwise stated(1) 
Acetone 1 in 15 
Chloroform 1 in 3300 
1 in 11 at 608C 
Cottonseed oil 1 in 1670 
Ethanol 1 in 8 
1 in 1.7 at 708C 
Ethanol (95%) 1 in 9.3 
Ethanol (50%) 1 in 2500 
Ether 1 in 132 
Methanol 1 in 5.5 
1 in 1.7 at 608C 
Olive oil 1 in 3300 
Peanut oil 1 in 3300 
Propan-2-ol 1 in 20 
1 in 5 at 708C 
Sunflower oil 1 in 3300 
Water Practically insoluble 
1 in 500 at 708C 
1 in 100 at 1008C 
11 Stability and Storage Conditions 
Ascorbyl palmitate is stable in the dry state, but is gradually 
oxidized and becomes discolored when exposed to light and 
high humidity. In an unopened container, stored in a cool place, 
it has a shelf life of at least 12 months. During processing, 
temperatures greater than 658C should be avoided. 
The bulk material should be stored in an airtight container 
at 8158C, protected from light.

12 Incompatibilities 
Incompatibilities are known with oxidizing agents, e.g., in 
solution oxidation is catalyzed by trace metal ions such as Cu2. 
and Fe3.. 
13 Method of Manufacture 
Ascorbyl palmitate is prepared synthetically by the reaction of 
ascorbic acid with sulfuric acid followed by reesterification 
with palmitic acid. 
14 Safety 
Ascorbyl palmitate is used in oral pharmaceutical formulations 
and food products and is generally regarded as an essentially 
nontoxic and nonirritant material. The WHO has set an 
estimated acceptable daily intake for ascorbyl palmitate at up 
to 1.25 mg/kg body-weight.(2) 
LD50 (mouse, oral): 25 g/kg(3) 
LD50 (rat, oral): 10 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Ascorbyl palmitate dust may 
cause irritation to the eyes and respiratory tract. Eye protection 
is recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral, rectal, 
topical preparations). Included in nonparenteral medicines 
licensed in the UK. 
17 Related Substances 
Ascorbic acid; sodium ascorbate. 
18 Comments 
The EINECS number for ascorbyl palmitate is 205-305-4. 
In order to maximize the stability and efficacy of ascorbyl 
palmitate the following precautions are recommended: stainless 
steel, enamel, or glass should be used; deaeration (vacuum) 
procedures and inert gas treatment are recommended where 
feasible; protect from light and radiant energy. 
The formation of ascorbyl palmitate vesicles (Aspasomes) 
and their pharmaceutical applications has recently been 
investigated.(4) 
19 Specific References 
1 Kla. ui H. Tocopherol, carotene and ascorbyl palmitate. Int 
Flavours Food Addit 1976; 7(4): 165172. 
2 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
3 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987. 
4 Gopinath D, Ravi D, Rao BR, et al. Ascorbyl palmitate vesicles 
(Aspasomes): formation, characterization and applications. Int J 
Pharm 2004; 271: 95113. 
20 General References 
Austria R, Semenzato A, Bettero A. Stability of vitamin C derivatives in 
solution and topical formulations. J Pharm Biomed Anal 1997; 15: 
795801. 
Daniel JW. Metabolic aspects of antioxidants and preservatives. 
Xenobiotica 1986; 16(1011): 10731078. 
Johnson DM, Gu LC. Autoxidation and antioxidants. In: Swarbrick J, 
Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 1. 
New York: Marcel Dekker, 1988: 415449. 
Pongracz G. Antioxidant mixtures for use in food. Int J Vitam Nutr Res 
1973; 43: 517525. 
S.
piclin P, Gas.perlin M, Kmetec V. Stability of ascorbyl palmitate in 
topical microemulsions. Int J Pharm 2001; 222: 271279. 
Weller PJ, Newman CM, Middleton KR, Wicker SM. Stability of a 
novel dithranol ointment formulation, containing ascorbyl palmitate 
as an anti-oxidant. J Clin Pharm Ther 1990; 15: 419423. 
21 Authors 
PJ Weller. 
22 Date of Revision 
4 August 2005. 
52 Ascorbyl Palmitate

Aspartame 
1 Nonproprietary Names 
BP: Aspartame 
PhEur: Aspartamum 
USPNF: Aspartame 
2 Synonyms 
3-Amino-N-(a-carboxyphenethyl)succinamic acid N-methyl 
ester; 3-amino-N-(a-methoxycarbonylphenethyl)succinamic 
acid; APM; aspartyl phenylamine methyl ester; Canderel; 
E951; Equal; methyl N-a-L-aspartyl-L-phenylalaninate; 
NutraSweet; Pal Sweet; Pal Sweet Diet; Sanecta; SC-18862; 
Tri-Sweet. 
3 Chemical Name and CAS Registry Number 
N-a-L-Aspartyl-L-phenylalanine 1-methyl ester [22839-47-0] 
4 Empirical Formula and Molecular Weight 
C14H18N2O5 294.31 
5 Structural Formula 
6 Functional Category 
Sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Aspartame is used as an intense sweetening agent in beverage 
products, food products, and table-top sweeteners, and in 
pharmaceutical preparations including tablets,(1,2) powder 
mixes, and vitamin preparations. It enhances flavor systems 
and can be used to mask some unpleasant taste characteristics; 
the approximate sweetening power is 180200 times that of 
sucrose. 
Unlike some other intense sweeteners, aspartame is metabolized 
in the body and consequently has some nutritive value: 
1 g provides approximately 17 kJ (4 kcal). However, in practice, 
the small quantity of aspartame consumed provides a minimal 
nutritive effect. 
Therapeutically, aspartame has also been used in the 
treatment of sickle cell anemia.(3) 
8 Description 
Aspartame occurs as an off white, almost odorless crystalline 
powder with an intensely sweet taste. 
SEM: 1 
Excipient: Aspartame 
Magnification: 70 Voltage: 3kV 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for aspartame. 
Test PhEur 2005 USPNF 23 
Characters .  
Identification . . 
Appearance of solution .  
Conductivity 430 mS/cm  
Specific optical rotation .14.58 to .16.58 .14.58 to .16.58 
Related substances .  
Heavy metals 410 ppm 40.001% 
Loss on drying 44.5% 44.5% 
Sulfated ash 40.2% 40.2% 
Impurities .  
Transmittance  . 
Limit of 5-benzyl-3,6-dioxo- 
2-piperazineacetic acid 
 41.5% 
Organic volatile impurities  . 
Assay 98.0102.0% 98.0102.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 4.56.0 (0.8% w/v aqueous solution). 
Brittle fracture index: 1.05(4)

Bonding index: 
0.8102 (worst case)(4) 
2.3102 (best case)(4) 
Flowability: 44% (Carr compressibility index)(4) 
Density (bulk): 
0.50.7 g/cm3 for granular grade; 
0.20.4 g/cm3 for powder grade; 
0.17 g/cm3 (Spectrum Quality Products).(4) 
Density (tapped): 0.29 g/cm3 (Spectrum Quality Products)(4) 
Density (true): 1.347 g/cm3 
Effective angle of internal friction: 43.08(4) 
Melting point: 2462478C 
Solubility: slightly soluble in ethanol (95%); sparingly soluble 
in water. At 208C the solubility is 1% w/v at the isoelectric 
point (pH 5.2). Solubility increases at higher temperature 
and at more acidic pH, e.g., at pH 2 and 208C solubility is 
10% w/v. 
Specific rotation [a]D
22: 2.38 in 1N HCl 
11 Stability and Storage Conditions 
Aspartame is stable in dry conditions. In the presence of 
moisture, hydrolysis occurs to form the degradation products 
L-aspartyl-L-phenylalanine and 3-benzyl-6-carboxymethyl-2,5- 
diketopiperazine. A third-degradation product is also known, 
b-L-aspartyl-L-phenylalanine methyl ester. For the stability 
profile at 258C in aqueous buffers, see Figure 1. 
Stability in aqueous solutions has been enhanced by the 
addition of cyclodextrins,(5,6) and by the addition of polyethylene 
glycol 400 at pH 2.(7) However, at pH 3.54.5 stability 
is not enhanced by the replacement of water with organic 
solvents.(8) 
Aspartame degradation also occurs during prolonged heat 
treatment; losses of aspartame may be minimized by using 
processes that employ high temperatures for a short time 
followed by rapid cooling. 
The bulk material should be stored in a well-closed 
container, in a cool, dry place. 
Figure 1: Stability profile of aspartame in aqueous buffers at 258C.(9) 
12 Incompatibilities 
Differential scanning calorimetry experiments with some 
directly compressible tablet excipients suggests that aspartame 
is incompatible with dibasic calcium phosphate and also with 
the lubricant magnesium stearate.(10) Reactions between 
aspartame and sugar alcohols are also known. 
13 Method of Manufacture 
Aspartame is produced by coupling together L-phenylalanine 
(or L-phenylalanine methyl ester) and L-aspartic acid, either 
chemically or enzymatically. The former procedure yields both 
the sweet a-aspartame and nonsweet b-aspartame from which 
the a-aspartame has to be separated and purified. The 
enzymatic process yields only a-aspartame. 
14 Safety 
Aspartame is widely used in oral pharmaceutical formulations, 
beverages, and food products as an intense sweetener and is 
generally regarded as a nontoxic material. However, the use of 
aspartame has been of some concern owing to the formation of 
the potentially toxic metabolites methanol, aspartic acid, and 
phenylalanine. Of these materials, only phenylalanine is 
produced in sufficient quantities, at normal aspartame intake 
levels, to cause concern. In the normal healthy individual any 
phenylalanine produced is harmless, however it is recommended 
that aspartame be avoided or its intake restricted by 
those persons with phenylketonuria.(11) 
The WHO has set an acceptable daily intake for aspartame 
at up to 40 mg/kg body-weight.(12) Additionally, the acceptable 
daily intake of diketopiperazine (an impurity found in 
aspartame) has been set by the WHO at up to 7.5 mg/kg 
body-weight.(13) 
A number of adverse effects have been reported following 
the consumption of aspartame,(11,13) particularly in individuals 
who drink large quantities (up to 8 liters per day in one case) of 
aspartame-sweetened beverages. Reported adverse effects 
include: headaches;(14) grand mal seizure;(15) memory loss;(16) 
gastrointestinal symptoms; and dermatological symptoms. 
Although aspartame has been reported to cause hyperactivity 
and behavioral problems in children, a double-blind 
controlled trial of 48 preschool-age children fed diets containing 
a daily intake of 38  13 mg/kg body-weight of aspartame 
for 3 weeks showed no adverse effects attributable to 
aspartame, or dietary sucrose, on childrens behavior or 
cognitive function.(17) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Measures should be taken to 
minimize the potential for dust explosion. Eye protection is 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral powder 
for reconstitution, buccal patch, granules, film-coated, and 
tablets). Included in nonparenteral medicines licensed in the 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
54 Aspartame

17 Related Substances 
Alitame. 
18 Comments 
The intensity of sweeteners relative to sucrose depends upon 
their concentration, temperature of tasting, and pH, and on the 
flavor and texture of the product concerned. 
Intense sweetening agents will not replace the bulk, textural, 
or preservative characteristics of sugar, if sugar is removed from 
a formulation. 
Synergistic effects for combinations of sweeteners have been 
reported, e.g., aspartame with acesulfame potassium. 
Aspartame can cause browning when used at high 
temperatures. 
A specification for aspartame is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Joachim J, Kalantzis G, Delonca H, et al. The compression of 
effervescent aspartame tablets: the influence of particle size on the 
strain applied on the punches during compression [in French]. J 
Pharm Belg 1987; 42: 1728. 
2 Joachim J, Kalantzis G, Delonca H, et al. The compression of 
effervescent aspartame tablets: the influence of particle size and 
temperature on the effervescence time and carbon dioxide 
liberation kinetics [in French]. J Pharm Belg 1987; 42: 303314. 
3 Manion CV, Howard J, Ogle B, et al. Aspartame effect in sickle cell 
anemia. Clin Pharmacol Ther 2001; 69: 346355. 
4 Mullarney MP, Hancock BC, Carlson GT, et al. The powder flow 
and compact mechanical properties of sucrose and three highintensity 
sweeteners used in chewable tablets. Int J Pharm 2003; 
257(12): 227236. 
5 Brewster ME, Loftsson T, Baldvinsdo. ttir J, Bodor N. Stabilization 
of aspartame by cyclodextrins. Int J Pharm 1991; 75: R5R8. 
6 Prankerd RJ, Stone HW, Sloan KB, Perrin JH. Degradation of 
aspartame in acidic aqueous media and its stabilization by 
complexation with cyclodextrins or modified cyclodextrins. Int J 
Pharm 1992; 88: 189199. 
7 Yalkowsky SH, Davis E, Clark T. Stabilization of aspartame by 
polyethylene glycol 400. J Pharm Sci 1993; 82: 978. 
8 Sanyude S, Locock RA, Pagliaro LA. Stability of aspartame in 
water: organic solvent mixtures with different dielectric constants. 
J Pharm Sci 1991; 80: 674676. 
9 The NutraSweet Company. Technical literature: NutraSweet 
technical bulletin, 1991. 
10 El-Shattawy HE, Peck GE, Kildsig DO. Aspartame-direct compression 
excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7: 
605619. 
11 Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical 
excipients: adverse effects associated with inactive ingredients in 
drug products (part II). Med Toxicol 1988; 3: 209240. 
12 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-fifth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1981; No. 669. 
13 Butchko HH, Kotsonis FN. Aspartame: review of recent research. 
Comments Toxicol 1989; 3(4): 253278. 
14 Schiffman SS, Buckley E, Sampson HA, et al. Aspartame and 
susceptibility to headache. N Engl J Med 1987; 317: 11811185. 
15 Wurtman RJ. Aspartame: possible effect on seizure susceptibility 
[letter]. Lancet 1985; ii: 1060. 
16 Anonymous. Sweetener blamed for mental illnesses. New Scientist 
1988; February 18: 33. 
17 Wolraich ML, Lindgreen SD, Stumbo PJ, et al. Effects of diets high 
in sucrose or aspartame on the behavior and cognitive performance 
of children. N Engl J Med 1994; 330: 301307. 
20 General References 
Marie S. Sweeteners. In: Smith J, ed. Food Additives Users Handbook. 
Glasgow: Blackie, 1991: 4774. 
Roy GM. Taste masking in oral pharmaceuticals. Pharm Technol Eur 
1994; 6(6): 24, 2628, 3032, 34, 35. 
Stegink LD, Filer LJ, eds. Aspartame, Physiology and Biochemistry. 
New York: Marcel Dekker, 1984. 
21 Authors 
H Wang. 
22 Date of Revision 
12 August 2005. 
Aspartame 55

Attapulgite 
1 Nonproprietary Names 
BP: Attapulgite 
2 Synonyms 
Actapulgite; Attaclay; Attacote; Attagel; attapulgus; palygorscite; 
palygorskite; Pharmsorb Regular. 
3 Chemical Name and CAS Registry Number 
Attapulgite [12174-11-7] 
4 Empirical Formula and Molecular Weight 
Attapulgite is a purified native hydrated magnesium aluminum 
silicate consisting of the clay mineral palygorskite, with the 
empirical formula Mg(Al0.51Fe00.5)Si4O10(OH)4H2O. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Adsorbent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Attapulgite is widely used as an adsorbent in solid dosage 
forms. Colloidal clays (such as attapulgite) absorb considerable 
amounts of water to form gels and in concentrations of 25% 
w/v usually form oil-in-water emulsions. Activated attapulgite, 
which is attapulgite that has been carefully heated to increase its 
absorptive capacity, is used therapeutically as an adjunct in the 
management of diarrhea. 
8 Description 
Attapulgite occurs as a light cream colored, very fine powder. 
Particle size ranges depend on the grade and manufacturer. 
9 Pharmacopeial Specifications 
See Table I. See also Section 17. 
10 Typical Properties 
Acidity/alkalinity: pH = 9.5 (5% w/v aqueous suspension) 
Angle of repose: 37.245.28(1) 
Density: 2.2 g/cm3 
Density (tapped): 0.33 g/cm3(1) 
Flowability: 20.929.6% (Carr compressibility index)(1) 
Particle size distribution: 
<2 mm in size for powder; 
25 mm in size for aggregate.(1) 
Table I: Pharmacopeial specifications for attapulgite. 
Test BP 2004 
Identification . 
Characters . 
Acidity or alkalinity (5% w/v aqueous 
suspension) 
7.09.5 
Adsorptive capacity 514% 
Arsenic 48 ppm 
Heavy metals 420 ppm 
Acid-insoluble matter 412.5% 
Water-soluble matter 40.5% 
Loss on drying 417.0% 
Loss on ignition 15.027.0% 
11 Stability and Storage Conditions 
Attapulgite can adsorb water. It should be stored in an airtight 
container in a cool, dry, location. 
12 Incompatibilities 
Attapulgite may decrease the bioavailability of some drugs 
such as loperamide(2) and riboflavin.(3) Oxidation of hydrocortisone 
is increased in the presence of attapulgite.(4) 
13 Method of Manufacture 
Attapulgite occurs naturally as the mineral palygorskite. 
14 Safety 
Attapulgite is widely used in pharmaceutical formulations and 
is generally regarded as an essentially nontoxic and nonirritant 
material. It is not absorbed following oral administration. In 
oral preparations, activated attapulgite up to 9 g is used in daily 
divided doses as an adjunct in the management of diarrhea.(5) 
LD50 (rat, IP): 0.34 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask are recommended. Attapulgite should be handled in 
a well-ventilated environment and dust generation should be 
minimized. When heated to decomposition, attapulgite emits 
acrid smoke and irritating fumes. 
16 Regulatory Status 
Included in nonparenteral medicines licensed in a number of 
countries worldwide including the UK and US. 
17 Related Substances 
Activated attapulgite; magnesium aluminum silicate.

Activated attapulgite 
Comments: activated attapulgite is a processed native magnesium 
aluminum silicate that has been carefully heated to 
increase its adsorptive capacity. Monographs for activated 
attapulgite are included in the BP 2004, USP 28, and other 
pharmacopeias. The USP 28 also includes a monograph for 
colloidal activated attapulgite. 
18 Comments 
The EINECS number for attapulgite is 302-243-0. 
19 Specific References 
1 Viseras C, Lo. pez-Galindo A. Characteristics of pharmaceutical 
grade phyllosilicate powders. Pharm Dev Technol 2000; 5(1): 47 
52. 
2 Mboya SA, Bhargava HN. Adsorption and desorption of 
loperamide hydrochloride by activated attapulgites. Am J Health 
Syst Pharm 1995; 52: 28162818. 
3 Khalil SAH, Mortada LM, Shams-Eldeen MA, El-Khawas MM. 
Effect of attapulgite on the bioavailability of a model low dose 
drug (riboflavine) in humans. Drug Dev Ind Pharm 1987; 13: 
369382. 
4 Cornejo J, Hernosin MC, White JL, et al. Oxidative degradation of 
hydrocortisone in the presence of attapulgite. J Pharm Sci 1980; 
69: 945948. 
5 Sweetman SC, ed. Martindale: the Complete Drug Reference, 34th 
edn. London: Pharmaceutical Press, 2005: 1251. 
20 General References 
Anonymous. The silicates: attapulgite, kaolin, kieselguhr, magnesium 
trisilicate, pumice, talc. Int J Pharm Compound 1998; 2(2): 162 
163. 
Viseras C, Yebra A, Lo. pez-Galindo A. Characteristics of pharmaceutical 
grade phyllosilicate compacts. Pharm Dev Technol 2000; 5(1): 
5358. 
21 Authors 
A Palmieri. 
22 Date of Revision 
8 August 2005. 
Attapulgite 57

Bentonite 
1 Nonproprietary Names 
BP: Bentonite 
JP: Bentonite 
PhEur: Bentonitum 
USPNF: Bentonite 
2 Synonyms 
Albagel; E558; Magnabrite; mineral soap; Polargel; soap clay; 
taylorite; Veegum HS; wilkinite. 
3 Chemical Name and CAS Registry Number 
Bentonite [1302-78-9] 
4 Empirical Formula and Molecular Weight 
Al2O34SiO2H2O 359.16 
Bentonite is a native colloidal hydrated aluminum silicate 
consisting mainly of montmorillonite, Al2O34SiO2H2O; it 
may also contain calcium, magnesium, and iron. The average 
chemical analysis is expressed as oxides, see Table I, in 
comparison with magnesium aluminum silicate. 
Table I: Average chemical analysis of bentonite expressed as oxides 
in comparison with magnesium aluminum silicate. 
Bentonite Magnesium aluminum silicate 
Silicon dioxide 59.92% 61.1% 
Aluminum oxide 19.78% 9.3% 
Magnesium oxide 1.53% 13.7% 
Ferric oxide 2.96% 0.9% 
Calcium oxide 0.64% 2.7% 
Sodium oxide 2.06% 2.9% 
Potassium oxide 0.57% 0.3% 
5 Structural Formula 
The PhEur 2005 describes bentonite as a natural clay containing 
a high proportion of montmorillonite, a native hydrated 
aluminum silicate in which some aluminum and silicon atoms 
may be replaced by other atoms such as magnesium and iron. 
The USPNF 23 describes bentonite, purified benonite, and 
bentonite magma in three separate monographs. Bentonite is 
described as a native, colloidal, hydrated aluminum silicate; 
and purified bentonite is described as a colloidal montmorillonite 
that has been processed to remove grit and nonswellable 
ore compounds. 
See also Section 4. 
6 Functional Category 
Adsorbent; stabilizing agent; suspending agent; viscosityincreasing 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Bentonite is a naturally occurring hydrated aluminum silicate 
used primarily in the formulation of suspensions, gels, and sols, 
for topical pharmaceutical applications. It is also used to 
suspend powders in aqueous preparations and to prepare 
cream bases containing oil-in-water emulsifying agents. 
Bentonite may also be used in oral pharmaceutical preparations, 
cosmetics, and food products, see Section 18. In oral 
preparations, bentonite, and other similar silicate clays, can be 
used to adsorb cationic drugs and so retard their release.(13) 
Adsorbents are also used to mask the taste of certain drugs. See 
Table II. 
Bentonite has been investigated as a diagnostic agent for 
magnetic resonance imaging.(4) 
Therapeutically, bentonite has been investigated as an 
adsorbent for lithium poisoning.(5) 
8 Description 
Bentonite is a crystalline, claylike mineral, and is available as an 
odorless, pale buff, or cream to grayish-colored fine powder, 
which is free from grit. It consists of particles about 50150 mm 
in size along with numerous particles about 12 mm. Microscopic 
examination of samples stained with alcoholic methylene 
blue solution reveals strongly stained blue particles. 
Bentonite may have a slight earthy taste. 
SEM: 1 
Excipient: Bentonite 
Manufacturer: American Colloid Co. 
Lot No.: NMD 11780 
Magnification: 600 Voltage: 10 kV

SEM: 2 
Excipient: Bentonite 
Manufacturer: American Colloid Co. 
Lot No: NMD 11780 
Magnification: 2400 Voltage: 20 kV 
9 Pharmacopeial Specifications 
See Table III. 
Table III: Pharmacopeial specifications for bentonite. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . .  
Alkalinity  .  
Microbial limit  4103/g . 
Coarse particles  40.5%  
pH (2% w/v suspension) 9.010.5  9.510.5 
Loss on drying 5.010.0% 415% 5.08.0% 
Arsenic 42 ppm  45 ppm 
Lead   40.004% 
Heavy metals 450 ppm 450 ppm  
Organic volatile impurities   . 
Gel formation .  . 
Sedimentation volume  42mL  
Swelling power 520 mL 522 mL 524 mL 
Fineness of powder .  . 
The USPNF 23 also contains specifications for bentonite 
magma and purified bentonite. See Section 17. 
10 Typical Properties 
Acidity/alkalinity: pH = 9.510.5 for a 2% w/v aqueous 
suspension. 
Flowability: no flow. 
Hygroscopicity: bentonite is hygroscopic.(6) See also Figure 1. 
Moisture content: 512%. 
Solubility: practically insoluble in ethanol, fixed oils, glycerin, 
propan-2-ol, and water. Bentonite swells to about 12 times 
its original volume in water, to form viscous homogeneous 
suspensions, sols, or gels depending upon the concentration. 
Bentonite does not swell in organic solvents. Sols and gels 
may be conveniently prepared by sprinkling the bentonite 
on the surface of hot water and allowing to stand for 24 
hours, stirring occasionally when the bentonite has become 
thoroughly wetted. Water should not be added to bentonite 
alone, but bentonite may be satisfactorily dispersed in water 
if it is first triturated with glycerin or mixed with a powder 
such as zinc oxide. A 7% w/v aqueous suspension of 
bentonite is just pourable. See also Section 12. 
Viscosity (dynamic): 75225 mPa s (75225 cP) for a 5.5% w/v 
aqueous suspension at 258C. Viscosity increases with 
increasing concentration. 
11 Stability and Storage Conditions 
Bentonite is hygroscopic, and sorption of atmospheric water 
should be avoided. 
Aqueous bentonite suspensions may be sterilized by autoclaving. 
The solid material may be sterilized by maintaining it at 
1708C for 1 hour after drying at 1008C. 
Bentonite should be stored in an airtight container in a cool, 
dry place. 
Figure 1: Equilibrium, moisture content of bentonite USPNF. 
12 Incompatibilities 
Aqueous bentonite suspensions retain their viscosity above 
pH 6, but are precipitated by acids. Acid-washed bentonite 
Table II: Uses of bentonite. 
Use Concentration (%) 
Adsorbent (clarifying agent) 1.02.0 
Emulsion stabilizer 1.0 
Suspending agent 0.55.0 
Bentonite 59

does not have suspending properties. The addition of alkaline 
materials, such as magnesium oxide, increases gel formation. 
Addition of significant amounts of alcohol to aqueous 
preparations will precipitate bentonite, primarily by dehydration 
of the lattice structure; see also Section 18. 
Bentonite particles are negatively charged and flocculation 
occurs when electrolytes or positively charged suspensions are 
added. Bentonite is thus said to be incompatible with strong 
electrolytes, although this effect is sometimes used beneficially 
to clarify turbid liquids. 
The antimicrobial efficacy of cationic preservatives may be 
reduced in aqueous bentonite suspensions, but nonionic and 
anionic preservatives are unaffected.(7) 
Bentonite is incompatible with acriflavine hydrochloride. 
13 Method of Manufacture 
Bentonite is a native, colloidal, hydrated aluminum silicate, 
found in regions of Canada and the USA. The mined ore is 
processed to remove grit and nonswelling materials so that it is 
suitable for pharmaceutical applications. 
14 Safety 
Bentonite is mainly used in topical pharmaceutical formulations 
but has also been used in oral pharmaceutical preparations, 
food products, and cosmetics. 
Following oral administration, bentonite is not absorbed 
from the gastrointestinal tract. Bentonite is generally regarded 
as a nontoxic and nonirritant material. 
LD50 (rat, IV): 0.035 g/kg(8) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask are recommended. Bentonite should be handled in a 
well-ventilated environment and dust generation minimized. 
16 Regulatory Status 
Accepted in Europe as a food additive in certain applications. 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
tablets and suspensions, topical suspensions, controlled release 
transdermal films and vaginal suppositories). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Bentonite magma; kaolin; magnesium aluminum silicate; 
magnesium trisilicate; purified bentonite; talc. 
Bentonite magma 
Comments: a 5%w/w suspension of bentonite in purified water 
appears in some pharmacopeias, such as the USPNF 23. 
Purified bentonite 
Acidity/alkalinity: pH = 9.010.0 for a 5% w/w aqueous 
suspension. 
Viscosity (dynamic): 40200 mPa s (40200 cP) for a 5% w/w 
aqueous suspension. 
Comments: specifications for purified bentonite occur in some 
pharmacopeias such as the USPNF 23. Purified bentonite is 
bentonite that has been processed to remove grit and 
nonswellable ore components. 
18 Comments 
Bentonite may be used with concentrations of up to 30% 
ethanol or propan-2-ol; 50% glycerin; 30% propylene glycol; 
or high molecular weight polyethylene glycols. The EINECS 
number for bentonite is 215-108-5. 
Bentonite is used in the food industry as a processing aid as a 
clarifying or filter agent. A specification for bentonite is 
contained in the Food Chemicals Codex (FCC). 
19 Specific References 
1 Stul MS, Vliers DP, Uytterhoven JB. In vitro adsorption-desorption 
of phenethylamines and phenylimidazoles by a bentonite and a 
resin. J Pharm Sci 1984; 73: 13721375. 
2 Shrivastava R, Jain SR, Frank SG. Dissolution dialysis studies of 
metronidazolemontmorillonite adsorbates. J Pharm Sci 1985; 74: 
214216. 
3 Forni F, Iannuccelli V, Coppi G, Bernabei MT. Effect of 
montmorillonite on drug release from polymeric matrices. Arch 
Pharm 1989; 322: 789793. 
4 Listinsky JJ, Bryant RG. Gastrointestinal contrast agents: a 
diamagnetic approach. Magn Reson Med 1988; 8(3): 285292. 
5 Ponampalam R, Otten EJ. In vitro adsorption of lithium by 
bentonite. Singapore Med J 2002; 43(2): 8689. 
6 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355369. 
7 Harris WA. The inactivation of cationic antiseptics by bentonite 
suspensions. Aust J Pharm 1961; 42: 583588. 
8 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 351. 
20 General References 
Altagracia M, Ford I, Garzon ML, Kravzov J. A comparative 
mineralogical and physico-chemical study of some crude Mexican 
and pharmaceutical grade montmorillonites. Drug Dev Ind Pharm 
1987; 13: 22492262. 
Sadik F, Fincher JH, Hartman CW. X-Ray diffraction analysis for 
identification of kaolin NF and bentonite USP. J Pharm Sci 1971; 
60: 916918. 
21 Authors 
A Palmieri. 
22 Date of Revision 
8 August 2005. 
60 Bentonite

Benzalkonium Chloride 
1 Nonproprietary Names 
BP: Benzalkonium chloride 
JP: Benzalkonium chloride 
PhEur: Benzalkonii chloridum 
USPNF: Benzalkonium chloride 
2 Synonyms 
Alkylbenzyldimethylammonium chloride; alkyl dimethyl benzyl 
ammonium chloride; BKC; Hyamine 3500; Pentonium; 
Zephiran. 
3 Chemical Name and CAS Registry Number 
Alkyldimethyl(phenylmethyl)ammonium chloride [8001-54-5] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes benzalkonium chloride as a mixture of 
alkylbenzyldimethylammonium chlorides of the general formula 
[C6H5CH2N(CH3)2R]Cl, where R represents a mixture 
of alkyls, including all or some of the group beginning with 
n-C8H17 and extending through higher homologs, with 
n-C12H25, n-C14H29, and n-C16H33 comprising the major 
portion. 
The average molecular weight of benzalkonium chloride is 
360. 
5 Structural Formula 
R = mixture of alkyls: n-C8H17 to n-C18H37; mainly 
n-C12H25 (dodecyl), n-C14H29 (tetradecyl), and n-C16H33 
(hexadecyl). 
6 Functional Category 
Antimicrobial preservative; antiseptic; disinfectant; solubilizing 
agent; wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Benzalkonium chloride is a quaternary ammonium compound 
used in pharmaceutical formulations as an antimicrobial 
preservative in applications similar to other cationic surfactants, 
such as cetrimide. 
In ophthalmic preparations, benzalkonium chloride is one 
of the most widely used preservatives,(1) at a concentration of 
0.010.02% w/v. Often it is used in combination with other 
preservatives or excipients, particularly 0.1% w/v disodium 
edetate, to enhance its antimicrobial activity against strains of 
Pseudomonas. 
In nasal,(2) and otic formulations a concentration of 
0.0020.02% w/v is used, sometimes in combination with 
0.0020.005% w/v thimerosal. Benzalkonium chloride 0.01% 
w/v is also employed as a preservative in small-volume 
parenteral products. Benzalkonium chloride was also shown 
to enhance the topical penetration of lorazepam.(3) 
Benzalkonium chloride is additionally used as a preservative 
in cosmetics. 
8 Description 
Benzalkonium chloride occurs as a white or yellowish-white 
amorphous powder, a thick gel, or gelatinous flakes. It is 
hygroscopic, soapy to the touch, and has a mild aromatic odor 
and very bitter taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for benzalkonium chloride. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . .  
Acidity or alkalinity  .  
Appearance of 
solution 
. .  
Water 415.0% 410.0% 415.0% 
Residue on ignition 40.2%  42.0% 
Sulfated ash  40.1%  
Water-insoluble 
matter 
  . 
Foreign amines  . . 
Ratio of alkyl 
components 
  . 
Petroleum ethersoluble 
substances 
41.0%   
Assay (dried basis) 
of n-C12H25   540.0% 
of n-C14H29   520.0% 
of n-C12H25 and 
n-C14H29 
  570.0% 
for total alkyl 
content 
95.0105.0% 95.0104.0% 97.0103.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 58 for a 10% w/v aqueous solution.

Antimicrobial activity: benzalkonium chloride solutions are 
active against a wide range of bacteria, yeasts, and fungi. 
Activity is more marked against Gram-positive than Gramnegative 
bacteria and minimal against bacterial endospores 
and acid-fast bacteria, see Table II. The antimicrobial 
activity of benzalkonium chloride is significantly dependent 
upon the alkyl composition of the homolog mixture.(4) 
Benzalkonium chloride is ineffective against some Pseudomonas 
aeruginosa strains, Mycobacterium tuberculosis, 
Trichophyton interdigitale, and T. rubrum. However, 
combined with disodium edetate (0.010.1% w/v), benzyl 
alcohol, phenylethanol, or phenylpropanol, the activity 
against Pseudomonas aeruginosa is increased.(5) Antimicrobial 
activity may also be enhanced by the addition of 
phenylmercuric acetate, phenylmercuric borate, chlorhexidine, 
cetrimide, or m-cresol.(6,7) In the presence of citrate 
and phosphate buffers (but not borate), activity against 
Pseudomonas can be reduced. See also Sections 11 and 12. 
Benzalkonium chloride is relatively inactive against spores 
and molds, but is active against some viruses, including 
HIV.(8) Inhibitory activity increases with pH, although 
antimicrobial activity occurs at pH 410. 
Table II: Minimum inhibitory concentrations (MICs) of benzalkonium 
chloride. 
Microorganism MIC (mg/mL) 
Aerobacter aerogenes 64 
Clostridium histolyticum 5 
Clostridium oedematiens 5 
Clostridium tetani 5 
Clostridium welchii 5 
Escherichia coli 16 
Pneumococcus II 5 
Proteus vulgaris 64 
Pseudomonas aeruginosa 30 
Salmonella enteritidis 30 
Salmonella paratyphi 16 
Salmonella typhosa 4 
Shigella dysenteriae 2 
Staphylococcus aureus 1.25 
Streptococcus pyrogenes 1.25 
Vibrio cholerae 2 
Density: 0.98 g/cm3 at 208C 
Melting point: 408C 
Partition coefficients: the octanol : water partition coefficient 
varies with the alkyl chain length of the homolog; 9.98 for 
C12, 32.9 for C14, and 82.5 for C16. 
Solubility: practically insoluble in ether; very soluble in acetone, 
ethanol (95%), methanol, propanol, and water. Aqueous 
solutions of benzalkonium chloride foam when shaken, 
have a low surface tension and possess detergent and 
emulsifying properties. 
11 Stability and Storage Conditions 
Benzalkonium chloride is hygroscopic and may be affected by 
light, air, and metals. 
Solutions are stable over a wide pH and temperature range 
and may be sterilized by autoclaving without loss of effectiveness. 
Solutions may be stored for prolonged periods at room 
temperature. Dilute solutions stored in polyvinyl chloride or 
polyurethane foam containers may lose antimicrobial activity. 
The bulk material should be stored in an airtight container, 
protected from light and contact with metals, in a cool, dry 
place. 
12 Incompatibilities 
Incompatible with aluminum, anionic surfactants, citrates, 
cotton, fluorescein, hydrogen peroxide, hypromellose,(9) 
iodides, kaolin, lanolin, nitrates, nonionic surfactants in high 
concentration, permanganates, protein, salicylates, silver salts, 
soaps, sulfonamides, tartrates, zinc oxide, zinc sulfate, some 
rubber mixes, and some plastic mixes. 
Benzalkonium chloride has been shown to be adsorbed to 
various filtering membranes, especially those that are hydrophobic 
or anionic.(10) 
13 Method of Manufacture 
Benzalkonium chloride is formed by the reaction of a solution 
of N-alkyl-N-methylbenzamine with methyl chloride in an 
organic solvent suitable for precipitating the quaternary 
compound as it is formed. 
14 Safety 
Benzalkonium chloride is usually nonirritating, nonsensitizing, 
and is well tolerated in the dilutions normally employed on the 
skin and mucous membranes. However, benzalkonium chloride 
has been associated with adverse effects when used in some 
pharmaceutical formulations.(11) 
Ototoxicity can occur when benzalkonium chloride is 
applied to the ear(12) and prolonged contact with the skin can 
occasionally cause irritation and hypersensitivity. Benzalkonium 
chloride is also known to cause bronchoconstriction 
in some asthmatics when used in nebulizer solutions.(1317) 
Toxicity experiments with rabbits have shown benzalkonium 
chloride to be harmful to the eye in concentrations 
higher than that normally used as a preservative. However, the 
human eye appears to be less affected than the rabbit eye and 
many ophthalmic products have been formulated with benzalkonium 
chloride 0.01% w/v as the preservative. 
Benzalkonium chloride is not suitable for use as a 
preservative in solutions used for storing and washing 
hydrophilic soft contact lenses, as the benzalkonium chloride 
can bind to the lenses and may later produce ocular toxicity 
when the lenses are worn.(18) Solutions stronger than 0.03% 
w/v concentration entering the eye require prompt medical 
attention. 
Local irritation of the throat, esophagus, stomach, and 
intestine can occur following contact with strong solutions 
(>0.1% w/v). The fatal oral dose of benzalkonium chloride in 
humans is estimated to be 13 g. Adverse effects following oral 
ingestion include vomiting, collapse, and coma. Toxic doses 
lead to paralysis of the respiratory muscles, dyspnea, and 
cyanosis. 
LD50 (mouse, oral): 150 mg/kg(19) 
LD50 (rat, IP): 14.5 mg/kg 
LD50 (rat, IV): 13.9 mg/kg 
LD50 (rat, oral): 300 mg/kg 
LD50 (rat, skin): 1.42 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Benzalkonium chloride is 
62 Benzalkonium Chloride

irritant to the skin and eyes and repeated exposure to the skin 
may cause hypersensitivity. Concentrated benzalkonium chloride 
solutions accidentally spilled on the skin may produce 
corrosive skin lesions with deep necrosis and scarring, and 
should be washed immediately with water, followed by soap 
solutions applied freely. Gloves, eye protection, and suitable 
protective clothing should be worn. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (inhalations, 
IM injections, nasal, ophthalmic, otic, and topical preparations). 
Included in nonparenteral medicines licensed in the UK. 
It is also included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Benzethonium chloride; cetrimide. 
18 Comments 
Benzalkonium chloride has been used in antiseptic wipes and 
has been shown to produce significantly less stinging or burning 
than isopropyl alcohol and hydrogen peroxide.(20) The 
EINECS numbers for benzalkonium chloride are 264-151-6; 
260-080-8; 269-919-4; 270-325-2; 287-089-1. 
19 Specific References 
1 Sklubalova Z. Antimicrobial substances in ophthalmic drops. 
Ceska Slov Form 2004; 53(3): 107116. 
2 Pisal SS, Poradkar AR, Mahadik KR, Kadam SS. Pluronic gels for 
nasal delivery of vitamin B. Int J Pharm 2004; 270(12): 3745. 
3 Nokodchi A, Shokri J, Dashbolaphi A, et al. The enhancement 
effect of surfactants in the penetration of lorazepam through rat 
skin. Int J Pharm 2003; 250(2): 359369. 
4 Euerby MR. High performance liquid chromatography of 
benzalkonium chlorides  variation in commercial preparations. 
J Clin Hosp Pharm 1985; 10: 7377. 
5 Richards RME, McBride RJ. Enhancement of benzalkonium 
chloride and chlorhexidine acetate activity against Pseudomonas 
aeruginosa by aromatic alcohols. J Pharm Sci 1973; 62: 2035 
2037. 
6 Hugbo PG. Additivity and synergism in vitro as displayed by 
mixtures of some commonly employed antibacterial preservatives. 
Can J Pharm Sci 1976; 11: 1720. 
7 McCarthy TJ, Myburgh JA, Butler N. Further studies on the 
influence of formulation on preservative activity. Cosmet Toilet 
1977; 92(3): 3336. 
8 Chermann JC, Barre-Sinoussi F, Henin Y, Marechal V. HIV 
inactivation by a spermicide containing benzalkonium. AIDS 
Forsch 1987; 2: 8586. 
9 Richards RME. Effect of hypromellose on the antibacterial activity 
of benzalkonium chloride. J Pharm Pharmacol 1976; 28: 264. 
10 Bin T, Kulshreshtha AK, Al-Shakhshir R, Hem SL. Adsorption of 
benzalkonium chloride by filter membranes: mechanisms and 
effect of formulation and processing parameters. Pharm Dev 
Technol 1999; 4(2): 151165. 
11 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 3139. 
12 Honigman JL. Disinfectant ototoxicity [letter]. Pharm J 1975; 215: 
523. 
13 Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor properties 
of preservatives in ipratropium bromide (Atrovent) nebuliser 
solution. Br Med J 1987; 294: 11971198. 
14 Miszkiel KA, Beasley R, Rafferty P, Holgate ST. The contribution 
of histamine release to bronchoconstriction provoked by inhaled 
benzalkonium chloride in asthma. Br J Clin Pharmacol 1988; 25: 
157163. 
15 Miszkiel KA, Beasley R, Holgate ST. The influence of ipratropium 
bromide and sodium cromoglycate on benzalkonium chlorideinduced 
bronchoconstriction in asthma. Br J Clin Pharmacol 
1988; 26: 295301. 
16 Worthington I. Bronchoconstriction due to benzalkonium chloride 
in nebulizer solutions. Can J Hosp Pharm 1989; 42: 165166. 
17 Boucher M, Roy MT, Henderson J. Possible association of 
benzalkonium chloride in nebulizer solutions with respiratory 
arrest. Ann Pharmacother 1992; 26: 772774. 
18 Gasset AR. Benzalkonium chloride toxicity to the human cornea. 
Am J Ophthalmol 1977; 84: 169171. 
19 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 104. 
20 Pagnoni A, Spinelli G, Berger RS, et al. Lack of burning and 
stinging from a novel first-aid formulation applied to experimental 
wounds. J Cosmet Sci 2004; 55(2): 157162. 
20 General References 
Cowen RA, Steiger B. Why a preservative system must be tailored to a 
specific product. Cosmet Toilet 1977; 92(3): 1520. 
El-Falaha BMA, Rogers DT, Furr JR, Russell AD. Surface changes in 
Pseudomonas aeruginosa exposed to chlorhexidine diacetate and 
benzalkonium chloride. Int J Pharm 1985; 23: 239243. 
El-Falaha BMA, Russell AD, Furr JR, Rogers DT. Activity of 
benzalkonium chloride and chlorhexidine diacetate against wildtype 
and envelope mutants of Escherichia coli and Pseudomonas 
aeruginosa. Int J Pharm 1985; 25: 329337. 
Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation of 
preservative efficacy III: the determination of antimicrobial characteristics 
of benzalkonium chloride. Int J Pharm 1988; 46: 141 
147. 
Lien EJ, Perrin JH. Effect of chain length on critical micelle formation 
and protein binding of quaternary ammonium compounds. J Med 
Chem 1976; 19: 849850. 
Martin AR. Anti-infective agents. In: Doerge RF, ed. Wilson and 
Gisvolds Textbook of Organic, Medicinal and Pharmaceutical 
Chemistry. Philadelphia: JB Lippincott, 1982: 141142. 
Pense. AM, Vauthier C, Puisieux F, Benoit JP. Microencapsulation of 
benzalkonium chloride. Int J Pharm 1992; 81: 111117. 
Prince HN, Nonemaker WS, Norgard RC, Prince DL. Drug resistance 
studies with topical antiseptics. J Pharm Sci 1978; 67: 16291631. 
Wallha. usser KH. Benzalkonium chloride. In: Kabara JJ, ed. Cosmetic 
and Drug Preservation Principles and Practice. New York: Marcel 
Dekker, 1984: 731734. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
12 August 2005. 
Benzalkonium Chloride 63

Benzethonium Chloride 
1 Nonproprietary Names 
BP: Benzethonium chloride 
JP: Benzethonium chloride 
PhEur: Benzethonii chloridum 
USP: Benzethonium chloride 
2 Synonyms 
Benzyldimethyl-[2-[2-(p-1,1,3,3-tetramethylbutylphenoxy) 
ethoxy]ethyl]ammonium chloride; BZT; diisobutylphenoxyethoxyethyl 
dimethyl benzyl ammonium chloride; Hyamine 
1622. 
3 Chemical Name and CAS Registry Number 
N,N-Dimethyl-N-[2-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy] 
ethoxy]ethyl]benzene-methanaminium chloride [121-54-0] 
4 Empirical Formula and Molecular Weight 
C27H42ClNO2 448.10 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic; disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Benzethonium chloride is a quaternary ammonium compound 
used in pharmaceutical formulations as an antimicrobial 
preservative. Typically, it is used for this purpose in injections, 
ophthalmic and otic preparations at concentrations 
0.010.02% w/v. Benzethonium chloride may also be used as 
a wetting and solubilizing agent, and as a topical disinfectant. 
In cosmetics such as deodorants, benzethonium chloride 
may be used as an antimicrobial preservative in concentrations 
up to 0.5% w/v. 
The physical properties and applications of benzethonium 
chloride are similar to those of other cationic surfactants such 
as cetrimide. 
8 Description 
Benzethonium chloride occurs as a white crystalline material 
with a mild odor and very bitter taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for benzethonium chloride. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters  .  
Appearance of 
solution 
 .  
Acidity or alkalinity  .  
Melting range 1581648C 1581648C 1581638C 
Loss on drying 45.0% 45.0% 45.0% 
Residue on ignition 40.1%  40.1% 
Sulfated ash  40.1%  
Ammonium 
compounds 
. 450 ppm . 
Assay (dried basis) 597.0% 97.0103.0% 97.0103.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 4.85.5 for a 1% w/v aqueous 
solution. 
Antimicrobial activity: optimum antimicrobial activity occurs 
between pH 410. Preservative efficacy is enhanced by 
ethanol and reduced by soaps and other anionic surfactants. 
For typical minimum inhibitory concentrations (MICs) see 
Table II.(1) 
Table II: Minimum inhibitory concentration (MIC) for benzethonium 
chloride. 
Microorganism MIC (mg/mL) 
Aspergillus niger 128 
Candida albicans 64 
Escherichia coli 32 
Penicillium notatum 64 
Proteus vulgaris 64 
Pseudomonas aeruginosa 250 
Pseudomonas cepacia 250 
Pseudomonas fluorescens 250 
Staphylococcus aureus 0.5 
Streptococcus pyogenes 0.5 
Solubility: soluble 1 in less than 1 of acetone, chloroform, 
ethanol (95%), and water; soluble 1 in 6000 of ether. 
Dissolves in water to produce a foamy, soapy solution. 
11 Stability and Storage Conditions 
Benzethonium chloride is stable. Aqueous solutions may be 
sterilized by autoclaving. 
The bulk material should be stored in an airtight container 
protected from light, in a cool, dry place.

12 Incompatibilities 
Benzethonium chloride is incompatible with soaps and other 
anionic surfactants and may be precipitated from solutions 
greater than 2% w/v concentration by the addition of mineral 
acids and some salt solutions. 
13 Method of Manufacture 
p-Diisobutylphenol is condensed in the presence of a basic 
catalyst with b,b0-dichlorodiethyl ether to yield 2-[2-[4- 
(1,1,3,3-tetramethylbutyl)phenoxy]ethoxy]ethyl chloride. 
Alkaline dimethylamination then produces the corresponding 
tertiary amine which, after purification by distillation, is 
dissolved in a suitable organic solvent and treated with benzyl 
chloride to precipitate benzethonium chloride.(2) 
14 Safety 
Benzethonium chloride is readily absorbed and is generally 
regarded as a toxic substance when administered orally. 
Ingestion may cause vomiting, collapse, convulsions, and 
coma. The probable lethal human oral dose is estimated to be 
50500 mg/kg body-weight. 
The topical use of solutions containing greater than 5% w/v 
benzethonium chloride can cause irritation although benzethonium 
chloride is not regarded as a sensitizer. The use of 0.5% 
w/v benzethonium chloride in cosmetics is associated with few 
adverse effects. A maximum concentration of 0.02% w/v 
benzethonium chloride is recommended for use in cosmetics 
used in the eye area and this is also the maximum concentration 
generally used in pharmaceutical formulations such as injections 
and ophthalmic preparations.(3) 
See also Benzalkonium Chloride. 
LD50 (mouse, IP): 15.5 mg/kg(4) 
LD50 (mouse, IV): 30 mg/kg 
LD50 (mouse, oral): 338 mg/kg 
LD50 (rat, IP): 16.5 mg/kg 
LD50 (rat, IV): 19 mg/kg 
LD50 (rat, oral): 368 mg/kg 
LD50 (rat, SC): 119 mg/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM and IV 
injections, ophthalmic and otic preparations). Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Benzalkonium chloride; cetrimide. 
18 Comments 
Benzethonium chloride has been used therapeutically as a 
disinfectant and topical anti-infective agent. However, its use in 
these applications has largely been superseded by other more 
effective antimicrobials and it is now largely used solely as a 
preservative in a limited number of pharmaceutical and 
cosmetic formulations. 
The EINECS number for benzethonium chloride is 204- 
479-9. 
19 Specific References 
1 Wallha. usser KH. Benzethonium chloride. In: Kabara JJ, ed. 
Cosmetic and Drug Preservation Principles and Practice. New 
York: Marcel Dekker, 1984: 734735. 
2 Gennaro AR, ed. Remington: The Science and Practice of 
Pharmacy, 20th edn. Baltimore: Lippincott Williams and Wilkins, 
2000: 1508. 
3 The Expert Panel of the American College of Toxicology. Final 
report on the safety assessment of benzethonium chloride and 
methylbenzethonium chloride. J AmColl Toxicol 1985; 4: 65106. 
4 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 407. 
20 General References 

21 Authors 
LME McIndoe. 
22 Date of Revision 
12 August 2005. 
Benzethonium Chloride 65

Benzoic Acid 
1 Nonproprietary Names 
BP: Benzoic acid 
JP: Benzoic acid 
PhEur: Acidum benzoicum 
USP: Benzoic acid 
2 Synonyms 
Benzenecarboxylic acid; benzeneformic acid; carboxybenzene; 
dracylic acid; E210; phenylcarboxylic acid; phenylformic acid. 
3 Chemical Name and CAS Registry Number 
Benzoic acid [65-85-0] 
4 Empirical Formula and Molecular Weight 
C7H6O2 122.12 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Benzoic acid is widely used in cosmetics, foods, and pharmaceuticals 
(see Table I), as an antimicrobial preservative.(13) 
Greatest activity is seen at pH values between 2.54.5; see 
Section 10. 
Benzoic acid also has a long history of use as an antifungal 
agent(4) in topical therapeutic preparations such as Whitfields 
ointment (benzoic acid 6% and salicylic acid 3%). 
Table I: Uses of benzoic acid. 
Use Concentration (%) 
IM and IV injections 0.17 
Oral solutions 0.010.1 
Oral suspensions 0.1 
Oral syrups 0.15 
Topical preparations 0.10.2 
Vaginal preparations 0.10.2 
8 Description 
Benzoic acid occurs as feathery, light, white or colorless crystals 
or powder. It is essentially tasteless and odorless or with a slight 
characteristic odor suggestive of benzoin. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for benzoic acid. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters  .  
Congealing range 1211248C 1211248C 1211238C 
Water 40.5%  40.7% 
Residue on ignition 40.05% 40.1% 40.05% 
Readily carbonizable 
substances 
. . . 
Readily oxidizable 
substances 
. . . 
Heavy metals 420 ppm 410 ppm 410 ppm 
Halogenated 
compounds and 
halides 
. 4300 ppm  
Appearance of solution  .  
Assay 599.5% 99.0100.5% 99.5100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.8 (saturated aqueous solution at 
258C) 
Antimicrobial activity: only the undissociated acid shows 
antimicrobial properties, the activity therefore depends on 
the pH of the medium. Optimum activity occurs at pH 
values below 4.5; at values above pH 5, benzoic acid is 
almost inactive.(5) It has been reported that antimicrobial 
activity is enhanced by the addition of protamine, a basic 
protein.(6) 
Bacteria: moderate bacteriostatic activity against most 
species of Gram-positive bacteria. Typical MIC is 
100 mg/mL. Activity is less, in general, against Gramnegative 
bacteria. MIC for Gram-negative bacteria may be 
up to 1600 mg/mL. 
Molds: moderate activity. Typical MICs are 
4001000 mg/mL at pH 3; 10002000 mg/mL at pH 5. 
Spores: inactive against spores. 
Yeasts: moderate activity. Typical MIC is 1200 mg/mL. The 
addition of propylene glycol may enhance the fungistatic 
activity of benzoic acid. 
Autoignition temperature: 5708C 
Boiling point: 249.28C 
Density: 
1.311 g/cm3 for solid at 248C; 
1.075 g/cm3 for liquid at 1308C. 
Dissociation constant: the dissociation of benzoic acid in mixed 
solvents is dictated by specific solutesolvent interactions as

well as by relative solvent basicity. Increasing the organic 
solvent fraction favors the free acid form.(7) 
pKa = 4.19 at 258C; 
pKa = 5.54 in methanol 60%. 
Flash point: 1211318C 
Melting point: 1228C (begins to sublime at 1008C). 
Moisture content: 0.170.42% w/w 
Partition coefficients: 
Benzene : water = 0.0044;(8) 
Cyclohexane : water = 0.30;(9) 
Octanol : water = 1.87.(10) 
Refractive index: 
nD
15 = 1.5397 for solid; 
nD
132 = 1.504 for liquid. 
Solubility: apparent aqueous solubility of benzoic acid may be 
enhanced by the addition of citric acid or sodium acetate to 
the solution; see Table III. 
Table III: Solubility of benzoic acid. 
Solvent Solubility at 258C unless otherwise stated 
Acetone 1 in 2.3 
Benzene 1 in 9.4 
Carbon disulfide 1 in 30 
Carbon tetrachloride 1 in 15.2 
Chloroform 1 in 4.5 
Cyclohexane 1 in 14.6(9) 
Ethanol 1 in 2.7 at 158C 
1 in 2.2 
Ethanol (76%) 1 in 3.72(11) 
Ethanol (54%) 1 in 6.27(11) 
Ethanol (25%) 1 in 68(11) 
Ether 1 in 3 
Fixed oils Freely soluble 
Methanol 1 in 1.8 
Toluene 1 in 11 
Water 1 in 300 
11 Stability and Storage Conditions 
Aqueous solutions of benzoic acid may be sterilized by 
autoclaving or by filtration. 
A 0.1% w/v aqueous solution of benzoic acid has been 
reported to be stable for at least 8 weeks when stored in 
polyvinyl chloride bottles, at room temperature.(12) 
When added to a suspension, benzoic acid dissociates, with 
the benzoate anion adsorbing onto the suspended drug 
particles. This adsorption alters the charge at the surface of 
the particles, which may in turn affect the physical stability of 
the suspension.(13) 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Undergoes typical reactions of an organic acid, e.g. with alkalis 
or heavy metals. Preservative activity may be reduced by 
interaction with kaolin.(14) 
13 Method of Manufacture 
Although benzoic acid occurs naturally, it is produced 
commercially by several synthetic methods. One process 
involves the continuous liquid-phase oxidation of toluene in 
the presence of a cobalt catalyst at 1502008C and 
0.55.0MPa (5.050.0 atm) pressure to give a yield of 
approximately 90% benzoic acid. 
Benzoic acid can also be produced commercially from 
benzotrichloride or phthalic anhydride. Benzotrichloride, 
produced by chlorination of toluene, is reacted with 1 mole 
of benzoic acid to yield 2 moles of benzoyl chloride. The 
benzoyl chloride is then converted to 2 moles of benzoic acid by 
hydrolysis. Yield is 7580%. 
In another commercial process, phthalic anhydride is 
converted to benzoic acid, in about an 85% yield, by hydrolysis 
in the presence of heat and chromium and disodium phthalates. 
Crude benzoic acid is purified by sublimation or recrystallization. 
14 Safety 
Ingested benzoic acid is conjugated with glycine in the liver to 
yield hippuric acid, which is then excreted in the urine;(15) care 
should be taken when administering benzoic acid to patients 
with chronic liver disease.(16) Benzoic acid is a gastric irritant, 
and a mild irritant to the skin.(1719) It is also a mild irritant to 
the eyes and mucous membranes.(20) Allergic reactions to 
benzoic acid have been reported, although a controlled study 
indicated that the incidence of urticaria in patients given 
benzoic acid is no greater than in those given a lactose 
placebo.(21) 
The WHO acceptable daily intake of benzoic acid and other 
benzoates, calculated as benzoic acid, has been set at up to 
5 mg/kg body-weight.(22,23) The minimum lethal human oral 
dose of benzoic acid is 500 mg/kg body-weight.(24) 
LD50 (cat, oral): 2 g/kg(24) 
LD50 (dog, oral): 2 g/kg 
LD50 (mouse, IP): 1.46 g/kg 
LD50 (mouse, oral): 1.94 g/kg 
LD50 (rat, oral): 1.7 g/kg 
See also Sodium benzoate. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Benzoic acid may be harmful 
by inhalation, ingestion, or skin absorption and may be irritant 
to the eyes, skin, and mucous membranes. Benzoic acid should 
be handled in a well-ventilated environment; eye protection, 
gloves, and a dust mask or respirator are recommended. 
Benzoic acid is flammable. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (IM and IV injections, 
irrigation solutions, oral solutions, suspensions, syrups and 
tablets, rectal, topical, and vaginal preparations). Included in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Potassium benzoate; sodium benzoate. 
18 Comments 
Benzoic acid is known to dimerize in many nonpolar solvents. 
This property, coupled with pH-dependent dissociation in 
Benzoic Acid 67

aqueous media, comprises a classic textbook example of the 
effects of dissociation and molecular association on apparent 
partitioning behavior. The principles involved may be practically 
applied in determination of the total concentration of 
benzoate necessary to provide a bacteriostatic level of benzoic 
acid in the aqueous phase of an oil-in-water emulsion. 
A specification for benzoic acid is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for benzoic acid is 200-618-2. 
19 Specific References 
1 Buzzi MM, Marth EH. Characteristics of sodium benzoate injury 
of Listeria monocytogenes. Microbios 1992; 700: 199207. 
2 Elder DJ, Kelly DJ. The bacterial degradation of benzoic acid and 
benzenoid compounds under anaerobic conditions: unifying trends 
and new perspectives. FEMS Microbiol Rev 1994; 13(4): 441468. 
3 Hwang CA, Beuchat LR. Efficacy of a lactic acid/sodium benzoate 
wash solution in reducing bacterial contamination in raw chicken. 
Int J Food Microbiol 1995; 27(1): 9198. 
4 Burlini N, Pellegrine R, Facheris P, et al. Metabolic effects of 
benzoate and sorbate in the yeast Saccharomyes cerevisiae at 
neutral pH. Arch Microbiol 1993; 159(3): 220224. 
5 Hurwitz SJ, McCarthy TJ. The effect of pH and concentration on 
the rates of kill of benzoic acid solutions against E. coli. J Clin 
Pharm Ther 1987; 12: 107115. 
6 Boussard P, Devleeschouwer MJ, Dony J. In vitro modification of 
antimicrobial efficacy by protamine. Int J Pharm 1991; 72: 5155. 
7 Ghosh SK, Hazra DK. Solvent effects on the dissociation of 
benzoic acid in aqueous mixtures of 2-methoxyethanol and 1,2- 
dimethoxyethane at 258C. J Chem Soc Perkin Trans 1989; 2: 
10211024. 
8 Pawlowski W, Wieckowska E. Hydration of benzoic acid in 
benzene solution II: calculation of hydration constant. Z Phys 
Chem 1990; 168: 205215. 
9 Dearden JC, Roberts MJ. Cyclohexanewater partition coefficients 
of some pharmaceuticals. J Pharm Pharmacol 1989; 41: 
102P. 
10 Yalkowsky SH, Valvani SC, Roseman TJ. Solubility and partitioning 
VI: octanol solubility and octanolwater partition coefficients. 
J Pharm Sci 1983; 72: 866870. 
11 Pal A, Lahiri SC. Solubility and the thermodynamics of transfer of 
benzoic acid in mixed solvents. Indian J Chem 1989; 28A: 276 
279. 
12 The Pharmaceutical Society of Great Britain, Department of 
Pharmaceutical Sciences. Plastic medicine bottles of rigid PVC. 
Pharm J 1973; 210: 100. 
13 Gallardo V, Salcedo J, Parera A, Delgado A. Effect of the 
preservatives antipyrin, benzoic acid and sodium metabisulfite 
on properties of the nitrofurantoin/solution interface. Int J Pharm 
1991; 71: 223227. 
14 Clarke CD, Armstrong NA. Influence of pH on the adsorption of 
benzoic acid by kaolin. Pharm J 1972; 209: 4445. 
15 Tremblay GC, Qureshi IA. The biochemistry and toxicology of 
benzoic acid metabolism and its relationship to the elimination of 
waste nitrogen. Pharmacol Ther 1993; 60(1): 6390. 
16 Yamada S, Yamamota T, Suou T, et al. Clinical significance of 
benzoate-metabolizing capacity in patients with chronic liver 
disease: pharmacokinetic analysis. Res Commun Chem Pathol 
Pharmacol 1992; 76(1): 5362. 
17 Downward CE, Roberts LJ, Morrow JD. Topical benzoic acid 
induces the increased biosynthesis of PGD2 in human skin in vivo. 
Clin Pharmacol Ther 1995; 57(4): 441445. 
18 Lahti A, Pylvanen V, Hannuksels M. Immediate irritant reactions 
to benzoic acid are enhanced in washed skin areas. Contact 
Dermatitis 1996; 35(1): 51. 
19 Munoz FJ, Bellido J, Moyano JC, et al. Perioral contact urticaria 
from sodium benzoate in a toothpaste. Contact Dermatitis 1996; 
35(1): 51. 
20 Takeichi Y, Kimura T. Improvement of aqueous solubility and 
rectal absorption of 6-mercaptopurine by addition of sodium 
benzoate. Biol Pharm Bull 1994; 17(10): 13911394. 
21 Lahti A, Hannuksela M. Is benzoic acid really harmful in cases of 
atopy and urticaria? Lancet 1981; ii: 1055. 
22 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
23 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1983; No. 696. 
24 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 379. 
20 General References 
Garrett ER, Woods OR. The optimum use of acid preservatives in oil 
water systems: benzoic acid in peanut oilwater. J Am Pharm Assoc 
(Sci) 1953; 42: 736739. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
68 Benzoic Acid

Benzyl Alcohol 
1 Nonproprietary Names 
BP: Benzyl alcohol 
JP: Benzyl alcohol 
PhEur: Alcohol benzylicus 
USPNF: Benzyl alcohol 
2 Synonyms 
Benzenemethanol; a-hydroxytoluene; phenylcarbinol; phenylmethanol; 
a-toluenol. 
3 Chemical Name and CAS Registry Number 
Benzenemethanol [100-51-6] 
4 Empirical Formula and Molecular Weight 
C7H8O 108.14 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; disinfectant; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Benzyl alcohol is an antimicrobial preservative used in 
cosmetics, foods, and a wide range of pharmaceutical 
formulations,(14) including oral and parenteral preparations, 
at concentrations up to 2.0% v/v. In cosmetics, concentrations 
up to 3.0% v/v may be used as a preservative. Concentrations 
of 5% v/v or more are employed as a solubilizer, while a 10% 
v/v solution is used as a disinfectant. 
Benzyl alcohol 10% v/v solutions also have some local 
anesthetic properties, which are exploited in some parenterals, 
cough products, ophthalmic solutions, ointments, and dermatological 
aerosol sprays. 
Although widely used as an antimicrobial preservative, 
benzyl alcohol has been associated with some fatal adverse 
reactions when administered to neonates. It is now recommended 
that parenteral products preserved with benzyl 
alcohol, or other antimicrobial preservatives, should not be 
used in newborn infants if at all possible; see Section 14. 
8 Description 
A clear, colorless, oily liquid with a faint aromatic odor and a 
sharp, burning taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for benzyl alcohol. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . .  
Solubility  .  
Acidity . . . 
Clarity of solution . .  
Specific gravity 1.0431.053 1.0431.049 1.0421.047 
Distilling range 202.5206.58C  
Refractive index 1.5381.541 1.5381.541 1.5391.541 
Residue on ignition 40.005%  40.005% 
Nonvolatile matter  40.05% 41mg 
Chlorinated 
compounds 
.  40.03% 
Benzaldehyde . . 40.2% 
Peroxide value  45  
Organic volatile 
impurities 
  . 
Assay 598.0% 98.0100.5% 97.0100.5% 
10 Typical Properties 
Acidity/alkalinity: aqueous solutions are neutral to litmus. 
Antimicrobial activity: benzyl alcohol is bacteriostatic and is 
used as an antimicrobial preservative against Gram-positive 
bacteria, molds, fungi, and yeasts, although it possesses only 
modest bactericidal properties. Optimum activity occurs at 
pH below 5; little activity is shown above pH 8. 
Antimicrobial activity is reduced in the presence of nonionic 
surfactants, such as polysorbate 80. However, the reduction 
in activity is less than is the case with either hydroxybenzoate 
esters or quaternary ammonium compounds. The 
activity of benzyl alcohol may also be reduced by 
incompatibilities with some packaging materials, particularly 
polyethylene; see Section 12. 
See Table II for reported minimum inhibitory concentrations 
(MICs). 
Table II: Minimum inhibitory concentrations (MICs) of benzyl 
alcohol.(4) 
Microorganism MIC (mg/mL) 
Aspergillus niger 5000 
Candida albicans 2500 
Escherichia coli 2000 
Pseudomonas aeruginosa 2000 
Staphylococcus aureus 25 
Bacteria: benzyl alcohol is moderately active against most 
Gram-positive organisms (typical MICs are 35 mg/mL), 
although some Gram-positive bacteria are very sensitive

(MICs 0.0250.05 mg/mL). In general, benzyl alcohol is less 
active against Gram-negative organisms. 
Fungi: benzyl alcohol is effective against molds and yeasts; 
typical MICs are 35 mg/mL. 
Spores: benzyl alcohol is inactive against spores, but activity 
may be enhanced by heating. Benzyl alcohol 1% v/v, at pH 
56, has been claimed to be as effective as phenylmercuric 
nitrate 0.002% w/v against Bacillus stearothermophilus at 
1008C for 30 min. 
Autoignition temperature: 436.58C 
Boiling point: 204.78C 
Flammability: flammable. Limits in air 1.715.0% v/v. 
Flash point: 
100.68C (closed cup); 
104.58C (open cup). 
Freezing point: 158C 
Partition coefficients: 
Liquid paraffin : water = 0.2; 
Peanut oil : water = 1.3. 
Solubility: see Table III. 
Table III: Solubility of benzyl alcohol. 
Solvent Solubility at 208C unless otherwise stated 
Chloroform Miscible in all proportions 
Ethanol Miscible in all proportions 
Ethanol (50%) 1 in 2.5 
Ether Miscible in all proportions 
Fixed and volatile oils Miscible in all proportions 
Water 1 in 25 at 258C 
1 in 14 at 908C 
Surface tension: 38.8mN/m (38.8 dynes/cm) 
Vapor density (relative): 3.72 (air = 1) 
Vapor pressure: 
13.3 Pa (0.1 mmHg) at 308C; 
1.769 kPa (13.3 mmHg) at 1008C. 
Viscosity (dynamic): 6 mPa s (6 cP) at 208C 
11 Stability and Storage Conditions 
Benzyl alcohol oxidizes slowly in air to benzaldehyde and 
benzoic acid; it does not react with water. Aqueous solutions 
may be sterilized by filtration or autoclaving; some solutions 
may generate benzaldehyde during autoclaving. 
Benzyl alcohol may be stored in metal or glass containers. 
Plastic containers should not be used; exceptions to this include 
polypropylene containers or vessels coated with inert fluorinated 
polymers such as Teflon; see Section 12. 
Benzyl alcohol should be stored in an airtight container, 
protected from light, in a cool, dry place. 
12 Incompatibilities 
Benzyl alcohol is incompatible with oxidizing agents and strong 
acids. It can also accelerate the autoxidation of fats. 
Although antimicrobial activity is reduced in the presence of 
nonionic surfactants, such as polysorbate 80, the reduction is 
less than is the case with hydroxybenzoate esters or quaternary 
ammonium compounds. 
Benzyl alcohol is incompatible with methylcellulose and is 
only slowly sorbed by closures composed of natural rubber, 
neoprene, and butyl rubber closures, the resistance of which 
can be enhanced by coating with fluorinated polymers.(5) 
However, a 2% v/v aqueous solution in a polyethylene 
container, stored at 208C, may lose up to 15% of its benzyl 
alcohol content in 13 weeks.(6) Losses to polyvinyl chloride and 
polypropylene containers under similar conditions are usually 
negligible. Benzyl alcohol can damage polystyrene syringes by 
extracting some soluble components.(7) 
13 Method of Manufacture 
Benzyl alcohol is prepared commercially by the distillation of 
benzyl chloride with potassium or sodium carbonate. It may 
also be prepared by the Cannizzaro reaction of benzaldehyde 
and potassium hydroxide. 
14 Safety 
Benzyl alcohol is used in a wide variety of pharmaceutical 
formulations. It is metabolized to benzoic acid, which is further 
metabolized in the liver by conjugation with glycine to form 
hippuric acid, which is excreted in the urine. 
Ingestion or inhalation of benzyl alcohol may cause headache, 
vertigo, nausea, vomiting, and diarrhea. Overexposure 
may result in CNS depression and respiratory failure. However, 
the concentrations of benzyl alcohol normally employed as a 
preservative are not associated with such adverse effects. 
Reports of adverse reactions to benzyl alcohol(8,9) used as an 
excipient include toxicity following intravenous administration;(
10,11) neurotoxicity in patients administered benzyl 
alcohol in intrathecal preparations;(12) hypersensitivity,(13,14) 
although relatively rare; and a fatal toxic syndrome in 
premature infants.(1517) 
The fatal toxic syndrome in low-birth-weight neonates, 
which includes symptoms of metabolic acidosis and respiratory 
depression, was attributed to the use of benzyl alcohol as a 
preservative in solutions used to flush umbilical catheters. As a 
result of this, the FDA has recommended that benzyl alcohol 
should not be used in such flushing solutions and has advised 
against the use of medicines containing preservatives in the 
newborn.(18,19) 
The WHO has set the estimated acceptable daily intake of 
the benzyl/benzoic moiety at up to 5 mg/kg body-weight 
daily.(20) 
LD50 (mouse, IV): 0.32 g/kg(21) 
LD50 (mouse, oral): 1.36 g/kg 
LD50 (rat, IP): 0.4 g/kg 
LD50 (rat, IV): 0.05 g/kg 
LD50 (rat, oral): 1.23 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Benzyl alcohol (liquid and 
vapor) is irritant to the skin, eyes, and mucous membranes. Eye 
protection, gloves, and protective clothing are recommended. 
Benzyl alcohol should be handled in a well-ventilated environment; 
a self-contained breathing apparatus is recommended in 
areas of poor ventilation. Benzyl alcohol is flammable. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (dental 
injections, oral capsules, solutions and tablets, topical, and 
vaginal preparations). Included in parenteral and nonparenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
70 Benzyl Alcohol

17 Related Substances 

18 Comments 
The EINECS number for benzyl alcohol is 202-859-9. 
19 Specific References 
1 Croshaw B. Preservatives for cosmetics and toiletries. J Soc Cosmet 
Chem 1977; 28: 316. 
2 Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation 
of preservative efficacy II: the determination of antimicrobial 
characteristics of benzyl alcohol. J Clin Hosp Pharm 1986; 11: 
281289. 
3 Shah AK, Simons KJ, Briggs CJ. Physical, chemical, and 
bioavailability studies of parenteral diazepam formulations containing 
propylene glycol and polyethylene glycol 400. Drug Dev 
Ind Pharm 1991; 17: 16351654. 
4 Wallha. usser KH. Benzyl alcohol. In: Kabara JJ, ed. Cosmetic and 
Drug Preservation Principles and Practice. New York: Marcel 
Dekker, 1984: 627628. 
5 Royce A, Sykes G. Losses of bacteriostats from injections in 
rubber-closed containers. J Pharm Pharmacol 1957; 9: 814823. 
6 Roberts MS, Polack AE, Martin G, Blackburn HD. The storage of 
selected substances in aqueous solution in polyethylene containers: 
the effect of some physicochemical factors on the disappearance 
kinetics of the substances. Int J Pharm 1979; 2: 295306. 
7 Doull J, Klaassen CD, Amdur MO, eds. Casarett and Doulls 
Toxicology: The Basic Science of Poisons. New York: Macmillan, 
1980. 
8 Reynolds RD. Nebulizer bronchitis induced by bacteriostatic 
saline [letter]. J Am Med Assoc 1990; 264: 35. 
9 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 4754. 
10 Evens RP. Toxicity of intravenous benzyl alcohol [letter]. Drug 
Intell Clin Pharm 1975; 9: 154155. 
11 Lo. pez-Herce J, Bonet C, Meana A, Albajara L. Benzyl alcohol 
poisoning following diazepam intravenous infusion [letter]. Ann 
Pharmacother 1995; 29: 632. 
12 Hahn AF, Feasby TE, Gilbert JJ. Paraparesis following intrathecal 
chemotherapy. Neurology 1983; 33: 10321038. 
13 Grant JA, Bilodeau PA, Guernsey BG, Gardner FH. Unsuspected 
benzyl alcohol hypersensitivity [letter]. N Engl J Med 1982; 306: 
108. 
14 Wilson JP, Solimando DA, Edwards MS. Parenteral benzyl 
alcohol-induced hypersensitivity reaction. Drug Intell Clin Pharm 
1986; 20: 689691. 
15 Brown WJ, Buist NRM, Cory Gipson HT, et al. Fatal benzyl 
alcohol poisoning in a neonatal intensive care unit [letter]. Lancet 
1982; i: 1250. 
16 Gershanik J, Boecler B, Ensley H, et al. The gasping syndrome and 
benzyl alcohol poisoning. N Engl J Med 1982; 307: 13841388. 
17 McCloskey SE, Gershanik JJ, Lertora JJL, et al. Toxicity of benzyl 
alcohol in adult and neonatal mice. J Pharm Sci 1986; 75: 702 
705. 
18 Anonymous. Benzyl alcohol may be toxic to newborns. FDA Drug 
Bull 1982; 12: 1011. 
19 Belson JJ. Benzyl alcohol questionnaire. Am J Hosp Pharm 1982; 
39: 1850, 1852. 
20 FAO/WHO. Evaluation of certain food additives. Twenty-third 
report of the joint FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1980; No. 648. 
21 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 398399. 
20 General References 
Akers MJ. Considerations in selecting antimicrobial preservative agents 
for parenteral product development. Pharm Technol 1984; 8(5): 
3640, 43, 44, 46. 
Bloomfield SF. Control of microbial contamination part 2: current 
problems in preservation. Br J Pharm Pract 1986; 8: 72, 7476, 78, 
80. 
Carter DV, Charlton PT, Fenton AH, et al. The preparation and the 
antibacterial and antifungal properties of some substituted benzyl 
alcohols. J Pharm Pharmacol 1958; 10 (Suppl.): 149T159T. 
Harrison SM, Barry BW, Dugard PH. Benzyl alcohol vapour diffusion 
through human skin: dependence on thermodynamic activity in the 
vehicle. J Pharm Pharmacol 1982; 34 (Suppl.): 36P. 
Russell AD, Jenkins J, Harrison IH. The inclusion of antimicrobial 
agents in pharmaceutical products. Adv Appl Microbiol 1967; 9: 1 
38. 
Sklubalova Z. Antimicrobial substances in ophthalmic drops. Ceska 
Slov Form 2004; 53(3): 107116. 
21 Authors 
E Cahill. 
22 Date of Revision 
15 August 2005. 
Benzyl Alcohol 71

Benzyl Benzoate 
1 Nonproprietary Names 
BP: Benzyl benzoate 
JP: Benzyl benzoate 
PhEur: Benzylis benzoas 
USP: Benzyl benzoate 
2 Synonyms 
Benzoic acid benzyl ester; benzylbenzenecarboxylate; benzyl 
phenylformate. 
3 Chemical Name and CAS Registry Number 
Benzoic acid phenylmethyl ester [120-51-4] 
4 Empirical Formula and Molecular Weight 
C14H12O2 212.24 
5 Structural Formula 
6 Functional Category 
Plasticizer; solubilizing agent; solvent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Benzyl benzoate is used as a solubilizing agent and nonaqueous 
solvent in intramuscular injections at concentrations of 
0.0146.0% v/v,(1) and as a solvent and plasticizer for cellulose 
and nitrocellulose. It is also used in the preparation of spraydried 
powders using nanocapsules.(2) 
However, the most widespread pharmaceutical use of benzyl 
benzoate is as a topical therapeutic agent in the treatment of 
scabies.(3) Benzyl benzoate is also used therapeutically as a 
parasiticide in veterinary medicine.(4) 
Other applications of benzyl benzoate include its use as a 
pediculicide and as a solvent and fixative for flavors and 
perfumes in cosmetics and food products. 
8 Description 
Benzyl benzoate is a clear, colorless, oily liquid with a slightly 
aromatic odor. It produces a sharp, burning sensation on the 
tongue. At temperatures below 178C it exists as clear, colorless 
crystals. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for benzyl benzoate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . .  
Specific gravity 1.123 1.1181.122 1.1161.120 
Congealing 
temperature 
178C 517.08C 518.08C 
Boiling point 3238C 3208C  
Refractive index 1.5681.570 1.5681.570 1.5681.570 
Aldehyde   40.05% 
Acidity . . . 
Sulfated ash 40.05% 40.1%  
Organic volatile 
impurities 
  . 
Assay 599.0% 99.0100.5% 99.0100.5% 
10 Typical Properties 
Autoignition temperature: 4818C 
Boiling point: 3238C 
Flash point: 1488C 
Freezing point: 178C 
Refractive index: nD
21 = 1.5681 
Solubility: practically insoluble in glycerin and water; miscible 
with chloroform, ethanol (95%), ether, and with fatty acids 
and essential oils. 
Specific gravity: 1.12 
Vapor density (relative): 7.3 (air = 1) 
11 Stability and Storage Conditions 
Benzyl benzoate is stable when stored in tight, well-filled, lightresistant 
containers. Exposure to excessive heat (above 408C) 
should be avoided. 
12 Incompatibilities 
Benzyl benzoate is incompatible with alkalis and oxidizing 
agents. 
13 Method of Manufacture 
Benzyl benzoate is a constituent of Peru balsam and occurs 
naturally in certain plant species. Commercially, benzyl 
benzoate is produced synthetically by the dry esterification of 
sodium benzoate and benzoyl chloride in the presence of 
triethylamine or by the reaction of sodium benzylate with 
benzaldehyde.

14 Safety 
Benzyl benzoate is metabolized by rapid hydrolysis to benzoic 
acid and benzyl alcohol. Benzyl alcohol is then further 
metabolized to hippuric acid, which is excreted in the urine. 
Benzyl benzoate is widely used as a 25% v/v topical 
application in the treatment of scabies and as an excipient in 
intramuscular injections and oral products. Adverse reactions 
to benzyl benzoate include skin irritation and hypersensitivity 
reactions. Oral ingestion may cause harmful stimulation of the 
CNS and convulsions. 
LD50 (cat, oral): 2.24 g/kg(57) 
LD50 (guinea pig, oral): 1.0 g/kg 
LD50 (mouse, oral): 1.4 g/kg 
LD50 (rabbit, oral): 1.68 g/kg 
LD50 (rabbit, skin): 4.0 g/kg 
LD50 (rat, oral): 0.5 g/kg 
LD50 (rat, skin): 4.0 g/kg 
15 Handling Precautions 
Benzyl benzoate may be harmful if ingested and is irritating to 
the skin, eyes, and mucous membranes. Observe normal 
precautions appropriate to the circumstances and quantity of 
material handled. Eye protection, gloves, and a respirator are 
recommended. It is recommended that benzyl benzoate is 
handled in a fume cupboard. Benzyl benzoate is flammable. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM injections 
and oral capsules). Included, as an active ingredient, in 
nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
 
18 Comments 
The EINECS number for benzyl benzoate is 204-402-9. 
19 Specific References 
1 Spiegel AJ, Noseworthy MM. Use of nonaqueous solvents in 
parenteral products. J Pharm Sci 1963; 52: 917927. 
2 Guterres SS, Weiss V, de Lucca Freitas L, Pohlmann AR. Influence 
of benzyl benzoate as oil core on the physicochemical properties of 
spray-dried powders from polymeric nanocapsules containing 
indomethacin. Drug Deliv 2000; 7(4): 195199. 
3 Gilman AG, Rall TW, Nies AS, et al, eds. Goodman and Gilmans 
The Pharmacological Basis of Therapeutics, 8th edn. New York: 
Pergamon Press, 1990: 1630. 
4 Bishop Y, ed. The Veterinary Formulary, 6th edn. London: 
Pharmaceutical Press, 2005: 56. 
5 Graham BE, Kuizenga MH. Toxicity studies on benzyl benzoate 
and related benzyl compounds. J Pharmacol Exp Ther 1945; 84: 
358362. 
6 Draize JH, Alvarez E, Whitesell MF, et al. Toxicological investigations 
of compounds proposed for use as insect repellents. J 
Pharmacol Exp Ther 1948; 93: 2639. 
7 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 965. 
20 General References 
Gupta VD, Ho HW. Quantitative determination of benzyl benzoate in 
benzyl benzoate lotion NF. Am J Hosp Pharm 1976; 33: 665666. 
Hassan MMA, Mossa JS. Benzyl benzoate. In: Florey K, ed. Analytical 
Profiles of Drug Substances, volume 10. New York: Academic 
Press, 1981: 5574. 
21 Authors 
E Cahill. 
22 Date of Revision 
15 August 2005. 
Benzyl Benzoate 73

Boric Acid 
1 Nonproprietary Names 
BP: Boric acid 
JP: Boric acid 
PhEur: Acidum boricum 
USPNF: Boric acid 
2 Synonyms 
Boracic acid; boraic acid; Borofax; boron trihydroxide; E284; 
orthoboric acid; trihydroxyborene. 
3 Chemical Name and CAS Registry Number 
Orthoboric acid [10043-35-3] 
Metaboric acid [13460-50-9] 
4 Empirical Formula and Molecular Weight 
H3BO3 61.83 (for trihydrate) 
HBO2 43.82 (for monohydrate) 
5 Structural Formula 
H3BO3 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Boric acid is used as an antimicrobial preservative in eye 
drops,(1,2) cosmetic products,(3) ointments,(4,5) and topical 
creams.(6) It is also used as an antimicrobial preservative in 
foods. 
Boric acid has also been used therapeutically in the form of 
suppositories to treat yeast infections,(79) and in dilute 
concentrations as a mild antiseptic, although it has been 
superseded by more effective and less toxic disinfectants.(10) See 
Section 14. 
Boric acid and borate have good buffering capacity and are 
used to control pH; they have been used for this purpose in 
external preparations such as eye drops.(11) 
8 Description 
Boric acid occurs as a hygroscopic, white crystalline powder, 
colorless shiny plates, or white crystals. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for boric acid. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Appearance of 
solution 
. .  
Loss on drying 40.50%  40.50% 
Sulfate  4450 ppm  
Heavy metals 410 ppm 415 ppm 40.002% 
Organic matter  .  
Arsenic 45 ppm   
pH  3.84.8  
Solubility in alcohol  . . 
Assay 499.5% 99.5100.5% 99.5100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 3.54.1 (5% w/v aqueous solution) 
Density: 1.435 
Melting point: 170.98C. When heated slowly to 181.08C, boric 
acid loses water to form metaboric acid (HBO2); at 1408C, 
tetraboric acid (H2B4O7) is formed; and at higher temperatures, 
boron trioxide (B2O3) is formed.(12) 
Solubility: miscible with ethanol, ether, glycerin, water, and 
other fixed and volatile oils. Solubility in water is increased 
by addition of hydrochloric, citric, or tartaric acids. 
Specific gravity: 1.517 
11 Stability and Storage Conditions 
Boric acid is hygroscopic and should therefore be stored in an 
air-tight, sealed container. The container must be labeled Not 
for Internal Use. 
12 Incompatibilities 
Boric acid is incompatible with water, strong bases and alkali 
metals. It reacts violently with potassium and acid anhydrides. 
It also forms a complex with glycerin, which is a stronger acid 
than boric acid. 
13 Method of Manufacture 
Boric acid occurs naturally as the mineral sassolite. However, 
the majority of boric acid is produced by reacting inorganic 
borates with sulfuric acid in an aqueous medium. Sodium 
borate and partially refined calcium borate (colemanite) are the 
principal raw materials. When boric acid is made from 
colemanite, the fine-ground ore is vigorously stirred with 
mother liquor and sulfuric acid at about 908C. The by-product 
calcium sulfate is removed by filtration, and the boric acid is 
crystallized by cooling the filtrate. 
14 Safety 
Boric acid is a weak bacteriostatic and antimicrobial agent, and 
has been used in topical preparations such as eye lotions,

mouthwashes and gargles. It has also been used in US- and 
Japanese-approved intravenous products. Solutions of boric 
acid were formerly used to wash out body cavities, and as 
applications to wounds and ulcers, although the use of boric 
acid for these purposes is now regarded as inadvisable owing to 
the possibility of absorption.(13) Boric acid is not used internally 
owing to its toxicity. It is poisonous by ingestion and 
moderately toxic by skin contact. Experimentally it has proved 
to be toxic by inhalation and subcutaneous routes, and 
moderately toxic by intraperitoneal and intravenous routes. 
Boric acid is absorbed from the gastrointestinal tract and 
from damaged skin, wounds, and mucous membranes, 
although it does not readily permeate intact skin. The main 
symptoms of boric acid poisoning are abdominal pain, 
diarrhea, erythematous rash involving both skin and mucous 
membrane, and vomiting. These symptoms may be followed by 
desquamation, and stimulation or depression of the central 
nervous system. Convulsions, hyperpyrexia, and renal tubular 
damage have been known to occur. 
Death has occurred from ingestion of less than 5 g in young 
children, and of 520 g in adults. Fatalities have occurred most 
frequently in young children after the accidental ingestion of 
solutions of boric acid, or after the application of boric acid 
powder to abraded skin. 
The permissible exposure limit (PEL) of boric acid is 
15 mg/m3 total dust, and 5 mg/m3 respirable fraction for 
nuisance dusts.(14) 
LD50 (mouse, oral): 3.45 g/kg(15) 
LD50 (mouse, IV): 1.24 g/kg 
LD50 (mouse, SC): 1.74 g/kg 
LD50 (rat, oral): 2.660 g/kg 
LD50 (rat, IV): 1.33 g/kg 
LD50 (rat, SC): 1.4 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Boric acid is irritating to the 
skin and is potentially toxic by inhalation. Gloves, eye 
protection, protective clothing, and a respirator are recommended. 
16 Regulatory Status 
Accepted for use as a food additive in Europe. Included in the 
FDA Inactive Ingredients Guide (IV injections; ophthalmic 
preparations; otic solutions; topical preparations). Reported in 
the EPA TSCA Inventory. In the UK, the use of boric acid in 
cosmetics and toiletries is restricted. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Sodium borate. 
18 Comments 
Boric acid has been used experimentally as a model oxo-acid to 
retard mannitol crystallization in the solid state.(16) 
The EINECS number for boric acid is 233-139-2. 
19 Specific References 
1 Kodym A, Marcinkowski A, Kukula H. Technology of eye drops 
containing aloe (Aloe arborescens MLiliaceae) and eye drops 
containing both aloe and neomycin sulphate. Acta Pol Pharm 
2003; 60(1): 3139. 
2 Tromp TFJ, Nusman-Schoterman Z, et al. Preservation of eye 
drops. Pharm Weekbl 1975; 110(465472): 485492. 
3 Seller R, Caldini O, Orzalesi G, et al. Preservation of cosmetic 
products: protection of the talc powders. Boul Chim Farm 1974; 
113(Dec): 617627. 
4 Allen LV, Stiles ML. Compounds corner: diaper rash paste. 
Maryland Pharm 1986: 62(Dec): 30. 
5 Dawson CR, Daghfous T, Whitcher J, et al. Intermittent trachoma 
chemotherapy: controlled trial of tetracycline or erythromycin. 
Bull World Health Organ 1981; 59: 9197. 
6 Shaw K. Vaginal yeast infections. Pharm Times 1998; 64(Dec): 57 
58, 60. 
7 Allen LV. Boric acid suppositories. US Pharm 1996; 21(Jan): 92 
93. 
8 Van Slyke KK, Michel VP, Rein MF. Treatment of vulvovaginal 
candidaisis with boric acid powder. Am J Obstet Gynecol 1981; 
141: 145. 
9 Allen ES. Multiple-ingredient drug for use in the treatment of 
vaginitis. Clin Med 1971; 78: 3132. 
10 Sweetman SC, ed. Martindale: The Complete Drug Reference, 
34th edn. London: Pharmaceutical Press, 2005: 1662. 
11 LundW, ed. The Pharmaceutical Codex: Principles and Practice of 
Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 67. 
12 LundW, ed. The Pharmaceutical Codex: Principles and Practice of 
Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 
109. 
13 Zabka M, Vitkova Z, Burelova A, Mandak M. Formulation and 
local anesthetic activity of carbizocaine in collyria. Cesk Farm 
1988; 37(10): 457460. 
14 Dean JA, ed. Langs Handbook of Chemistry, 13th edn. New York: 
McGraw-Hill, 1985: 457. 
15 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 536. 
16 Yoshinari T, Forbes RT, York P, et al. Crystallisation of amorphous 
mannitol is retarded using boric acid. Int J Pharm 2003; 258: 109 
120. 
20 General References 

21 Authors 
M Yelvigi. 
22 Date of Revision 
15 August 2005. 
Boric Acid 75

Bronopol 
1 Nonproprietary Names 
BP: Bronopol 
2 Synonyms 
2-Bromo-2-nitro-1,3-propanediol; b-bromo-b-nitrotrimethyleneglycol; 
Myacide. 
3 Chemical Name and CAS Registry Number 
2-Bromo-2-nitropropane-1,3-diol [52-51-7] 
4 Empirical Formula and Molecular Weight 
C3H6BrNO4 200.00 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Bronopol 0.010.1% w/v is used as an antimicrobial preservative 
either alone or in combination with other preservatives 
in topical pharmaceutical formulations, cosmetics, and 
toiletries; the usual concentration is 0.02% w/v. 
8 Description 
Bronopol is a white or almost white crystalline powder; 
odorless or with a faint characteristic odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for bronopol. 
Test BP 2004 
Identification . 
Characters . 
Acidity or alkalinity (1% w/v solution) 5.07.0 
Related substances . 
Sulfated ash 40.1% 
Water 40.5% 
Assay (anhydrous basis) 99.0101.0% 
10 Typical Properties 
Antimicrobial activity: bronopol is active against both Grampositive 
and Gram-negative bacteria including Pseudomonas 
aeruginosa, with typical minimum inhibitory concentrations 
(MICs) between 1050 mg/mL;(18) see also Table II. 
At room temperature, a 0.08% w/v aqueous solution may 
reduce the viability of culture collection strains of Escherichia 
coli and Pseudomonas aeruginosa by 100-fold or more 
in 15 minutes. Antimicrobial activity is not markedly 
influenced by pH in the range 5.08.0, nor by common 
anionic and nonionic surfactants, lecithin, or proteins.(2,5,6) 
Bronopol is less active against yeasts and molds, with typical 
MICs of 50400 mg/mL or more, and has little or no useful 
activity against bacterial spores. See also Section 12. 
Table II: Minimum inhibitory concentrations (MICs) of bronopol.(2,9) 
Microorganism MIC (mg/mL) 
Aspergillus niger 3200 
Bacillus subtilis 12.5 
Burkholderia (Pseudomonas) cepacia 25 
Candida albicans 1600 
Escherichia coli 12.550 
Klebsiella aerogenes 25 
Legionella pneumophilia 50 
Penicillium roqueforti 400 
Penicillium funiculosum 1600 
Pityrosporum ovale 125 
Proteus mirabilis 2550 
Proteus vulgaris 12.550 
Pseudomonas aeruginosa 12.550 
Saccharomyces cerevisiae 3200 
Salmonella gallinarum 25 
Staphylococcus aureus 12.550 
Staphylococcus epidermidis 50 
Streptococcus faecalis 50 
Trichophyton mentagrophytes 200 
Trichoderma viride 6400 
Melting point: 1281328C 
Partition coefficients: 
Mineral oil : water = 0.043 at 22248C; 
Peanut oil : water = 0.11 at 22248C. 
Solubility: see Table III. 
Table III: Solubility of bronopol. 
Solvent Solubility at 208C 
Cottonseed oil Slightly soluble 
Ethanol (95%) 1 in 2 
Glycerol 1 in 100 
Isopropyl myristate 1 in 200 
Mineral oil Slightly soluble 
Propan-2-ol 1 in 4 
Propylene glycol 1 in 2 
Water 1 in 4

11 Stability and Storage Conditions 
Bronopol is stable and its antimicrobial activity is practically 
unaffected when stored as a solid at room temperature and 
ambient relative humidity for up to 2 years.(3) 
The pH of a 1.0% w/v aqueous solution is 5.06.0 and falls 
slowly during storage; solutions are more stable in acid 
conditions. Half-lives of bronopol in buffered aqueous solutions 
at 0.03% w/v are shown in Table IV.(9) 
Microbiological assay results indicate longer half-lives than 
those obtained by HPLC and thus suggest that degradation 
products may contribute to antimicrobial activity. Formaldehyde 
and nitrites are among the decomposition products, but 
formaldehyde arises in such low concentrations that its 
antimicrobial effect is not likely to be significant. On exposure 
to light, especially under alkaline conditions, solutions become 
yellow or brown-colored but the degree of discoloration does 
not directly correlate with loss of antimicrobial activity. 
The bulk material should be stored in a well-closed, nonaluminum 
container protected from light, in a cool, dry place. 
Table IV: Half-lives of bronopol under different storage conditions. 
Temperature (8C) pH 4 pH 6 pH 8 
5 >5 years >5 years 6 months 
25 >5 years >5 years 4 months 
40 2 years 4 months 8 days 
60 2 weeks <2 days <1 day 
12 Incompatibilities 
Sulfhydryl compounds cause significant reductions in the 
activity of bronopol, and cysteine hydrochloride may be used 
as the deactivating agent in preservative efficacy tests; lecithin/ 
polysorbate combinations are unsuitable for this purpose.(5) 
Bronopol is incompatible with sodium thiosulfate, with sodium 
metabisulfite, and with amine oxide or protein hydrolysate 
surfactants. Owing to an incompatibility with aluminum, the 
use of aluminum in the packaging of products that contain 
bronopol should be avoided. 
13 Method of Manufacture 
Bronopol is synthesized by the reaction of nitromethane with 
paraformaldehyde in an alkaline environment, followed by 
bromination. After crystallization, bronopol powder may be 
milled to produce a powder of the required fineness. 
14 Safety 
Bronopol is used widely in topical pharmaceutical formulations 
and cosmetics as an antimicrobial preservative. 
Although bronopol has been reported to cause both irritant 
and hypersensitivity adverse reactions following topical 
use,(1013) it is generally regarded as a nonirritant and 
nonsensitizing material at concentrations up to 0.1% w/v. At 
a concentration of 0.02% w/v, bronopol is frequently used as a 
preservative in hypoallergenic formulations. 
Animal toxicity studies have shown no evidence of 
phototoxicity or tumor occurrence when bronopol is applied 
to rodents topically or administered orally; and there is no in 
vitro or in vivo evidence of mutagenicity;(1) this is despite the 
demonstrated potential of bronopol to liberate nitrite on 
decomposition, which in the presence of certain amines may 
generate nitrosamines. Formation of nitrosamines in formulations 
containing amines may be reduced by limiting the 
concentration of bronopol to 0.01% w/v and including an 
antioxidant such as 0.2% w/v alpha tocopherol or 0.05% w/v 
butylated hydroxytoluene;(14) other inhibitor systems may also 
be appropriate.(15) 
LD50 (dog, oral): 250 mg/kg (16) 
LD50 (mouse, IP): 15.5 mg/kg 
LD50 (mouse, IV): 48 mg/kg 
LD50 (mouse, oral): 270 mg/kg 
LD50 (mouse, SC): 116 mg/kg 
LD50 (mouse, skin): 4.75 g/kg 
LD50 (rat, IP): 26 mg/kg 
LD50 (rat, IV): 37.4 mg/kg 
LD50 (rat, oral): 180 mg/kg 
LD50 (rat, SC): 170 mg/kg 
LD50 (rat, skin): 1.6 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Bronopol may be harmful 
upon inhalation and the solid or concentrated solutions can be 
irritant to the skin and eyes. Eye protection, gloves, and dust 
respirator are recommended. Bronopol burns to produce toxic 
fumes. 
16 Regulatory Status 
Included in topical pharmaceutical formulations licensed in 
Europe. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 

18 Comments 
Bronopol owes its usefulness as a preservative largely to its 
activity against Pseudomonas aeruginosa, and its affinity for 
polar solvents, which prevents the loss of preservative into the 
oil phase of emulsions that is seen with some other preservatives. 
Other advantages include a low incidence of microbial 
resistance; low concentration exponent;(17) and good compatibility 
with most surfactants, other excipients, and preservatives, 
with which it can therefore be used in combination. 
The major disadvantages of bronopol are relatively poor 
activity against yeasts and molds, instability at alkaline pH, and 
the production of formaldehyde and nitrite on decomposition, 
although there is no evidence of serious toxicity problems 
associated with bronopol that are attributable to these 
compounds. 
The EINECS number for bronopol is 200-143-0. 
19 Specific References 
1 Croshaw B, Groves MJ, Lessel B. Some properties of bronopol, a 
new antimicrobial agent active against Pseudomonas aeruginosa. J 
Pharm Pharmacol 1964; 16 (Suppl.): 127T130T. 
2 Anonymous. Preservative properties of bronopol. Cosmet Toilet 
1977; 92(3): 8788. 
3 Bryce DM, Croshaw B, Hall JE, et al. The activity and safety of the 
antimicrobial agent bronopol (2-bromo-2-nitropropane-1,3-diol). 
J Soc Cosmet Chem 1978; 29: 324. 
Bronopol 77

4 Moore KE, Stretton RJ. A method for studying the activity of 
preservatives and its application to bronopol. J Appl Bacteriol 
1978; 45: 137141. 
5 Myburgh JA, McCarthy TJ. Effect of certain formulation factors 
on the activity of bronopol. Cosmet Toilet 1978; 93(2): 4748. 
6 Moore KE, Stretton RJ. The effect of pH, temperature and certain 
media constituents on the stability and activity of the preservative 
bronopol. J Appl Bacteriol 1981; 51: 483494. 
7 Sondossi M. The effect of fifteen biocides on formaldehyde 
resistant strains of Pseudomonas aeruginosa. J Ind Microbiol 
1986; 1: 8796. 
8 Kumanova R, Vassileva M, Dobreva S, et al. Evaluating bronopol. 
Manuf Chem 1989; 60(9): 3638. 
9 BASF Corp. Technical literature: Bronopol products, 2000. 
10 Maibach HI. Dermal sensitization potential of 2-bromo-2- 
nitropropane-1,3-diol (bronopol). Contact Dermatitis 1977; 3: 99. 
11 Elder RL. Final report on the safety assessment for 2-bromo-2- 
nitropropane-1,3-diol. J Environ Pathol Toxicol 1980; 4: 4761. 
12 Storrs FJ, Bell DE. Allergic contact dermatitis to 2-bromo-2- 
nitropropane-1,3-diol in a hydrophilic ointment. J Am Acad 
Dermatol 1983; 8: 157170. 
13 Grattan CEH, Harman RRM. Bronopol contact dermatitis in a 
milk recorder. Br J Dermatol 1985; 113 (Suppl. 29): 43. 
14 Dunnett PC, Telling GM. Study of the fate of bronopol and the 
effects of antioxidants on N-nitrosamine formation in shampoos 
and skin creams. Int J Cosmet Sci 1984; 6: 241247. 
15 Challis BC, Trew DF, Guthrie WG, Roper DV. Reduction of 
nitrosamines in cosmetic products. Int J Cosmet Sci 1995; 17: 119 
131. 
16 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 566. 
17 Denyer SP, Wallha. usser KH. Antimicrobial preservatives and their 
properties. In: Denyer SP, Baird RM, eds. Guide to Microbiological 
Control in Pharmaceuticals. London: Ellis Horwood, 1990: 251 
273. 
20 General References 
Croshaw B. Preservatives for cosmetics and toiletries. J Soc Cosmet 
Chem 1977; 28: 316. 
Rossmore HW, Sondossi M. Applications and mode of action of 
formaldehyde condensate biocides. Adv Appl Microbiol 1988; 33: 
223273. 
Shaw S. Patch testing bronopol. Cosmet Toilet 1997; 112(4): 67, 68, 
7173. 
Toler JC. Preservative stability and preservative systems. Int J Cosmet 
Sci 1985; 7: 157164. 
Wallha. usser KH. Bronopol. In: Kabara JJ, ed. Cosmetic and Drug 
Preservation Principles and Practice. New York: Marcel Dekker, 
1984: 635638. 
21 Authors 
SP Denyer, NA Hodges. 
22 Date of Revision 
15 August 2005. 
78 Bronopol

Butylated Hydroxyanisole 
1 Nonproprietary Names 
BP: Butylated hydroxyanisole 
PhEur: Butylhydroxyanisolum 
USPNF: Butylated hydroxyanisole 
2 Synonyms 
BHA; tert-butyl-4-methoxyphenol; 1,1-dimethylethyl-4-methoxyphenol; 
E320; Nipanox BHA; Nipantiox 1-F; Tenox BHA. 
3 Chemical Name and CAS Registry Number 
2-tert-Butyl-4-methoxyphenol [25013-16-5] 
4 Empirical Formula and Molecular Weight 
C11H16O2 180.25 
The PhEur 2005 describes butylated hydroxyanisole as 2-(1,1- 
dimethylethyl)-4-methoxyphenol containing not more than 
10% of 3-(1,1-dimethylethyl)-4-methoxyphenol. 
5 Structural Formula 
6 Functional Category 
Antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Butylated hydroxyanisole is an antioxidant (see Table I) with 
some antimicrobial properties.(1) It is used in a wide range of 
cosmetics, foods, and pharmaceuticals. When used in foods, it 
is used to delay or prevent oxidative rancidity of fats and oils 
and to prevent loss of activity of oil-soluble vitamins. 
Butylated hydroxyanisole is frequently used in combination 
with other antioxidants, particularly butylated hydroxytoluene 
and alkyl gallates, and with sequestrants or synergists such as 
citric acid. 
FDA regulations direct that the total content of antioxidant 
in vegetable oils and direct food additives shall not exceed 
0.02% w/w (200 ppm) of fat or oil content or essential (volatile) 
oil content of food. 
USDA regulations require that the total content of 
antioxidant shall not exceed 0.01% w/w (100 ppm) of any 
one antioxidant or 0.02% w/w combined total of any 
antioxidant combination in animal fats. 
Japanese regulations allow up to 1 g/kg in animal fats. 
Table I: Antioxidant uses of butylated hydroxyanisole. 
Antioxidant use Concentration (%) 
b-Carotene 0.01 
Essential oils and flavoring agents 0.020.5 
IM injections 0.03 
IV injections 0.00020.0005 
Oils and fats 0.02 
Topical formulations 0.0050.02 
Vitamin A 10mg per million units 
8 Description 
Butylated hydroxyanisole occurs as a white or almost white 
crystalline powder or a yellowish-white waxy solid with a faint, 
characteristic aromatic odor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for butylated hydroxyanisole. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Appearance of solution .  
Residue on ignition  40.01% 
Sulfated ash 40.1%  
Related substances .  
Heavy metals 410 ppm 40.001% 
Organic volatile impurities  . 
Assay  598.5% 
10 Typical Properties 
Antimicrobial activity: activity is similar to that of the 
p-hydroxybenzoate esters (parabens). The greatest activity 
is against molds and Gram-positive bacteria, with less 
activity against Gram-negative bacteria. 
Boiling point: 2648C at 745mmHg 
Density (true): 1.117 g/cm3 
Flash point: 1308C 
Melting point: 478C (for pure 2-tert-butyl-4-methoxyphenol); 
see also Section 18. 
Solubility: practically insoluble in water; soluble in methanol; 
freely soluble in 550% aqueous ethanol, propylene glycol, 
chloroform, ether, hexane, cottonseed oil, peanut oil, 
soybean oil, glyceryl monooleate, and lard, and in solutions 
of alkali hydroxides. 
Viscosity (kinematic): 3.3mm2/s (3.3 cSt) at 998C.

11 Stability and Storage Conditions 
Exposure to light causes discoloration and loss of activity. 
Butylated hydroxyanisole should be stored in a well-closed 
container, protected from light, in a cool, dry place. 
12 Incompatibilities 
Butylated hydroxyanisole is phenolic and undergoes reactions 
characteristic of phenols. It is incompatible with oxidizing 
agents and ferric salts. Trace quantities of metals and exposure 
to light cause discoloration and loss of activity. 
13 Method of Manufacture 
Prepared by the reaction of p-methoxyphenol with isobutene. 
14 Safety 
Butylated hydroxyanisole is absorbed from the gastrointestinal 
tract and is metabolized and excreted in the urine with less than 
1% unchanged within 24 hours of ingestion.(2) Although there 
have been some isolated reports of adverse skin reactions to 
butylated hydroxyanisole,(3,4) it is generally regarded as 
nonirritant and nonsensitizing at the levels employed as an 
antioxidant. 
Concern over the use of butylated hydroxyanisole has 
occurred following long-term animal feeding studies. Although 
previous studies in rats and mice fed butylated hydroxyanisole 
at several hundred times the US-permitted level in the human 
diet showed no adverse effects, a study in which rats, hamsters, 
and mice were fed butylated hydroxyanisole at 12% of the 
diet produced benign and malignant tumors of the forestomach, 
but in no other sites. However, humans do not have any 
region of the stomach comparable to the rodent forestomach 
and studies in animals that also do not have a comparable 
organ (dogs, monkeys, and guinea pigs) showed no adverse 
effects. Thus, the weight of evidence does not support any 
relevance to the human diet where butylated hydroxyanisole is 
ingested at much lower levels.(5) The WHO acceptable daily 
intake of butylated hydroxyanisole has been set at 500 mg/kg 
body-weight.(5) 
LD50 (mouse, oral): 1.12.0 g/kg(6) 
LD50 (rabbit, oral): 2.1 g/kg 
LD50 (rat, IP): 0.88 g/kg 
LD50 (rat, oral): 2.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Butylated hydroxyanisole 
may be irritant to the eyes and skin and on inhalation. It should 
be handled in a well-ventilated environment; gloves and eye 
protection are recommended. On combustion, toxic fumes may 
be given off. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (IM and IV injections, nasal 
sprays, oral capsules and tablets, and sublingual, rectal, topical, 
and vaginal preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Butylated hydroxytoluene. 
18 Comments 
The commercially available material can have a wide melting 
point range (47578C) owing to the presence of varying 
amounts of 3-tert-butyl-4-methoxyphenol. 
Tenox brands contain 0.1% w/w citric acid as a stabilizer. 
A specification for butylated hydroxyanisole is contained in 
the Food Chemicals Codex (FCC). 
The EINECS number for butylated hydroxyanisole is 246- 
563-8. 
19 Specific References 
1 Lamikanra A, Ogunbayo TA. A study of the antibacterial activity 
of butyl hydroxy anisole (BHA). Cosmet Toilet 1985; 100(10): 69 
74. 
2 El-Rashidy R, Niazi S. A new metabolite of butylated hydroxyanisole 
in man. Biopharm Drug Dispos 1983; 4: 389396. 
3 Roed-Peterson J, Hjorth N. Contact dermatitis from antioxidants: 
hidden sensitizers in topical medications and foods. Br J Dermatol 
1976; 94: 233241. 
4 Juhlin L. Recurrent urticaria: clinical investigation of 330 patients. 
Br J Dermatol 1981; 104: 369381. 
5 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-third report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1989; 
No. 776. 
6 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 609. 
20 General References 
Babich H, Borenfreund E. Cytotoxic effects of food additives and 
pharmaceuticals on cells in culture as determined with the neutral 
red assay. J Pharm Sci 1990; 79: 592594. 
Verhagen H. Toxicology of the food additives BHA and BHT. Pharm 
Weekbl Sci 1990; 12: 164166. 
21 Authors 
RT Guest. 
22 Date of Revision 
23 August 2005. 
80 Butylated Hydroxyanisole

Butylated Hydroxytoluene 
1 Nonproprietary Names 
BP: Butylated hydroxytoluene 
PhEur: Butylhydroxytoluenum 
USPNF: Butylated hydroxytoluene 
2 Synonyms 
Agidol; BHT; 2,6-bis(1,1-dimethylethyl)-4-methylphenol; 
butylhydroxytoluene; Dalpac; dibutylated hydroxytoluene; 
2,6-di-tert-butyl-p-cresol; 3,5-di-tert-butyl-4-hydroxytoluene; 
E321; Embanox BHT; Impruvol; Ionol CP; Nipanox BHT; 
OHS28890; Sustane; Tenox BHT; Topanol; Vianol. 
3 Chemical Name and CAS Registry Number 
2,6-Di-tert-butyl-4-methylphenol [128-37-0] 
4 Empirical Formula and Molecular Weight 
C15H24O 220.35 
5 Structural Formula 
6 Functional Category 
Antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Butylated hydroxytoluene is used as an antioxidant (see Table I) 
in cosmetics, foods, and pharmaceuticals. It is mainly used to 
delay or prevent the oxidative rancidity of fats and oils and to 
prevent loss of activity of oil-soluble vitamins. 
Butylated hydroxytoluene is also used at 0.51.0% w/w 
concentration in natural or synthetic rubber to provide 
enhanced color stability. 
Butylated hydroxytoluene has some antiviral activity(1) and 
has been used therapeutically to treat herpes simplex labialis.(2) 
8 Description 
Butylated hydroxytoluene occurs as a white or pale yellow 
crystalline solid or powder with a faint characteristic odor. 
Table I: Antioxidant uses of butylated hydroxytoluene. 
Antioxidant use Concentration (%) 
b-Carotene 0.01 
Edible vegetable oils 0.01 
Essential oils and flavoring agents 0.020.5 
Fats and oils 0.02 
Fish oils 0.010.1 
Inhalations 0.01 
IM injections 0.03 
IV injections 0.00090.002 
Topical formulations 0.00750.1 
Vitamin A 10mg per million units 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for butylated hydroxytoluene. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Appearance of solution .  
Congealing temperature  569.28C 
Freezing point 69708C  
Residue on ignition  40.002% 
Sulfated ash 40.1%  
Heavy metals  40.001% 
Organic volatile impurities  . 
Related substances .  
Assay  599.0% 
10 Typical Properties 
Boiling point: 2658C 
Density (bulk): 0.480.60 g/cm3 
Density (true): 1.031 g/cm3 
Flash point: 1278C (open cup) 
Melting point: 708C 
Moisture content: 40.05% 
Partition coefficient: Octanol : water = 4.175.80 
Refractive index: nD
75 = 1.4859 
Solubility: practically insoluble in water, glycerin, propylene 
glycol, solutions of alkali hydroxides, and dilute aqueous 
mineral acids. Freely soluble in acetone, benzene, ethanol 
(95%), ether, methanol, toluene, fixed oils, and mineral oil. 
More soluble than butylated hydroxyanisole in food oils 
and fats. 
Specific gravity: 
1.006 at 208C; 
0.890 at 808C; 
0.883 at 908C; 
0.800 at 1008C. 
Specific heat: 
1.63 J/g/8C (0.39 cal/g/8C) for solid;

2.05 J/g/8C (0.49 cal/g/8C) for liquid. 
Vapor density (relative): 7.6 (air = 1) 
Vapor pressure: 
1.33 Pa (0.01 mmHg) at 208C; 
266.6 Pa (2 mmHg) at 1008C. 
Viscosity (kinematic): 3.47mm2/s (3.47 cSt) at 808C. 
11 Stability and Storage Conditions 
Exposure to light, moisture, and heat causes discoloration and 
a loss of activity. Butylated hydroxytoluene should be stored in 
a well-closed container, protected from light, in a cool, dry 
place. 
12 Incompatibilities 
Butylated hydroxytoluene is phenolic and undergoes reactions 
characteristic of phenols. It is incompatible with strong 
oxidizing agents such as peroxides and permanganates. 
Contact with oxidizing agents may cause spontaneous combustion. 
Iron salts cause discoloration with loss of activity. Heating 
with catalytic amounts of acids causes rapid decomposition 
with the release of the flammable gas isobutene. 
13 Method of Manufacture 
Prepared by the reaction of p-cresol with isobutene. 
14 Safety 
Butylated hydroxytoluene is readily absorbed from the gastrointestinal 
tract and is metabolized and excreted in the urine 
mainly as glucuronide conjugates of oxidation products. 
Although there have been some isolated reports of adverse 
skin reactions, butylated hydroxytoluene is generally regarded 
as nonirritant and nonsensitizing at the levels employed as an 
antioxidant.(3,4) 
The WHO has set a temporary estimated acceptable daily 
intake for butylated hydroxytoluene at up to 125 mg/kg bodyweight.(
5) 
Ingestion of 4 g of butylated hydroxytoluene, although 
causing severe nausea and vomiting, has been reported to be 
nonfatal.(6) 
LD50 (guinea pig, oral): 10.7 g/kg(7) 
LD50 (mouse, IP): 0.14 g/kg 
LD50 (mouse, IV): 0.18 g/kg 
LD50 (mouse, oral): 0.65 g/kg 
LD50 (rat, oral): 0.89 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Butylated hydroxytoluene 
may be irritant to the eyes and skin and on inhalation. It should 
be handled in a well-ventilated environment; gloves and eye 
protection are recommended. Closed containers may explode 
owing to pressure build-up when exposed to extreme heat. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (IM and IV injections, nasal 
sprays, oral capsules and tablets, rectal, topical, and vaginal 
preparations). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Butylated hydroxyanisole. 
18 Comments 
A specification for butylated hydroxytoluene is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for butylated hydroxytoluene is 204- 
881-4. 
19 Specific References 
1 Snipes W, Person S, Keith A, Cupp J. Butylated hydroxytoluene 
inactivates lipid-containing viruses. Science 1975; 188: 6466. 
2 Freeman DJ, Wenerstrom G, Spruance SL. Treatment of recurrent 
herpes simplex labialis with topical butylated hydroxytoluene. 
Clin Pharmacol Ther 1985; 38: 5659. 
3 Roed-Peterson J, Hjorth N. Contact dermatitis from antioxidants: 
hidden sensitizers in topical medications and foods. Br J Dermatol 
1976; 94: 233241. 
4 Juhlin L. Recurrent urticaria: clinical investigation of 330 patients. 
Br J Dermatol 1981; 104: 369381. 
5 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1991; No. 806. 
6 Shlian DM, Goldstone J. Toxicity of butylated hydroxytoluene. N 
Engl J Med 1986; 314: 648649. 
7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 430. 
20 General References 
Verhagen H. Toxicology of the food additives BHA and BHT. Pharm 
Weekbl (Sci) 1990; 12: 164166. 
21 Authors 
RT Guest. 
22 Date of Revision 
23 August 2005. 
82 Butylated Hydroxytoluene

Butylparaben 
1 Nonproprietary Names 
BP: Butyl hydroxybenzoate 
JP: Butyl parahydroxybenzoate 
PhEur: Butylis parahydroxybenzoas 
USPNF: Butylparaben 
2 Synonyms 
4-Hydroxybenzoic acid butyl ester; Lexgard B; Nipabutyl; 
Tegosept B; Trisept B; Uniphen P-23; Unisept B. 
3 Chemical Name and CAS Registry Number 
Butyl-4-hydroxybenzoate [94-26-8] 
4 Empirical Formula and Molecular Weight 
C11H14O3 194.23 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Butylparaben is widely used as an antimicrobial preservative in 
cosmetics and pharmaceutical formulations; see Table I. 
It may be used either alone or in combination with other 
paraben esters or with other antimicrobial agents. In cosmetics, 
it is the fourth most frequently used preservative.(1) 
As a group, the parabens are effective over a wide pH range 
and have a broad spectrum of antimicrobial activity, although 
they are most effective against yeasts and molds; see Section 10. 
Owing to the poor solubility of the parabens, paraben salts, 
particularly the sodium salt, are frequently used in formulations. 
However, this may raise the pH of poorly buffered 
formulations. 
See Methylparaben for further information. 
Table I: Uses of butylparaben. 
Use Concentration (%) 
Oral suspensions 0.0060.05 
Topical preparations 0.020.4 
SEM: 1 
Excipient: Butylparaben 
Magnification: 240 
SEM: 2 
Excipient: Butylparaben 
Magnification: 2400 
8 Description 
Butylparaben occurs as colorless crystals or a white, crystalline, 
odorless or almost odorless, tasteless powder. 
9 Pharmacopeial Specifications 
See Table II.

Table II: Pharmacopeial specifications for butylparaben. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . .  
Appearance of solution  .  
Melting range 69728C 68718C 68728C 
Acidity  . . 
Loss on drying 40.5%  40.5% 
Residue on ignition 40.1%  40.05% 
Sulfated ash  40.1%  
Related substances  .  
Chloride 40.035%   
Sulfate 40.024%   
Heavy metals 420 ppm   
Readily carbonizable 
substances 
.   
Parahydroxybenzoic 
acid and salicylic 
acid 
.   
Organic volatile 
impurities 
  . 
Assay (dried basis) 599.0% 98.0102.0% 99.0100.5% 
10 Typical Properties 
Antimicrobial activity: butylparaben exhibits antimicrobial 
activity between pH 48. Preservative efficacy decreases 
with increasing pH owing to the formation of the phenolate 
anion. Parabens are more active against yeasts and molds 
than against bacteria. They are also more active against 
Gram-positive than against Gram-negative bacteria; see 
Table III.(2) 
The activity of the parabens increases with increasing 
chain length of the alkyl moiety, but solubility decreases. 
Butylparaben is thus more active than methylparaben. 
Activity may be improved by using combinations of 
parabens since synergistic effects occur. Activity has also 
been reported to be improved by the addition of other 
excipients; see Methylparaben for further information. 
Density (bulk): 0.731 g/cm3 
Density (tapped): 0.819 g/cm3 
Melting point: 68728C 
Partition coefficients: values for different vegetable oils vary 
considerably and are affected by the purity of the oil; see 
Table IV.(3) 
Solubility: see Table V. 
Table IV: Partition coefficients for butylparaben between oils and 
water.(3) 
Solvent Partition coefficient oil : water 
Mineral oil 3.0 
Peanut oil 280 
Soybean oil 280 
Table V: Solubility of butylparaben. 
Solvent Solubility at 208C unless otherwise stated 
Acetone Freely soluble 
Ethanol 1 in 0.5 
Ethanol (95%) 1 in 1 
Ether Freely soluble 
Glycerin 1 in 330 
Methanol 1 in 0.5 
Mineral oil 1 in 1000 
Peanut oil 1 in 20 
Propylene glycol 1 in 1 
Water 1 in >5000 
1 in 670 at 808C 
11 Stability and Storage Conditions 
Aqueous butylparaben solutions at pH 36 can be sterilized by 
autoclaving, without decomposition.(4) At pH 36, aqueous 
solutions are stable (less than 10% decomposition) for up to 
about 4 years at room temperature, while solutions at pH 8 or 
above are subject to rapid hydrolysis (10% or more after about 
60 days at room temperature).(5) 
Butylparaben should be stored in a well-closed container, in 
a cool, dry place. 
12 Incompatibilities 
The antimicrobial activity of butylparaben is considerably 
reduced in the presence of nonionic surfactants as a result of 
micellization.(6) Absorption of butylparaben by plastics has not 
been reported but appears probable given the behavior of other 
parabens. Some pigments, e.g., ultramarine blue and yellow 
iron oxide, absorb butylparaben and thus reduce its preservative 
properties.(7) 
Butylparaben is discolored in the presence of iron and is 
subject to hydrolysis by weak alkalis and strong acids. 
See also Methylparaben. 
Table III: Minimum inhibitory concentrations (MICs) for butylparaben 
in aqueous solution.(2) 
Microorganism MIC (mg/mL) 
Aerobacter aerogenes ATCC 8308 400 
Aspergillus niger ATCC 9642 125 
Aspergillus niger ATCC 10254 200 
Bacillus cereus var. mycoides ATCC 6462 63 
Bacillus subtilis ATCC 6633 250 
Candida albicans ATCC 10231 125 
Enterobacter cloacae ATCC 23355 250 
Escherichia coli ATCC 8739 5000 
Escherichia coli ATCC 9637 5000 
Klebsiella pneumoniae ATCC 8308 250 
Penicillium chrysogenum ATCC 9480 70 
Penicillium digitatum ATCC 10030 32 
Proteus vulgaris ATCC 13315 125 
Pseudomonas aeruginosa ATCC 9027 >1000 
Pseudomonas aeruginosa ATCC 15442 >1000 
Pseudomonas stutzeri 500 
Rhizopus nigricans ATCC 6227A 63 
Saccharomyces cerevisiae ATCC 9763 35 
Salmonella typhosa ATCC 6539 500 
Serratia marcescens ATCC 8100 500 
Staphylococcus aureus ATCC 6538P 125 
Staphylococcus epidermidis ATCC 12228 250 
Trichophyton mentagrophytes 35 
84 Butylparaben

13 Method of Manufacture 
Butylparaben is prepared by esterification of p-hydroxybenzoic 
acid with n-butanol. 
14 Safety 
Butylparaben and other parabens are widely used as antimicrobial 
preservatives in cosmetics and oral and topical 
pharmaceutical formulations. 
Systemically, no adverse reactions to parabens have been 
reported, although they have been associated with hypersensitivity 
reactions. See Methylparaben for further information. 
LD50 (mouse, IP): 0.23 g/kg(8) 
LD50 (mouse, oral): 13.2 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Butylparaben may be irritant 
to the skin, eyes, and mucous membranes and should be 
handled in a well-ventilated environment. Eye protection, 
gloves, and a dust mask or respirator are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (injections, oral 
capsules, solutions, suspensions, syrups and tablets, rectal, and 
topical preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Butylparaben sodium; ethylparaben; methylparaben; propylparaben. 
Butylparaben sodium 
Empirical formula: C11H13NaO3 
Molecular weight: 216.23 
CAS number: [36457-20-2] 
Synonyms: butyl-4-hydroxybenzoate sodium salt; sodium butyl 
hydroxybenzoate. 
Appearance: white, odorless or almost odorless, hygroscopic 
powder. 
Acidity/alkalinity: pH = 9.510.5 (0.1% w/v aqueous solution) 
Solubility: 1 in 10 of ethanol (95%); 1 in 1 of water. 
Comments: butylparaben sodium may be used instead of 
butylparaben because of its greater aqueous solubility. In 
unbuffered formulations, pH adjustment may be required. 
18 Comments 
See Methylparaben for further information and references. 
The EINECS number for butylparaben is 202-318-7. 
19 Specific References 
1 Decker RL, Wenninger JA. Frequency of preservative use in 
cosmetic formulas as disclosed to FDA1987. Cosmet Toilet 
1987; 102(12): 2124. 
2 Haag TE, Loncrini DF. Esters of para-hydroxybenzoic acid. In: 
Kabara JJ, ed. Cosmetic and Drug Preservation. New York: 
Marcel Dekker, 1984: 6377. 
3 Wan LSC, Kurup TRR, Chan LW. Partition of preservatives in oil/ 
water systems. Pharm Acta Helv 1986; 61: 308313. 
4 Aalto TR, Firman MC, Rigler NE. p-Hydroxybenzoic acid esters 
as preservatives I: uses, antibacterial and antifungal studies, 
properties and determination. J Am Pharm Assoc (Sci) 1953; 42: 
449457. 
5 Kamada A, Yata N, Kubo K, Arakawa M. Stability of phydroxybenzoic 
acid esters in acidic medium. Chem Pharm Bull 
1973; 21: 20732076. 
6 Aoki M, Kameta A, Yoshioka I, Matsuzaki T. Application of 
surface active agents to pharmaceutical preparations I: effect of 
Tween 20 upon the antifungal activities of p-hydroxybenzoic acid 
esters in solubilized preparations [in Japanese]. J Pharm Soc Jpn 
1956; 76: 939943. 
7 Sakamoto T, Yanagi M, Fukushima S, Mitsui T. Effects of some 
cosmetic pigments on the bactericidal activities of preservatives. J 
Soc Cosmet Chem 1987; 38: 8398. 
8 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 637. 
See also Methylparaben. 
20 General References 
Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical 
excipients associated with inactive ingredients in drug products 
(part I). Med Toxicol 1988; 3: 128165. 
See also Methylparaben. 
21 Authors 
R Johnson, R Steer. 
22 Date of Revision 
23 August 2005. 
Butylparaben 85

Calcium Alginate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Alginic acid; calcium salt; Algin; CA33; calc algin; calcium 
polymannuronate; Calginate; E404; Kaltostat. 
3 Chemical Name and CAS Registry Number 
Calcium alginate [9005-35-0] 
4 Empirical Formula and Molecular Weight 
[(C6H7O6)2Ca]n 195.16 (calculated) 
219.00 (actual, average) 
Each calcium ion binds with two alginate molecules. The 
molecular weight of 195.16 relates to one alginate molecule, 
and the equivalent of half a calcium ion, therefore n = 1=2. 
Calcium alginate is a polyuronide made up of a sequence of 
two hexuronic acid residues, namely D-mannuronic acid and Lguluronic 
acid. The two sugars form blocks of up to 20 units 
along the chain, with the proportion of the blocks dependent on 
the species of seaweed and also the part of the seaweed used. 
The number and length of the blocks are important in 
determining the physical properties of the alginate produced; 
the number and sequence of the mannuronate and guluronate 
residues varies in the naturally occurring alginate. 
It has a typical macromolecular weight between 10 000 and 
600 000. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emulsifiying agent; stabilizing agent; tablet disintegrant; 
thickener. 
7 Applications in Pharmaceutical Formulation 
or Technology 
In pharmaceutical formulations, calcium alginate and calciumsodium 
alginate have been used as tablet disintegrants.(1) The 
use of a high concentration (10%) of calcium-sodium alginate 
has been reported to cause slight speckling of tablets.(1) 
A range of different types of delivery systems intended for 
oral administration have been investigated. These exploit the 
gelling properties of calcium alginate.(2) Calcium alginate beads 
have been used to prepare floating dosage systems(3,4) containing 
amoxicillin,(5) frusemide,(6) and barium sulfate;(7) and as a 
means of providing a sustained or controlled-release action for 
sulindac,(8) diclofenac,(9,10) tiaramide,(11) insulin,(12) and ampicillin.(
13) The use of calcium alginate beads, reinforced with 
chitosan, may be useful for the controlled release of protein 
drugs to the gastro-intestinal tract.(14) The bioadhesive properties 
of calcium alginate beads have also been investigated.(15) 
A series of studies investigating the production,(16) formulation,(
17) and drug release(18) from calcium alginate matrices for 
oral administration have been published. The release of 
diltiazem hydrochloride from a polyvinyl alcohol matrix was 
shown to be controlled by coating with a calcium alginate 
membrane; the drug release profile could be modified by 
increasing the coating thickness of the calcium alginate layer.(19) 
The microencapsulation of live attenuated Bacillus Calmette 
Gue.rin (BCG) cells within a calcium alginate matrix has also 
been reported.(20) 
It has been shown that a modified drug release can be 
obtained from calcium alginate microcapsules,(21) pellets,(22,23) 
and microspheres.(24) When biodegradable bone implants 
composed of calcium alginate spheres and containing gentamicin 
were introduced into the femur of rats, effective drug 
levels in bone and soft tissue were obtained for 30 days and 7 
days, respectively.(25) 
Therapeutically, the gelling properties of calcium alginate 
are utilized in wound dressings in the treatment of leg ulcers, 
pressure sores, and other exuding wounds. These dressings are 
highly absorbent and are suitable for moderately or heavily 
exuding wounds. Calcium alginate dressings also have hemostatic 
properties, with calcium ions being exchanged for sodium 
ions in the blood; this stimulates both platelet activation and 
whole blood coagulation. A mixed calciumsodium salt of 
alginic acid is used as fibers in dressings or wound packing 
material. 
Sterile powder consisting of a mixture of calcium and 
sodium alginates has been used in place of talc in glove 
powders. 
In foods, calcium alginate is used as an emulsifier, thickener, 
and stabilizer. 
8 Description 
Calcium alginate is an odorless or almost odorless, tasteless, 
white to pale yellowish-brown powder or fibers. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Moisture content: loses not more than 22% of its weight on 
drying. 
Solubility: practically insoluble in chloroform, ethanol, ether, 
water, and other organic solvents. Soluble in dilute solutions 
of sodium citrate and of sodium bicarbonate and in sodium 
chloride solution. Soluble in alkaline solutions or in 
solutions of substances that combine with calcium. 
11 Stability and Storage Conditions 
Calcium alginate can be sterilized by autoclaving at 1158C for 
30 minutes or by dry heat at 1508C for 1 hour. Calcium alginate 
should be stored in airtight containers.

12 Incompatibilities 
Calcium alginate is incompatible with alkalis and alkali salts. 
Propranolol hydrochloride has been shown to bind to alginate 
molecules, suggesting that propranolol and calcium ions share 
common binding sites in the alginate chains; the formation of 
the calcium alginate gel structure was impeded in the presence 
of propranolol molecules.(26) 
13 Method of Manufacture 
Calcium alginate can be obtained from seaweed, mainly species 
of Laminaria. 
Solutions of sodium alginate interact with an ionized 
calcium salt, resulting in the instantaneous precipitation of 
insoluble calcium alginate, which can then be further processed. 
Introducing varying proportions of sodium ions during 
manufacture can produce products having different absorption 
rates. 
14 Safety 
Calcium alginate is widely used in oral and topical formulations, 
and in foods. 
In 1974, the WHO set an estimated acceptable daily intake 
of calcium alginate of up to 25 mg, as alginic acid, per kilogram 
body-weight.(27) 
When heated to decomposition, it emits acrid smoke and 
irritating fumes. 
LD50 (rat, IP): 1.41 g/kg(28) 
LD50 (rat, IV): 0.06 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral tablets). 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 
Alginic acid; potassium alginate; sodium alginate; propylene 
glycol alginate. 
18 Comments 
Although not included in any pharmacopeias, a specification 
for calcium alginate is contained in the Food Chemicals Codex 
(FCC),(29) and has been included in the British Pharmaceutical 
Codex (BPC);(30) see Table I. 
Table I: FCC(29) and BPC(30) specifications for calcium alginate. 
Test FCC 1996 BPC 1973 
Arsenic 43 ppm 43ppm 
Ash 1218%  
Heavy metals 40.004% (as lead)  
Iron  4530 ppm 
Lead 410 ppm 410 ppm 
Loss on drying 415% 22.00% 
Sulfated ash  31.034.0% 
Assay 89.6104.5%  
19 Specific References 
1 Khan KA, Rhodes CT. A comparative evaluation of some alginates 
as tablet disintegrants. Pharm Acta Helv 1972; 47: 4150. 
2 Tonnesen HH, Karlsen J. Alginate in drug delivery systems. Drug 
Dev Ind Pharm 2002; 28(6): 621630. 
3 Iannuccelli V, Coppi G, Bernabei MT, Cameroni R. Air compartment 
multiple-unit system for prolonged gastric residence. Part 1 
Formulation study. Int J Pharm 1998; 174: 4754. 
4 Whitehead L, Fell JT, Collett JH, Sharma HL, Smith AM. Floating 
dosage forms: in vivo study demonstrating prolonged gastric 
retention. J Control Release 1998; 55: 312. 
5 Whitehead L, Collett JH, Fell JT. Amoxicillin release from a 
floating dosage form based on alginates. Int J Pharm 2000; 210: 
4549. 
6 Iannuccelli V, Coppi G, Leo E. PVP solid dispersions for the 
controlled release of frusemide from a floating multiple-unit 
system. Drug Dev Ind Pharm 2000; 26(6): 595603. 
7 Iannuccelli V, Coppi G, Sansone R, Ferolla G. Air compartment 
multiple-unit system for prolonged gastric residence. Part 2. In 
vivo evaluation. Int J Pharm 1998; 174: 5562. 
8 Abd-Elmageed A. Preparation and evaluation of sulindac alginate 
beads. Bull Pharm Sci Assiut Univ 1999; 22(1): 7380. 
9 Mirghani A, Idkaidek NM, Salem MS, Najib NM. Formulation 
and release behavior of diclofenac sodium in Compritol 888 
matrix beads encapsulated in alginate. Drug Dev Ind Pharm 2000; 
26(7): 791795. 
10 Turkoglu M, Gursoy A, Eroglu L, Okar I. Effect of aqueous 
polymer dispersions on properties of diclofenac/alginate beads and 
in vivo evaluation in rats. STP Pharm Sci 1997; 7(2): 135140. 
11 Fathy M, Safwat SM, El-Shanawany SM, Tous SS, Otagiri M. 
Preparation and evaluation of beads made of different calcium 
alginate compositions for oral sustained release of tiaramide. 
Pharm Dev Tech 1998; 3(3): 355364. 
12 Rasmussen MR, Snabe T, Pedersen LH. Numerical modelling of 
insulin and amyloglucosidase release from swelling Ca-alginate 
beads. J Controlled Release 2003; 91(3): 395405. 
13 Torre ML, Giunchedi P, Maggi L, et al. Formulation and 
characterization of calcium alginate beads containing ampicillin. 
Pharm Dev Tech 1998; 3(2): 193198. 
14 Anal AK, Bhopatkar D, Tokura S, Tamura H, Stevens WF. 
Chitosan-alginate multilayer beads for gastric passage and 
controlled intestinal release of protein. Drug Dev Ind Pharm 
2003; 29(6): 713724. 
15 Gaserod O, Jolliffe IG, Hampson FC, Dettmar PW, Skjak-Braek G. 
Enhancement of the bioadhesive properties of calcium alginate gel 
beads by coating with chitosan. Int J Pharm 1998; 175: 237246. 
16 Ostberg T, Graffner C. Calcium alginate matrices for oral multiple 
unit administration. Part 1. Pilot investigations of production 
method. Acta Pharm Nord 1992; 4(4): 201208. 
17 Ostberg T, Vesterhus L, Graffner C. Calcium alginate matrices for 
oral multiple unit administration. Part 2. Effect of process and 
formulation factors on matrix properties. Int J Pharm 1993; 97: 
183193. 
18 Ostberg T, Lund EM, Graffner C. Calcium alginate matrices for 
oral multiple unit administration. Part 4. Release characteristics in 
different media. Int J Pharm 1994; 112: 241248. 
Calcium Alginate 87

19 Coppi G, Iannuccelli V, Cameroni R. Polysaccharide film-coating 
for freely swellable hydrogels. Pharm Dev Tech 1998; 3(3): 347 
353. 
20 Esquisabel A, Hernandez RM, Igartua M, et al. Production of BCG 
alginate-PLL microcapsules by emulsification/internal gelation. J 
Microencapsul 1997; 14(5): 627638. 
21 El-Gibaly I, Anwar MM. Development, characterization and in 
vivo evaluation of polyelectrolyte complex membrane gel microcapsules 
containing melatonin-resin complex for oral use. Bull 
Pharm Sci Assiut Univ 1998; 21(2): 117139. 
22 Pillay V, Fassihi R. In vitro modulation from cross-linked pellets 
for site-specific drug delivery to the gastrointestinal tract. Part 1. 
Comparison of pH-responsive drug release and associated kinetics. 
J Control Release 1999; 59: 229242. 
23 Pillay V, Fassihi R. In vitro release modulation from cross-linked 
pellets for site-specific drug delivery to the gastrointestinal tract. 
Part 2. Physicochemical characterization of calcium-alginate, 
calcium-pectinate and calcium-alginate-pectinate pellets. J Control 
Release 1999; 59: 243256. 
24 Chickering DE, Jacob JS, Desai TA, et al. Bioadhesive microspheres. 
Part 3. In vivo transit and bioavailability study of drug 
loaded alginate and poly (fumaricco-sebacic anhydride) microspheres. 
J Control Release 1997; 48: 3546. 
25 Iannuccelli V, Coppi G, Bondi M, et al. Biodegradable intraoperative 
system for bone infection treatment. Part 2. In vivo evaluation. 
Int J Pharm 1996; 143: 187194. 
26 Lim LY, Wan LSC. Propranolol hydrochloride binding in calcium 
alginate beads. Drug Dev Ind Pharm 1997; 23(10): 973980. 
27 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
28 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 668. 
29 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 54. 
30 British Pharmaceutical Codex. London: Pharmaceutical Press, 
1973: 66. 
20 General References 

21 Authors 
CG Cable. 
22 Date of Revision 
22 August 2005. 
88 Calcium Alginate

Calcium Carbonate 
1 Nonproprietary Names 
BP: Calcium carbonate 
JP: Precipitated calcium carbonate 
PhEur: Calcii carbonas 
USP: Calcium carbonate 
2 Synonyms 
Calcium carbonate (1 : 1); carbonic acid calcium salt 1:1; creta 
preparada; Destab; E170; MagGran CC; Micromite; Pharma- 
Carb; precipitated carbonate of lime; precipitated chalk; 
Vivapress Ca; Witcarb. 
3 Chemical Name and CAS Registry Number 
Carbonic acid, calcium salt (1 : 1) [471-34-1] 
4 Empirical Formula and Molecular Weight 
CaCO3 100.09 
5 Structural Formula 
CaCO3 
6 Functional Category 
Buffering agent; coating agent; opacifier; tablet and capsule 
diluent; therapeutic agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Calcium carbonate, employed as a pharmaceutical excipient, is 
mainly used in solid-dosage forms as a diluent.(16) It is also 
used as a base for medicated dental preparations, as a buffering 
agent, and as a dissolution aid in dispersible tablets. Calcium 
carbonate is used as a bulking agent in tablet sugar-coating 
processes and as an opacifier in tablet film-coating. 
Calcium carbonate is also used as a food additive and 
therapeutically as an antacid and calcium supplement. 
8 Description 
Calcium carbonate occurs as an odorless and tasteless white 
powder or crystals. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for calcium carbonate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters  .  
Loss on drying 41.0% 42.0% 42.0% 
Substances 
insoluble in 
acetic acid 
40.2% 40.2% 40.2% 
Fluoride   40.005% 
Arsenic 45 ppm 44 ppm 43 ppm 
Barium . . . 
Chlorides  4330 ppm  
Lead   43 ppm 
Iron  4200 ppm 40.1% 
Heavy metals 420 ppm 420 ppm 40.002% 
Magnesium and 
alkali (metals) 
salts 
40.5% 41.5% 41.0% 
Sulfates  40.25%  
Mercury   40.5 mg/g 
Organic volatile 
impurities 
  . 
Assay (dried basis) 5 98.5% 98.5%100.5% 98.0%100.5% 
SEM: 1 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-3 
Magnification: 600 Voltage: 20 kV

SEM: 2 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-3 
Magnification: 2400 Voltage: 20 kV 
SEM: 3 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-4 
Magnification: 600 Voltage: 20 kV 
SEM: 4 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-4 
Magnification: 2400 Voltage: 20 kV 
SEM: 5 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-2 
Magnification: 600 Voltage: 20 kV 
90 Calcium Carbonate

SEM: 6 
Excipient: Calcium carbonate 
Manufacturer: Whittaker, Clark & Daniels 
Lot No.: 15A-2 
Magnification: 2400 Voltage: 20 kV 
10 Typical Properties 
Acidity/alkalinity: pH = 9.0 (10% w/v aqueous dispersion) 
Density (bulk): 0.8 g/cm3 
Density (tapped): 1.2 g/cm3 
Flowability: cohesive. 
Hardness (Mohs): 3.0 for Millicarb. 
Melting point: decomposes at 8258C. 
Moisture content: see Figure 1. 
Particle size: see Figure 2. 
Refractive index: 1.59 
Solubility: practically insoluble in ethanol (95%) and water. 
Solubility in water is increased by the presence of 
ammonium salts or carbon dioxide. The presence of alkali 
hydroxides reduces solubility. 
Specific gravity: 2.7 
Specific surface area: 6.216.47m2/g 
11 Stability and Storage Conditions 
Calcium carbonate is stable and should be stored in a wellclosed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with acids and ammonium salts (see also Sections 
10 and 18). 
13 Method of Manufacture 
Calcium carbonate is prepared by double decomposition of 
calcium chloride and sodium bicarbonate in aqueous solution. 
Density and fineness are governed by the concentrations of the 
solutions. Calcium carbonate is also obtained from the 
naturally occurring minerals aragonite, calcite, and vaterite. 
14 Safety 
Calcium carbonate is mainly used in oral pharmaceutical 
formulations and is generally regarded as a nontoxic material. 
However, calcium carbonate administered orally may cause 
constipation and flatulence. Consumption of large quantities 
(460 g daily) may also result in hypercalcemia or renal 
impairment.(7) Therapeutically, oral doses of up to about 
1.5 g are employed as an antacid. In the treatment of 
hyperphosphatemia in patients with chronic renal failure, oral 
daily doses of 2.517 g have been used. Calcium carbonate may 
interfere with the absorption of other drugs from the 
gastrointestinal tract if administered concomitantly. 
LD50 (rat, oral): 6.45 g/kg 
Figure 1: Moisture sorptiondesorption isotherm of calcium carbonate. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Calcium carbonate may be 
irritant to the eyes and on inhalation. Eye protection, gloves, 
and a dust mask are recommended. Calcium carbonate should 
be handled in a well-ventilated environment. In the UK, the 
long-term (8-hour TWA) occupational exposure limit for 
calcium carbonate is 10 mg/m3 for total inhalable dust and 
4 mg/m3 for respirable dust.(8) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets; otic solutions). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
 
Calcium Carbonate 91

Figure 2: Particle-size distribution of calcium carbonate (Sturcal, 
Rhodia). 
*: Sturcal F 
&: Sturcal H 
~: Sturcal L 
18 Comments 
When calcium carbonate is used in tablets containing aspirin 
and related substances, traces of iron may cause discoloration. 
This may be overcome by inclusion of a suitable chelating 
agent. Grades with reduced lead levels are commercially 
available for use in antacids and calcium supplements. 
Directly compressible tablet diluents containing calcium 
carbonate and other excipients are commercially available. 
Examples of such grades are Barcroft CS90 (containing 10% 
starch), Barcroft CX50 (containing 50% sorbitol), and 
Barcroft CZ50 (containing 50% sucrose) available from SPI 
Pharma. Available from DMV International, are Cal-Carb 
4450 PG (containing maltodextrin), and Cal-Carb 4457 and 
Cal-Carb 4462 (both containing pregelatinized corn starch). 
Two directly compressible grades containing only calcium 
carbonate are commercially available (Vivapress Ca 740 and 
Vivapress Ca 800, J. Rettenmaier and So. hne). 
A specification for calcium carbonate is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for calcium carbonate is 207-439-9. 
19 Specific References 
1 Haines-Nutt RF. The compression properties of magnesium and 
calcium carbonates. J Pharm Pharmacol 1976; 28: 468470. 
2 Ejiofor O, Esezebo S, Pilpel N. The plasto-elasticity and 
compressibility of coated powders and the tensile strength of their 
tablets. J Pharm Pharmacol 1986; 38: 17. 
3 Gorecki DKJ, Richardson CJ, Pavlakidis P, Wallace SM. Dissolution 
rates in calcium carbonate tablets: a consideration in product 
selection. Can J Pharm 1989; 122: 484487, 508. 
4 Allen LV. Featured excipient: capsule and tablet diluents. Int J 
Pharm Compound 2000; 4(4): 306310, 324325. 
5 Mattsson S, Nystrom C. Evaluation of strength-enhancing factors 
of a ductile binder in direct compression of sodium bicarbonate 
and calcium carbonate powders. Eur J Pharm Sci 2000; 10(1): 53 
66. 
6 Serra MD, Robles LV. Compaction of agglomerated mixtures of 
calcium carbonate and microcrystalline cellulose. Int J Pharm 
2003; 258(12): 153164. 
7 Orwoll ES. The milk-alkali syndrome: current concepts. Ann 
Intern Med 1982; 97: 242248. 
8 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Armstrong NA. Tablet manufacture. In: Swarbrick J, Boylan JC, eds. 
Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. New 
York: Marcel Dekker, 2002: 27132732. 
Ciancio SG. Dental products. In: Swarbrick J, Boylan JC, eds. 
Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. 
New York: Marcel Dekker, 2002: 691701. 
Roberts DE, Rogers CM, Richards CE, Lee MG. Calcium carbonate 
mixture. Pharm J 1986; 236: 577. 
21 Authors 
NA Armstrong. 
22 Date of Revision 
16 August 2005. 
92 Calcium Carbonate

Calcium Phosphate, Dibasic Anhydrous 
1 Nonproprietary Names 
BP: Anhydrous calcium hydrogen phosphate 
JP: Anhydrous dibasic calcium phosphate 
PhEur: Calcii hydrogenophosphas anhydricus 
USP: Dibasic calcium phosphate 
2 Synonyms 
A-TAB; calcium monohydrogen phosphate; calcium orthophosphate; 
Di-Cafos AN; dicalcium orthophosphate; E341; 
Emcompress Anhydrous; Fujicalin; phosphoric acid calcium 
salt (1 : 1); secondary calcium phosphate. 
3 Chemical Name and CAS Registry Number 
Dibasic calcium phosphate [7757-93-9] 
4 Empirical Formula and Molecular Weight 
CaHPO4 136.06 
5 Structural Formula 
CaHPO4 
6 Functional Category 
Tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Anhydrous dibasic calcium phosphate is used both as an 
excipient and as a source of calcium in nutritional supplements. 
It is used particularly in the nutritional/health food sectors. It is 
also used in pharmaceutical products because of its compaction 
properties, and the good flow properties of the coarse-grade 
material.(15) The predominant deformation mechanism of 
anhydrous dibasic calcium phosphate coarse-grade is brittle 
fracture and this reduces the strain-rate sensitivity of the 
material, thus allowing easier transition from the laboratory to 
production scale. However, unlike the dihydrate, anhydrous 
dibasic calcium phosphate when compacted at higher pressures 
can exhibit lamination and capping. This phenomenon can be 
observed when the material represents a substantial proportion 
of the formulation and is exacerbated by the use of deep 
concave tooling. This phenomenon also appears to be 
independent of rate of compaction. 
Anhydrous dibasic calcium phosphate is abrasive and a 
lubricant is required for tableting, for example 1% w/w 
magnesium stearate or 1% w/w sodium stearyl fumarate. 
Two particle-size grades of anhydrous dibasic calcium 
phosphate are used in the pharmaceutical industry. Milled 
material is typically used in wet-granulated or roller-compacted 
formulations. The unmilled or coarse-grade material is 
typically used in direct-compression formulations. 
Anhydrous dibasic calcium phosphate is nonhygroscopic 
and stable at room temperature. It does not hydrate to form the 
dihydrate. 
Anhydrous dibasic calcium phosphate is used in toothpaste 
and dentifrice formulations for its abrasive properties. 
8 Description 
Anhydrous dibasic calcium phosphate is a white, odorless, 
tasteless powder or crystalline solid. It occurs as triclinic 
crystals. 
SEM: 1 
Excipient: Emcompress Anhydrous 
Manufacturer: JRS Pharma LP 
Magnification: 50 Voltage: 5kV 
SEM: 2 
Excipient: Emcompress Anhydrous 
Manufacturer: JRS Pharma LP 
Magnification: 200 Voltage: 5kV

9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for calcium phosphate, dibasic 
anhydrous. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . .  
Loss on ignition   6.68.5% 
Loss on drying 41.0% 42.0%  
Acid insoluble substance 40.05%  40.2% 
Heavy metals 431 ppm 440 ppm 40.003% 
Chloride 40.248% 4330 ppm 40.25% 
Fluoride  4100 ppm 40.005% 
Sulfate 40.200% 40.5% 40.5% 
Carbonate . . . 
Barium . . . 
Arsenic 42 ppm 410 ppm 43 mg/g 
Organic volatile impurities   . 
Iron  4400 ppm  
Assay (dried basis) 598.0% 98.0101.0% 98.0105.0% 
10 Typical properties 
Acidity/alkalinity: 
pH = 7.3 (20% slurry); 
pH = 5.1 (20% slurry of A-TAB); 
pH = 6.17.2 (5% slurry of Fujicalin). 
Angle of repose: 328 (for Fujicalin) 
Density: 2.89 g/cm3 
Density (bulk): 
0.78 g/cm3 for A-TAB; 
0.45 g/cm3 for Fujicalin. 
Density (tapped): 
0.82 g/cm3 for A-TAB; 
0.46 g/cm3 for Fujicalin. 
Melting point: does not melt; decomposes at 4258C to form 
calcium pyrophosphate. 
Moisture content: 0.10.2%. The anhydrous material contains 
only surface-adsorbed moisture and cannot be rehydrated to 
form the dihydrate. 
Particle size distribution: 
A-TAB: average particle diameter 180 mm; 
Encompress Anhydrous: average particle diameter 136 mm; 
Fujicalin: average particle diameter 94 mm; 
Powder: average particle diameter: 15 mm. 
Solubility: practically insoluble in ether, ethanol, and water; 
soluble in dilute acids. 
Specific surface area: 
2030m2/g for A-TAB; 
35m2/g for Fujicalin. 
11 Stability and Storage Conditions 
Dibasic calcium phosphate anhydrous is a nonhygroscopic, 
relatively stable material. Under conditions of high humidity it 
does not hydrate to form the dihydrate. 
The bulk material should be stored in a well-closed 
container in a dry place. 
12 Incompatibilities 
Dibasic calcium phosphate should not be used to formulate 
tetracyline antibiotics.(6) 
The surface of milled anhydrous dibasic calcium phosphate 
is alkaline(2) and consequently it should not be used with drugs 
that are sensitive to alkaline pH. However, reports(7,8) suggest 
there are differences in the surface alkalinity/acidity between 
the milled and unmilled grades of anhydrous dibasic calcium 
phosphate; the unmilled form has an acidic surface environment. 
This difference has important implications for drug 
stability, particularly when reformulating from, e.g. roller 
compaction to direct compression, when the particle size of 
the anhydrous dibasic calcium phosphate might be expected to 
change. 
Dibasic calcium phosphate dihydrate has been reported to 
be incompatible with a number of drugs and excipients and 
many of these incompatibilities are expected to occur with 
dibasic calcium phosphate, anhydrous; see Calcium phosphate, 
dibasic dihydrate. 
13 Method of Manufacture 
Calcium phosphates are usually prepared by reacting very pure 
phosphoric acid with calcium hydroxide, Ca(OH)2 obtained 
from limestone, in stoichiometric ratio in aqueous suspension(2) 
followed by drying at a temperature that will allow the correct 
hydration state to be achieved. After drying, the coarse-grade 
material is obtained by means of a classification unit; the fine 
particle-size material is obtained by milling. Dibasic calcium 
phosphate, anhydrous, may also be prepared by spraydrying.(
9,10) 
14 Safety 
Dibasic calcium phosphate anhydrous is widely used in oral 
pharmaceutical products, food products, and toothpastes and 
is generally regarded as a relatively nontoxic and nonirritant 
material. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. The fine-milled grades can 
generate nuisance dusts and the use of a respirator or dust mask 
may be necessary. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (oral capsules and tablets). 
Included in nonparenteral medicines licensed in Europe. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Calcium phosphate, dibasic dihydrate; calcium phosphate, 
tribasic; calcium sulfate. 
18 Comments 
Grades of anhydrous dibasic calcium phosphate available for 
direct compression include A-TAB (Rhodia), Di-Cafos AN 
(Chemische Fabrik Budenheim), Emcompress Anhydrous (JRS 
Pharma LP), and Fujicalin (Fuji Chemical Industry Co. Ltd.). 
The EINECS number for calcium phosphate is 231-837-1. 
94 Calcium Phosphate, Dibasic Anhydrous

19 Specific References 
1 Fischer E. Calcium phosphate as a pharmaceutical excipient. 
Manuf Chem 1992; 64(6): 2527. 
2 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting 1: physico-pharmaceutical properties. Pharm World Sci 
1993; 15(3): 105115. 
3 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting 2: comparison of tableting properties. Pharm World Sci 
1993; 15(3): 116122. 
4 Hwang R-C, Peck GR. A systematic evaluation of the compression 
and tablet characteristics of various types of lactose and dibasic 
calcium phosphate. Pharm Technol 2001; 25(6): 54, 56, 58, 60, 
62, 64, 66, 68. 
5 Schlack H, Bauer-Brandl A, Schubert R, Becker D. Properties of 
Fujicalin, a new modified anhydrous dibasic calcium phosphate for 
direct compression: comparison with dicalcium phosphate dihydrate. 
Drug Dev Ind Pharm 2001; 27(8): 789801. 
6 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker. 
1989: 9394. 
7 Dulin WA. Degradation of bisoprolol fumarate in tablets 
formulated with dicalcium phosphate. Drug Dev Ind Pharm 
1995; 21(4): 393409. 
8 Glombitza BW, Oelkrug D, Schmidt PC. Surface acidity of solid 
pharmaceutical excipients I. Determination of the surface acidity. 
Eur J Pharm Biopharm 1994; 40(5): 289293. 
9 Takami K, Machimura H, Takado K, Inagaki M, Kawashima Y. 
Novel preparation of free-flowing spherically granulated dibasic 
calcium phosphate anhydrous for direct tabletting. Chem Pharm 
Bull 1996; 44(4): 868870. 
10 Schlack H, Bauer-Brandl A, Schubert R, Becker D. Properties of 
Fujicalin, a new modified anhydrous dibasic calcium phosphate 
dihydrate. Drug Dev Ind Pharm 2001; 27(9): 789801. 
20 General References 
Bryan JW, McCallister JD. Matrix forming capabilities of three calcium 
diluents. Drug Dev Ind Pharm 1992; 18(19): 20292047. 
Carstensen JT, Ertell C. Physical and chemical properties of calcium 
phosphates for solid state pharmaceutical formulations. Drug Dev 
Ind Pharm 1990; 16(7): 11211133. 
Fuji Chemical Industry Co. Ltd. Technical literature: Fujicalin, 1998. 
Rhodia. Technical literature: Calcium phosphate excipients, 1999. 
21 Authors 
RC Moreton. 
22 Date of Revision 
30 August 2005. 
Calcium Phosphate, Dibasic Anhydrous 95

Calcium Phosphate, Dibasic Dihydrate 
1 Nonproprietary Names 
BP: Calcium hydrogen phosphate 
JP: Dibasic calcium phosphate 
PhEur: Calcii hydrogenophosphas dihydricus 
USP: Dibasic calcium phosphate 
2 Synonyms 
Calcium hydrogen orthophosphate dihydrate; calcium monohydrogen 
phosphate dihydrate; Di-Cafos; dicalcium orthophosphate; 
DI-TAB; E341; Emcompress; phosphoric acid 
calcium salt (1 : 1) dihydrate; secondary calcium phosphate. 
3 Chemical Name and CAS Registry Number 
Dibasic calcium phosphate dihydrate [7789-77-7] 
4 Empirical Formula and Molecular Weight 
CaHPO42H2O 172.09 
5 Structural Formula 
CaHPO42H2O 
6 Functional Category 
Tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dibasic calcium phosphate dihydrate is widely used in tablet 
formulations both as an excipient and as a source of calcium 
and phosphorus in nutritional supplements.(18) It is one of the 
more widely used materials, particularly in the nutritional/ 
health food sectors. It is also used in pharmaceutical products 
because of its compaction properties, and the good flow 
properties of the coarse-grade material. The predominant 
deformation mechanism of dibasic calcium phosphate coarsegrade 
is brittle fracture and this reduces the strain-rate 
sensitivity of the material, thus allowing easier transition 
from the laboratory to production scale. However, dibasic 
calcium phosphate dihydrate is abrasive and a lubricant is 
required for tableting, for example about 1% w/w of 
magnesium stearate or about 1% w/w of sodium stearyl 
fumarate is commonly used. 
Two main particle-size grades of dibasic calcium phosphate 
dihydrate are used in the pharmaceutical industry. The milled 
material is typically used in wet-granulated, roller-compacted 
or slugged formulations. The unmilled or coarse-grade 
material is typically used in direct-compression formulations. 
Dibasic calcium phosphate dihydrate is nonhygroscopic and 
stable at room temperature. However, under certain conditions 
of temperature and humidity, it can lose water of crystallization 
below 1008C. This has implications for certain types of 
packaging and aqueous film coating since the loss of water of 
crystallization appears to be initiated by high humidity and by 
implication high moisture vapor concentrations in the vicinity 
of the dibasic calcium phosphate dihydrate particles.(8) 
Dibasic calcium phosphate dihydrate is also used in toothpaste 
and dentifrice formulations for its abrasive properties. 
8 Description 
Dibasic calcium phosphate dihydrate is a white, odorless, 
tasteless powder or crystalline solid. It occurs as monoclinic 
crystals. 
SEM: 1 
Excipient: Dibasic calcium phosphate dihydrate, coarse grade 
Manufacturer: JRS Pharma LP. 
Lot No.: W28C 
Magnification: 100

SEM: 2 
Excipient: Dibasic calcium phosphate dihydrate, coarse grade 
Manufacturer: JRS Pharma LP. 
Lot No.: W28C 
Magnification: 300 
SEM: 3 
Excipient: Dibasic calcium phosphate dihydrate 
Manufacturer: Rhodia. 
Lot No.: 16A-1 (89) 
Magnification: 120 
SEM: 4 
Excipient: Dibasic calcium phosphate dihydrate, coarse grade 
Manufacturer: Rhodia. 
Lot No.: 16A-1 (89) 
Magnification: 600 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for calcium phosphate, dibasic 
dihydrate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . .  
Loss on ignition   24.526.5% 
Loss on drying 19.522.0%   
Acid insoluble 
substances 
40.05%  40.2% 
Heavy metals 431 ppm 440 ppm 40.003% 
Chloride 40.248% 4330 ppm 40.25% 
Fluoride  4100 ppm 40.005% 
Sulfate 40.160% 40.5% 40.5% 
Carbonate . . . 
Barium . . . 
Arsenic 42 ppm 410 ppm 43 mg/g 
Organic volatile 
impurities 
  . 
Iron  4400 ppm  
Assay 598.0% 98.0105.0% 98.0105.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 7.4 (20% slurry of DI-TAB) 
Angle of repose: 28.38 for Emcompress.(9) 
Density (bulk): 0.915 g/cm3 
Density (tapped): 1.17 g/cm3 
Density (true): 2.389 g/cm3 
Calcium Phosphate, Dibasic Dihydrate 97

Flowability: 
27.3 g/s for DI-TAB; 
11.4 g/s for Emcompress.(9) 
Melting point: dehydrates below 1008C. 
Moisture content: dibasic calcium phosphate dihydrate contains 
two molecules of water of crystallization, which can be 
lost at temperatures well below 1008C. 
Particle size distribution: DI-TAB: average particle diameter 
180 mm 
Fine powder: average particle diameter 9 mm 
Solubility: practically insoluble in ethanol, ether, and water; 
soluble in dilute acids. 
Specific surface area: 0.440.46m2/g for Emcompress 
11 Stability and Storage Conditions 
Dibasic calcium phosphate dihydrate is a nonhygroscopic, 
relatively stable material. However, under certain conditions 
the dihydrate can lose water of crystallization. This has 
implications for both storage of the bulk material and coating 
and packaging of tablets containing dibasic calcium phosphate 
dihydrate. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Dibasic calcium phosphate dihydrate should not be used to 
formulate tetracycline antibiotics.(10) Dibasic calcium phosphate 
dihydrate has been reported to be incompatible with 
indomethacin,(11) aspirin,(12) aspartame,(13) ampicillin,(14) 
cephalexin,(15) and erythromycin.(16) The surface of dibasic 
calcium phosphate dihydrate is alkaline(16) and consequently it 
should not be used with drugs that are sensitive to alkaline pH. 
13 Method of Manufacture 
Calcium phosphates are usually manufactured by reacting very 
pure phosphoric acid with calcium hydroxide, Ca(OH)2 
obtained from limestone, in stoichiometric ratio in aqueous 
suspension followed by drying at a temperature that will allow 
the correct hydration state to be achieved. After drying, the 
coarse-grade material is obtained by means of a classification 
unit; the fine particle-size material is obtained by milling. 
14 Safety 
Dibasic calcium phosphate dihydrate is widely used in oral 
pharmaceutical products, food products, and toothpastes and 
is generally regarded as a nontoxic and nonirritant material. 
However, oral ingestion of large quantities may cause 
abdominal discomfort. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. The fine-milled grades can 
generate nuisance dusts and the use of a respirator or dust mask 
may be necessary. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (oral capsules and tablets). 
Included in nonparenteral medicines licensed in Europe. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Calcium phosphate, dibasic anhydrous; calcium phosphate, 
tribasic. 
18 Comments 
Grades of dibasic calcium phosphate dihydrate available for 
direct compression include Calstar (FMC Biopolymer), Di- 
Cafos (Chemische Fabrik Budenheim), DI-TAB (Rhodia), and 
Emcompress (JRS Pharma LP). 
Accelerated stability studies carried out at elevated temperatures 
on formulations containing significant proportions of 
dibasic calcium phosphate dihydrate can give erroneous results 
owing to irreversible dehydration of the dihydrate to the 
anhydrous form. Depending on the type of packaging and 
whether or not the tablet is coated, the phenomenon can be 
observed at temperatures as low as 408C after 6 weeks of 
storage. As the amount of dibasic calcium phosphate dihydrate 
in the tablet is reduced, the effect is less easy to observe. 
The EINECS number for calcium phosphate is 231-837-1. 
19 Specific References 
1 Lausier JM, Chiang C-W, Zompa HA, Rhodes CT. Aging of tablets 
made with dibasic calcium phosphate dihydrate as matrix. J Pharm 
Sci 1977; 66(11): 16361637. 
2 Carstensen JT, Ertell C. Physical and chemical properties of 
calcium phosphates for solid state pharmaceutical formulations. 
Drug Dev Ind Pharm 1990; 16(7): 11211133. 
3 Bryan JW, McCallister JD. Matrix forming capabilities of three 
calcium diluents. Drug Dev Ind Pharm 1992; 18(19): 20292047. 
4 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting I: physico-pharmaceutical properties. Pharm World Sci 
1993; 15(3): 105115. 
5 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting II: comparison of tableting properties. Pharm World Sci 
1993; 15(3): 116122. 
6 Land..n M, Mart..nez-Pacheco R, Go.mez-Amoza JL, et al. The 
effect of country of origin on the properties of dicalcium phosphate 
dihydrate powder. Int J Pharm 1994; 103: 918. 
7 Land..n M, Mart..nez-Pacheco R, Go.mez-Amoza JL, et al. 
Dicalcium phosphate dihydrate for direct compression: characterization 
and intermanufacturer variability. Int J Pharm 1994; 109: 
18. 
8 Land..n M, Rowe RC, York P. Structural changes during the 
dehydration of dicalcium phosphate dihydrate. Eur J Pharm Sci 
1994; 2: 245252. 
9 C. elik M, Okutgen E. A feasibility study for the development of a 
prospective compaction functionality test and the establishment of 
a compaction data bank. Drug Dev Ind Pharm 1993; 19(1718): 
23092334. 
10 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989: 9394. 
11 Eerika. inen S, Yliruusi J, Laakso R. The behaviour of the sodium 
salt of indomethacin in the cores of film-coated granules containing 
various fillers. Int J Pharm 1991; 71: 201211. 
12 Land..n M, Perez-Marcos B, Casalderrey M, et al. Chemical 
stability of acetyl salicylic acid in tablets prepared with different 
commercial brands of dicalcium phosphate dihydrate. Int J Pharm 
1994; 107: 247249. 
98 Calcium Phosphate, Dibasic Dihydrate

13 El-Shattawy HH, Peck GE, Kildsig DO. Aspartame direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7(5): 
605619. 
14 El-Shattaway HH. Ampicillin direct compression excipients: 
preformulation stability screening using differential scanning 
calorimetry. Drug Dev Ind Pharm 1982; 8(6): 819831. 
15 El-Shattaway HH, Kildsig DO, Peck GE. Cephalexin I direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6): 
897909. 
16 El-Shattaway HH, Kildsig DO, Peck GE. Erythromycin direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6): 
937947. 
20 General References 
Green CE, Makhija RG, Carstensen JT. R-P trials calcium excipient. 
Manuf Chem 1996; 67(8): 55, 57. 
Rhodia. Technical literature: Calcium phosphate excipients, 1999. 
21 Authors 
RC Moreton. 
22 Date of Revision 
22 August 2005. 
Calcium Phosphate, Dibasic Dihydrate 99

Calcium Phosphate, Tribasic 
1 Nonproprietary Names 
BP: Calcium phosphate 
PhEur: Tricalcii phosphas 
USPNF: Tribasic calcium phosphate 
2 Synonyms 
Calcium orthophosphate; E341; hydroxylapatite; phosphoric 
acid calcium salt (2 : 3); precipitated calcium phosphate; 
tertiary calcium phosphate; Tri-Cafos; tricalcium diorthophosphate; 
tricalcium orthophosphate; tricalcium phosphate; 
TRI-CALWG; TRI-TAB. 
3 Chemical Name and CAS Registry Number 
Tribasic calcium phosphate is not a clearly defined chemical 
entity but is a mixture of calcium phosphates. Several chemical 
names, CAS Registry Numbers, and molecular formulas have 
therefore been used to describe this material. Those most 
frequently cited are shown below. 
Calcium hydroxide phosphate [12167-74-7] 
Tricalcium orthophosphate [7758-87-4] 
See also Sections 4 and 8. 
4 Empirical Formula and Molecular Weight 
Ca3(PO4)2 310.20 
Ca5(OH)(PO4)3 502.32 
5 Structural Formula 
See Sections 3 and 4. 
6 Functional Category 
Anticaking agent; buffer; dietary supplement; glidant; tablet 
and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Tribasic calcium phosphate is widely used as a capsule diluent 
and tablet filler/binder in either direct-compression or wetgranulation 
processes. The primary bonding mechanism in 
compaction is plastic deformation. As with dibasic calcium 
phosphate, a lubricant and a disintegrant should usually be 
incorporated in capsule or tablet formulations that include 
tribasic calcium phosphate. In some cases tribasic calcium 
phosphate has been used as a disintegrant.(1) It is most widely 
used in vitamin and mineral preparations(2) as a filler and as a 
binder. It is a source of both calcium and phosphorus, the two 
main osteogenic minerals for bone health. The bioavailability 
of the calcium is well known to be improved by the presence of 
cholecalciferol. Recent research reports that combinations of 
tribasic calcium phosphate and vitamin D3 are a cost-effective 
advance in bone fracture prevention.(3) 
In food applications, tribasic calcium phosphate powder is 
widely used as an anticaking agent. See Section 18. 
See also Calcium phosphate, dibasic dihydrate. 
8 Description 
The PhEur 2005 states that tribasic calcium phosphate consists 
of a mixture of calcium phosphates. It contains not less than 
35.0% and not more than the equivalent of 40.0% of calcium. 
The USPNF 23 specifies that tribasic calcium phosphate 
consists of variable mixtures of calcium phosphates having 
the approximate composition 10CaO3P2O5H2O. This corresponds 
to a molecular formula of Ca5(OH)(PO4)3 or 
Ca10(OH)2(PO4)6. 
Tribasic calcium phosphate is a white, odorless and tasteless 
powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for tribasic calcium phosphate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Loss on ignition 48.0% 48.0% 
Water-soluble substances  40.5% 
Acid-insoluble substances 40.2% 40.2% 
Carbonate  . 
Chloride 40.15% 40.14% 
Fluoride 475 ppm 40.0075% 
Nitrate  . 
Sulfate 40.5% 40.8% 
Arsenic 44 ppm 43 ppm 
Barium  . 
Iron 4400 ppm  
Dibasic salt and calcium oxide  . 
Heavy metals 430 ppm 40.003% 
Assay (as Ca) 35.040.0% 34.040.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 6.8 (20% slurry in water) 
Density: 3.14 g/cm3 
Density (bulk): 
0.30.4 g/cm3 for powder form; 
0.80 g/cm3 for granular TRI-TAB.(4) 
Density (tapped): 0.95 g/cm3 for granular TRI-TAB.(4) 
Flowability: 25.0 g/s for granular TRI-TAB(4) 
Melting point: 16708C 
Moisture content: slightly hygroscopic. A well-defined crystalline 
hydrate is not formed although surface moisture may be 
picked up or contained within small pores in the crystal 
structure. At relative humidities between about 15% and 
65%, the equilibrium moisture content at 258C is about 
2.0%. At relative humidities above about 75%, tribasic 
calcium phosphate may absorb small amounts of moisture. 
Particle size distribution: Tribasic calcium phosphate powder: 
typical particle diameter 510 mm; 98% of particles <44 mm. 
TRI-CALWG: average particle diameter 180 mm;99%of 
particles<420 mm, 46%<149 mm, and 15%<44 mmin size.

TRI-TAB: average particle diameter 350 mm; 97% of 
particles <420 mm, and 2% <149 mm. 
Solubility: soluble in dilute mineral acids; very slightly soluble 
in water; practically insoluble in acetic acid and alcohols. 
Specific surface area: 7080m2/g(4) 
11 Stability and Storage Conditions 
Tribasic calcium phosphate is a chemically stable material, and 
is also not liable to cake during storage. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
All calcium salts are incompatible with tetracycline antibiotics. 
Tribasic calcium phosphate is incompatible with tocopheryl 
acetate (but not tocopheryl succinate). Tribasic calcium 
phosphate may form sparingly soluble phosphates with 
hormones. 
13 Method of Manufacture 
Tribasic calcium phosphate occurs naturally as the minerals 
hydroxylapatite, voelicherite, and whitlockite. Commercially, it 
is prepared by treating phosphate-containing rock with sulfuric 
acid. Tribasic calcium phosphate powder is then precipitated by 
the addition of calcium hydroxide. Tribasic calcium phosphate 
is alternatively prepared by treating calcium hydroxide from 
limestone with purified phosphoric acid. It may also be 
obtained from calcined animal bones.(5) Some tribasic calcium 
phosphate products may be prepared in coarser, directly 
compressible forms by granulating the powder using roller 
compaction or spray drying. 
14 Safety 
Tribasic calcium phosphate is widely used in oral pharmaceutical 
formulations and food products and is generally regarded 
as nontoxic and nonirritant at the levels employed as a 
pharmaceutical excipient. 
Ingestion or inhalation of excessive quantities may result in 
the deposition of tribasic calcium phosphate crystals in tissues. 
These crystals may lead to inflammation and cause tissue 
lesions in the areas of deposition. 
Oral ingestion of very large quantities of tribasic calcium 
phosphate may cause abdominal discomfort such as nausea and 
vomiting. 
No teratogenic effects were found in chicken embryos 
exposed to a dose of 2.5 mg of tribasic calcium phosphate.(6) 
LD50 (rat, oral): >1 g/kg(4) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Handle in a well-ventilated environment since 
dust inhalation may be an irritant. For processes generating 
large amounts of dust, the use of a respirator is recommended. 
16 Regulatory Acceptance 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules 
and tablets). Included in nonparenteral medicines licensed in 
the UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Calcium phosphate, dibasic anhydrous; calcium phosphate, 
dibasic dihydrate. 
18 Comments 
One gram of tribasic calcium phosphate represents approximately 
10.9 mmol of calcium and 6.4 mmol of phosphate; 38% 
calcium and 17.3% phosphorus by weight.(4) Tribasic calcium 
phosphate provides a higher calcium load than dibasic calcium 
phosphate and a higher Ca/P ratio. Granular and fine powder 
forms of tribasic calcium phosphate are available from various 
manufacturers. 
A specification for calcium phosphate tribasic is contained 
in the Food Chemicals Codex (FCC). 
The EINECS number for calcium phosphate is 231-837-1. 
19 Specific References 
1 Delonca H, Puech A, Segura G, Youakim J. Effect of excipients and 
storage conditions on drug stability I: acetylsalicylic acid-based 
tablets [in French]. J Pharm Belg 1969; 24: 243252. 
2 Magid L. Stable multivitamin tablets containing tricalcium 
phosphate. United States Patent No. 3,564,097; 1971. 
3 Lilliu H, Chapuy MC, Meunier PJ, et al. Calcium-vitamin D3 
supplementation is cost-effective in hip fractures prevention. 
Muturitas 2003; 44(4): 299305. 
4 Rhodia. Technical literature: Calcium phosphate pharmaceutical 
ingredients, 1995. 
5 Magami A. Basic pentacalcium triphosphate production. Japanese 
Patent 56 022 614; 1981. 
6 Verrett MJ, Scott WF, Reynaldo EF, et al. Toxicity and 
teratogenicity of food additive chemicals in the developing chicken 
embryo. Toxicol Appl Pharmacol 1980; 56: 265273. 
20 General References 
Bryan JW, McCallister JD. Matrix forming capabilities of three calcium 
diluents. Drug Dev Ind Pharm 1992; 18: 20292047. 
Chowhan ZT, Amaro AA. The effect of low- and high-humidity aging 
on the hardness, disintegration time and dissolution rate of tribasic 
calcium phosphate-based tablets. Drug Dev Ind Pharm 1979; 5: 
545562. 
Fischer E. Calcium phosphate as a pharmaceutical excipient. Manuf 
Chem 1992; 64(6): 2527. 
Kutty TRN. Thermal decomposition of hydroxylapatite. Indian J Chem 
1973; 11: 695697. 
Molokhia AM, Moustafa MA, Gouda MW. Effect of storage 
conditions on the hardness, disintegration and drug release from 
some tablet bases. Drug Dev Ind Pharm 1982; 8: 283292. 
Pontier C, Viana M. Energetic yields in apatitic calcium phosphate 
compression: influence of the Ca/P molar ratio. Polymer International 
2003; 52(4): 625628. 
Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting 1: physico-pharmaceutical properties. Pharm World Sci 
1993; 15(3): 105115. 
Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 
tableting 2: comparison of tableting properties. Pharm World Sci 
1993; 15(3): 116122. 
21 Authors 
V King, L Hendricks, W Camarco. 
22 Date of Revision 
15 August 2005. 
Calcium Phosphate, Tribasic 101

Calcium Stearate 
1 Nonproprietary Names 
BP: Calcium stearate 
JP: Calcium stearate 
PhEur: Calcii stearas 
USPNF: Calcium stearate 
2 Synonyms 
Calcium distearate; HyQual; stearic acid, calcium salt; calcium 
octadecanoate; octadecanoic acid, calcium salt. 
3 Chemical Name and CAS Registry Number 
Octadecanoic acid calcium salt [1592-23-0] 
4 Empirical Formula and Molecular Weight 
C36H70CaO4 607.03 (for pure material) 
The PhEur 2005 describes calcium stearate as a mixture of 
calcium salts of different fatty acids consisting mainly of stearic 
acid [(C17H35COO)2Ca] and palmitic acid [(C15H31COO)2Ca] 
with minor proportions of other fatty acids. It contains the 
equivalent of 9.010.5% of calcium oxide. 
5 Structural Formula 
6 Functional Category 
Tablet and capsule lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Calcium stearate is primarily used in pharmaceutical formulations 
as a lubricant in tablet and capsule manufacture at 
concentrations up to 1.0% w/w. Although it has good 
antiadherent and lubricant properties, calcium stearate has 
poor glidant properties. 
Calcium stearate is also employed as an emulsifier, stabilizing 
agent, and suspending agent, and is also used in cosmetics 
and food products. 
8 Description 
Calcium stearate occurs as a fine, white to yellowish-white, 
bulky powder having a slight, characteristic odor. It is unctuous 
and free from grittiness. 
SEM: 1 
Excipient: Calcium stearate (Standard) 
Manufacturer: Durham Chemicals 
Lot No.: 0364 
Voltage: 20 kV 
SEM: 2 
Excipient: Calcium stearate (Precipitated) 
Manufacturer: Witco Corporation 
Lot No.: 0438 
Voltage: 12 kV

SEM: 3 
Excipient: Calcium stearate (Fused) 
Manufacturer: Witco Corporation 
Voltage: 15 kV 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for calcium stearate. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . .  
Microbial limit  103/g  
Acidity or alkalinity  .  
Loss on drying 44.0% 46.0% 44.0% 
Arsenic 42 ppm   
Heavy metals 420 ppm  410 mg/g 
Chlorides  40.1%  
Sulfates  40.3%  
Cadmium  43 ppm  
Lead  410 ppm  
Nickel  45 ppm  
Organic volatile impurities   . 
Assay (as CaO)   9.010.5% 
Assay (as Ca) 6.47.1% 6.47.4%  
10 Typical Properties 
Acid value: 191203 
Ash: 9.910.3% 
Chloride: <200 ppm 
Density (bulk and tapped): see Table II. 
Density (true): 1.0641.096 g/cm3 
Flowability: 21.222.6% (Carr compressibility index) 
Free fatty acid: 0.30.5% 
Melting point: 1491608C 
Moisture content: 2.96% 
Particle size distribution: 1.760 mm; 100% through a 73.7 mm 
(#200 mesh); 99.5% through a 44.5 mm (#325 mesh). 
Table II: Density (bulk and tapped) of calcium stearate. 
Bulk density (g/cm3) Tapped density (g/cm3) 
Durham Chemicals 
Standard  0.26 
A  0.45 
AM  0.33 
Witco Corporation 
EA 0.21 0.27 
Fused 0.38 0.48 
Precipitated 0.16 0.20 
Shear strength: 14.71MPa 
Solubility: practically insoluble or insoluble in ethanol (95%), 
ether, chloroform, acetone and water. Slightly soluble in hot 
alcohol, and hot vegetable and mineral oils. Soluble in hot 
pyridine. 
Specific surface area: 4.738.03m2/g 
Sulfate: <0.25% 
11 Stability and Storage Conditions 
Calcium stearate is stable and should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 

13 Method of Manufacture 
Calcium stearate is prepared by the reaction of calcium chloride 
with a mixture of the sodium salts of stearic and palmitic acids. 
The calcium stearate formed is collected and washed with water 
to remove any sodium chloride. 
14 Safety 
Calcium stearate is used in oral pharmaceutical formulations 
and is generally regarded as a relatively nontoxic and 
nonirritant material. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Calcium stearate should be 
used in a well-ventilated environment; eye protection, gloves, 
and a respirator are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules and tablets). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Magnesium stearate; stearic acid; zinc stearate. 
18 Comments 
Calcium stearate exhibits interesting properties when heated; 
softening between 1201308C, and exhibiting a viscous 
Calcium Stearate 103

consistency at approximately 1608C. At approximately 1008C, 
it loses about 3% of its weight, corresponding to one mole of 
water of crystallization. The crystalline structure changes at this 
point, leading to the collapse of the crystal lattice at a 
temperature of about 1258C.(1) 
See Magnesium stearate for further information and 
references. 
A specification for calcium stearate is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for calcium stearate is 216-472-8. 
19 Specific References 
1 SpecialChem (2005). Metallic stearates center. 
http://www.specialchem4polymers.com/tc/metallic-stearates/ 
index.aspx?id-2404 (accessed 9 August 2005). 
20 General References 
Bu. sch G, Neuwald F. Metallic soaps as water-in-oil emulsifiers [in 
German]. J Soc Cosmet Chem 1973; 24: 763769. 
Phadke DS, Sack MJ. Evaluation of batch-to-batch and manufacturerto-
manufacturer variability in the physical and lubricant properties 
of calcium stearate. Pharm Technol 1996; 20(Mar): 126140. 
21 Authors 
LV Allen. 
22 Date of Revision 
9 August 2005. 
104 Calcium Stearate

Calcium Sulfate 
1 Nonproprietary Names 
BP: Calcium sulphate dihydrate 
PhEur: Calcii sulfas dihydricus 
USPNF: Calcium sulfate 
2 Synonyms 
Calcium sulfate anhydrous: anhydrite; anhydrous gypsum; 
anhydrous sulfate of lime; Destab; Drierite; E516; karstenite; 
muriacite; Snow White. 
Calcium sulfate dihydrate: alabaster; Cal-Tab; Compactrol; 
Destab; E516; gypsum; light spar; mineral white; native 
calcium sulfate; precipitated calcium sulfate; satinite; satin 
spar; selenite; terra alba; USG Terra Alba. 
3 Chemical Name and CAS Registry Number 
Calcium sulfate [7778-18-9] 
Calcium sulfate dihydrate [10101-41-4] 
4 Empirical Formula and Molecular Weight 
CaSO4 136.14 
CaSO42H2O 172.17 
5 Structural Formula 
CaSO4 
CaSO42H2O 
6 Functional Category 
Tablet and capsule diluent. The anhydrous form is used as a 
desiccant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Calcium sulfate dihydrate is used in the formulation of tablets 
and capsules. In granular form it has good compaction 
properties and moderate disintegration properties.(1,2) 
Calcium sulfate hemihydrate (see Section 17), is used in the 
preparation of plaster of Paris bandage, which is used for the 
immobilization of limbs and fractures; it should not be used in 
the formulation of tablets or capsules. 
Anhydrous calcium sulfate is hygroscopic and uptake of 
water can cause the tablets to become very hard and to fail to 
disintegrate on storage. It is not recommended for the 
formulation of tablets, capsules, or powders for oral administration. 
Therapeutically, calcium sulfate is used in dental and 
craniofacial surgical procedures.(3,4) 
8 Description 
A white or off-white, fine, odorless, and tasteless powder or 
granules. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for calcium sulfate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Acidity or alkalinity .  
Arsenic 410 ppm  
Chlorides 4300 ppm  
Heavy metals 420 ppm 40.001% 
Iron 4100 ppm 40.01% 
Loss on drying 
Anhydrous  41.5% 
Dihydrate  19.023.0% 
Loss on ignition 18.022.0%  
Assay 98.0102.0% 98.0101.0% 
10 Typical properties 
Acidity/alkalinity: 
pH = 7.3 (10% slurry) for dihydrate; 
pH = 10.4 (10% slurry) for anhydrous material. 
Angle of repose: 37.68 for Compactrol.(2) 
Compressibility: see Figure 1. 
Figure 1: Compression characteristics of calcium sulfate dihydrate. 
Tablet weight: 700 mg.

Density (bulk): 
0.94 g/cm3 for Compactrol;(2) 
0.67 g/cm3 for dihydrate; 
0.70 g/cm3 for anhydrous material. 
Density (tapped): 
1.10 g/cm3 for Compactrol;(2) 
1.12 g/cm3 for dihydrate; 
1.28 g/cm3 for anhydrous material. 
Density (true): 2.308 g/cm3 
Flowability: 48.4% (Carr compressibility index); 5.2 g/s for 
Compactrol.(2) 
Melting point: 14508C for anhydrous material. 
Particle size distribution: 93% less than 45 mm in size for the 
dihydrate (USG Terra Alba); 97% less than 45 mm in size for 
the anhydrous material (Snow White). Average particle size 
is 17 mm for the dihydrate and 8 mm for the anhydrous 
material. For Compactrol, not less than 98% passes through 
a #40 screen (425 mm), and not less than 85% is retained in a 
#140 screen (100 mm). 
Solubility: see Table II. 
Table II: Solubility of calcium sulfate dihydrate. 
Solvent Solubility at 208C unless otherwise stated 
Ethanol (95%) Practically insoluble 
Water 1 in 375 
1 in 485 at 1008C 
Specific gravity: 
2.32 for dihydrate; 
2.96 for anhydrous material. 
Specific surface area: 3.15m2/g (Strohlein apparatus) 
11 Stability and Storage Conditions 
Calcium sulfate is chemically stable. Anhydrous calcium sulfate 
is hygroscopic and may cake on storage. Store in a well-closed 
container in a dry place, avoiding heat. 
12 Incompatibilities 
In the presence of moisture, calcium salts may be incompatible 
with amines, amino acids, peptides, and proteins, which may 
form complexes. Calcium salts will interfere with the bioavailability 
of tetracycline antibiotics.(5) It is also anticipated that 
calcium sulfate would be incompatible with indomethacin,(6) 
aspirin,(7) aspartame,(8) ampicillin,(9) cephalexin,(10) and erythromycin(
11) since these materials are incompatible with other 
calcium salts. 
Calcium sulfate may react violently, at high temperatures, 
with phosphorus and aluminum powder; it can react violently 
with diazomethane. 
13 Method of Manufacture 
Anhydrous calcium sulfate occurs naturally as the mineral 
anhydrite. The naturally occurring rock gypsum may be 
crushed and ground for use as the dihydrate or calcined at 
1508C to produce the hemihydrate. A purer variety of calcium 
sulfate may also be obtained chemically by reacting calcium 
carbonate with sulfuric acid or by precipitation from calcium 
chloride and a soluble sulfate. 
14 Safety 
Calcium sulfate dihydrate is used as an excipient in oral capsule 
and tablet formulations. At the levels at which it is used as an 
excipient, it is generally regarded as nontoxic. However, 
ingestion of a sufficiently large quantity can result in obstruction 
of the upper intestinal tract after absorption of moisture. 
Owing to the limited intestinal absorption of calcium from 
its salts, hypercalcemia cannot be induced even after the 
ingestion of massive oral doses. 
Calcium salts are soluble in bronchial fluid. Pure salts do not 
induce pneumoconiosis. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. The fine-milled grades can 
generate nuisance dusts that may be irritant to the eyes or on 
inhalation. The use of a respirator or dust mask is recommended 
to prevent excessive powder inhalation since excessive 
inhalation may saturate the bronchial fluid, leading to 
precipitation and thus blockage of the air passages. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
sustained release, tablets). Included in nonparenteral medicines 
licensed in the UK and Europe. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Calcium phosphate, dibasic anhydrous; calcium phosphate, 
dibasic dihydrate; calcium phosphate, tribasic; calcium sulfate 
hemihydrate. 
Calcium sulfate hemihydrate 
Empirical formula: CaSO41=2H2O 
Molecular weight: 145.14 
CAS number: [26499-65-0] 
Synonyms: annalin; calcii sulfas hemihydricus; calcined gypsum; 
dried calcium sulfate; dried gypsum; E516; exsiccated 
calcium sulfate; plaster of Paris; sulfate of lime; yeso blanco. 
Appearance: a white or almost white, odorless, crystalline, 
hygroscopic powder. 
Solubility: practically insoluble in ethanol (95%); slightly 
soluble in water; more soluble in dilute mineral acids. 
Comments: the BP 2004 defines dried calcium sulfate as 
predominantly the hemihydrate, produced by drying powdered 
gypsum (CaSO42H2O) at about 1508C, in a 
controlled manner, such that minimum quantities of the 
anhydrous material are produced. Dried calcium sulfate 
may also contain suitable setting accelerators or decelerators. 
18 Comments 
Calcium sulfate will absorb moisture and therefore should be 
used with caution in the formulation of products containing 
drugs that easily decompose in the presence of moisture. A 
specification for calcium sulfate is contained in the Food 
Chemicals Codex (FCC). The EINECS number for calcium 
sulfate is 231-900-3. 
106 Calcium Sulfate

19 Specific References 
1 Bergman LA, Bandelin FJ. Effects of concentration, ageing and 
temperature on tablet disintegrants in a soluble direct compression 
system. J Pharm Sci 1965; 54: 445447. 
2 C. elik M, Okutgen E. A feasibility study for the development of a 
prospective compaction functionality test and the establishment of 
a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309 
2334. 
3 Cho BC, Park JW, Baik BS, Kim IS. Clinical application of 
injectable calcium sulfate on early bone consolidation in distraction 
osteogenesis for the treatment of craniofacial microsomia. J 
Craniofac Surg 2002; 13(3): 465474. 
4 Deporter DA, Todescan R. A possible rescue procedure for dental 
implants with a textured surface geometry: a case report. J 
Periodontol 2001; 72(10): 14201423. 
5 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989: 9394. 
6 Eerika. inen S, Yliruusi J, Laakso R. The behaviour of the sodium 
salt of indomethacin in the cores of film-coated granules containing 
various fillers. Int J Pharm 1991; 71: 201211. 
7 Land..n M, Pe.rez-Marcos B, Casalderrey M, et al. Chemical 
stability of acetylsalicylic acid in tablets prepared with different 
commercial brands of dicalcium phosphate dihydrate. Int J Pharm 
1994; 107: 247249. 
8 El-Shattawy HH, Peck GE, Kildsig DO. Aspartame  direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7(5): 
605619. 
9 El-Shattawy HH. Ampicillin  direct compression excipients: 
preformulation stability screening using differential scanning 
calorimetry. Drug Dev Ind Pharm 1982; 8(6): 819831. 
10 El-Shattawy HH, Kildsig DO, Peck GE. Cephalexin 1  direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6): 
897909. 
11 El-Shattawy HH, Kildsig DO, Peck GE. Erythromycin  direct 
compression excipients: preformulation stability screening using 
differential scanning calorimetry. Drug Dev Ind Pharm 1982; 8(6): 
937947. 
20 General References 
Bryan JW, McCallister JD. Matrix forming capabilities of three calcium 
diluents. Drug Dev Ind Pharm 1992; 18: 20292047. 
21 Authors 
RC Moreton. 
22 Date of Revision 
26 August 2005. 
Calcium Sulfate 107

Canola Oil 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Canbra oil; Colzao CT; Lipex 108; Lipex 204; Lipovol CAN; 
low erucic acid colza oil; low erucic acid rapeseed oil. 
3 Chemical Name and CAS Registry Number 
Canola oil [120962-03-0] 
4 Empirical Formula and Molecular Weight 
Canola oil contains approximately 6% saturated acids, 2% 
monounsaturated acids, and 32% polyunsaturated acids; see 
Table I. Additionally, sulfur-containing fatty acids may also be 
present as minor constituents. 
Table I: Typical composition of glycerides present in canola oil. 
Glyceride Amount present (%) 
Erucic acid 0.21.8 
Palmitic acid 3.04.5 
Palmitoleic acid 0.20.3 
Stearic acid 1.31.7 
Linoleic acid 19.024.0 
Oleic acid 56.062.0 
The sulfur-containing compounds have been held responsible 
for the unpleasant odors from heated rapeseed oil. It has 
been suggested that the sulfur compounds in rapeseed oil are of 
three types: volatile, thermolabile, and nonvolatile.(1) 
Unrefined canola oil is said to contain low levels of sulfurcontaining 
fatty acids, resulting in the presence of sulfur in the 
oil in the stable form of triglycerides. These triglycerides resist 
refining procedures.(2) See Table II for the sulfur content of 
crude, refined, and deodorized canola oils.(3) 
Table II: Total sulfur content in crude, refined and bleached and 
deodorized canola oil.(a) 
Oil sample Range (mg/kg) Mean Standard 
deviation 
Crude 23.624.1 23.8 1.0 
Refined 19.120.2 19.7 2.85 
Bleached and deodorized 15.616.5 16.2 2.7 
(a) Determined using five replicates of each sample analyzed by ion chromatography. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Lubricant; oleaginous vehicle. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Canola oil is a refined rapeseed oil obtained from particular 
species of rapeseed that have been genetically selected for their 
low erucic acid content.(4) In pharmaceutical formulations, 
canola oil is used mainly in topical preparations such as soft 
soaps and liniments. It is also used in cosmetics. 
8 Description 
A clear, light yellow-colored oily liquid with a bland taste. 
9 Pharmacopeial Specifications 

10 Typical Properties 
Acid value: 40.5 
Density: 0.9130.917 g/cm3 
Erucic acid: 42.0% 
Flash point: 2903308C 
Free fatty acid: 40.05% as oleic acid 
Freezing point: 10 to 28C 
Iodine number: 94126 
Refractive index: nD
40 = 1.4651.469 
Saponification value: 186198 
Solubility: soluble in chloroform and ether; practically insoluble 
in ethanol (95%); miscible with fixed oils. 
Viscosity (dynamic): 77.378.3 mPa s (77.378.3 cP) at 208C 
11 Stability and Storage Conditions 
Canola oil is stable and should be stored in an airtight, lightresistant 
container in a cool, dry place. During storage, grassy, 
paintlike, or rancid off-flavors can develop. 
Flavor deterioration has been attributed mainly to secondary 
oxidation products of linolenic acid, which normally makes 
up 915% of the fatty acids in canola oil. Storage tests of 
canola oil showed sensory changes after 24 days at 60658C 
in comparison to 16 weeks at room temperature. Canola oil 
seems to be more stable to storage in light than cottonseed oil 
and soybean oils, but is less stable than sunflower oil.(5) In 
addition, the effects of various factors on sediment formation in 
canola oil have been reported.(6) 
It has been reported that oils stored at 28C showed the 
highest rate of sediment formation, followed by those stored at 
68C.(5) All samples showed little sediment formation, as 
measured by turbidity, during storage at 128C. Removal of 
sediment from canola oil prior to storage by cold precipitation 
and filtration did not eliminate this phenomenon, which still 
developed rapidly at 28C. 
A study on the effect of heating on the oxidation of low 
linolenic acid canola oil at frying temperatures under nitrogen 
and air clearly showed that a significantly lower development 
of oxidation was evident for the low linolenic acid canola oil. 
Reduction in the linolenic acid content of canola oil reduced the 
development of room odor at frying temperatures.

12 Incompatibilities 

13 Method of Manufacture 
Canola oil is obtained by mechanical expression or n-hexane 
extraction from the seeds of Brassica napus (Brassica campestris) 
var. oleifera and certain other species of Brassica 
(Cruciferae). The crude oil thus obtained is refined, bleached, 
and deodorized to substantially remove free fatty acids, 
phospholipids, color, odor and flavor components, and 
miscellaneous nonoil materials. 
14 Safety 
Canola oil is generally regarded as an essentially nontoxic and 
nonirritant material and has been accepted by the FDA for use 
in cosmetics, foods, and pharmaceuticals. 
Rapeseed oil has been used for a number of years in food 
applications as a cheap alternative to olive oil. However, there 
are large amounts of erucic acid and glucosinolates in 
conventional rapeseed oil, both substances being toxic to 
humans and animals.(7) Canola oil derived from genetically 
selected rapeseed plants that are low in erucic acid content has 
been developed to overcome this problem. 
Feeding studies in rats have suggested that canola oil is 
nontoxic to the heart, although it has also been suggested that 
the toxicological data may be unclear.(8) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Spillages of this material are 
very slippery and should be covered with an inert absorbent 
material prior to disposal. Canola oil poses a slight fire hazard. 
16 Regulatory Status 
Accepted for use by the FDA in cosmetics and foods. Included 
in the FDA Inactive Ingredients Guide (oral capsules). Included 
in the Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Almond oil; corn oil; cottonseed oil; peanut oil; rapeseed oil; 
sesame oil; soybean oil. 
Rapeseed oil 
CAS number: [8002-13-9] 
Synonyms: Calchem H-102; colza oil; rape oil. 
Appearance: a clear, yellow to dark yellow-colored oily liquid. 
Iodine number: 94120 
Peroxide value: <5 
Saponification value: 168181 
Comments: rapeseed oil contains 4055% erucic acid. It is an 
edible oil and has been primarily used as an alternative, in 
foods and some pharmaceutical applications, to the more 
expensive olive oil. However, the safety of rapeseed oil as 
part of the diet has been questioned; see Section 14. 
18 Comments 
Canola oil has the lowest level of saturated fat compared to all 
other oils on the market at present. It has both a high protein 
(28%) and a high oil content (40%). When the oil is extracted, 
a high-quality and highly palatable feed concentrate of 37% 
protein remains. Canola oil is also high in the monounsaturated 
fatty acid oleic acid; see Table III. 
The content of tocopherol, a natural antioxidant in canola, 
is comparable to those of peanut and palm oil. This is an 
important factor for oils with high linolenic acid content, which 
can reduce the shelf-life of the product, while the natural 
antioxidant, if present, can prevent oxidation during storage 
and processing. 
Suggested specifications for refined, bleached, and deodorized 
canola oil are shown in Table IV. A specification for canola 
oil is contained in the Food Chemicals Codex (FCC). 
The EINECS number for canola oil is 232-313-5. 
Table III: Comparison of the composition of crude soybean, canola, 
palm, and peanut oils. 
Components Canola Palm Peanut Soybean 
Fatty acid (%) 0.41.0 4.6 0.51.0 0.30.7 
Phosphatides (gum) 
(%) 
3.6 0.050.1 0.30.4 1.21.5 
Sterols/triterpene 
alcohol (%) 
0.53 0.10.5 0.2 0.33 
Tocopherols (%) 0.06 0.0030.1 0.020.06 0.150.21 
Carotenoids (mg/kg) 2550 5001600 >1 4050 
Chlorophyll/ 
pheophytins (ppm) 
525   12 
Sulfur (ppm)    1217 
Iodine value 112131 4460 84100 123139 
Table IV: Suggested specifications for canola oil. 
Test Minimum Maximum 
Acid value  6 
Iodine value 110 126 
Heavy metal (as lead)  5 mg/kg 
Refractive index nD
40 1.465 1.467 
Free fatty acid (as oleic)  0.05% 
Erucic acid  2% 
Moisture and impurities  0.05% 
Saponification value (mg KOH/g oil) 182 193 
Unsaponifiable matter  15 g/kg 
19 Specific References 
1 Devinat G, Biasini S, Naudet M. Sulfur-compounds in the rapeseed 
oils. Rev Fr Corps Gras 1980; 27: 229236. 
2 Wijesundera RC, Ackman RG. Evidence for the probable presence 
of sulfur-containing fatty-acids as minor constituents in canola oil. 
J Am Oil Chem Soc 1988; 65: 959963. 
3 Abraham V, de Man JM. Determination of total sulfur in canola 
oil. J Am Oil Chem Soc 1987; 64: 384387. 
4 Hiltunen R, Huhtikangas A, Hovinen S. Breeding of a zero erucic 
spring turnip-rape cultivar, Brassica campestris L. adapted to 
Finnish climatic conditions. Acta Pharm Fenn 1979; 88: 3134. 
5 Przybylski R, Billiaderis CG, Eskin NAM. Formation and partial 
characterization of canola. J Am Oil Chem Soc 1993; 70: 1009 
1016. 
6 Liu H, Billiaderis CG, Przybylski R. Effects of crystalization 
conditions on sediment. J Am Oil Chem Soc 1994; 71: 409418. 
Canola Oil 109

7 Anonymous. Rapeseed oil revisited. Lancet 1974; ii: 13591360. 
8 Anonymous. Rapeseed oil and the heart. Lancet 1973; ii: 193. 
20 General References 
Koseoglu SS, Iusas EW. Recent advances in canola oil hydrogenations. J 
Am Oil Chem Soc 1990; 67: 3947. 
Malcolmson LJ, Vaisey-Genser M, Przybylski R, Eskin NAM. Sensory 
stability of canola oil: present status. J Am Oil Chem Soc 1994; 71: 
435440. 
21 Authors 
KS Alexander. 
22 Date of Revision 
22 August 2005. 
110 Canola Oil

Carbomer 
1 Nonproprietary Names 
BP: Carbomers 
PhEur: Carbomera 
USPNF: Carbomer 
Note that the USPNF 23 contains several individual carbomer 
monographs; see Sections 4 and 9. 
2 Synonyms 
Acritamer; acrylic acid polymer; Carbopol; carboxy polymethylene, 
polyacrylic acid; carboxyvinyl polymer; Pemulen; 
Ultrez. 
3 Chemical Name and CAS Registry Number 
Carbomer [9003-01-4] 
Note that carbomer 910, 934, 934P, 940, 941, 971P and 
974P resins share the common CAS registry number 9003-01- 
4. Carbomer 1342 is a copolymer and has a different CAS 
registry number. 
4 Empirical Formula and Molecular Weight 
Carbomers are synthetic high-molecular-weight polymers of 
acrylic acid that are crosslinked with either allyl sucrose or allyl 
ethers of pentaerythritol. They contain between 56% and 68% 
of carboxylic acid (COOH) groups calculated on the dry basis. 
The BP 2004 and PhEur 2005 have a single monograph 
describing carbomer; the USPNF 23 contains several monographs 
describing individual carbomer grades that vary in 
aqueous viscosity and in labeling for oral or non-oral use. The 
molecular weight of carbomer resins is theoretically estimated 
at 7  105 to 4  109. In an effort to measure the molecular 
weight between crosslinks, MC, researchers have extended the 
network theory of elasticity to swollen gels and have utilized the 
inverse relationship between the elastic modulus and MC.(13) 
EstimatedMC values of 237 600 g/mol for Carbopol 941 and of 
104 400 g/mol for Carbopol 940 have been reported.(4) In 
general, carbomer resins with lower viscosity and lower rigidity 
will have higher MC values. Conversely, higher-viscosity, more 
rigid carbomer resins will have lower MC values. 
5 Structural Formula 
Carbomer polymers are formed from repeating units of acrylic 
acid. The monomer unit is shown above. The polymer chains 
are crosslinked with allyl sucrose or allyl pentaerythritol. See 
also Section 4. 
6 Functional Category 
Bioadhesive; emulsifying agent; release-modifying agent; suspending 
agent; tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Carbomers are mainly used in liquid or semisolid pharmaceutical 
formulations as suspending or viscosity-increasing agents. 
Formulations include creams, gels, and ointments for use in 
ophthalmic,(57) rectal,(810) and topical preparations.(1117) 
Carbomer grades, even with a low residual benzene content, 
such as carbomer 934P, are no longer included in the PhEur 
2005. However, carbomer having low residuals only of other 
solvents than the ICH-defined Class I OVI solvents may be 
used in Europe. Carbomer having low residuals only of ethyl 
acetate, such as carbomer 971P or 974P, may be used in oral 
preparations, in suspensions, tablets, or sustained release tablet 
formulations.(1822) In tablet formulations, carbomers are used 
as dry or wet binders and as a rate controlling excipient. In wet 
granulation processes, water or an alcoholwater blend is used 
as the granulating fluid. Anhydrous organic solvents have also 
been used, with the inclusion of a polymeric binder. The 
tackiness of the wet mass can be reduced with the addition of 
certain cationic species to the granulating fluid(23) or, in the case 
of water, with talc in the formulation. Carbomer resins have 
also been investigated in the preparation of sustained-release 
matrix beads,(23) as enzyme inhibitors of intestinal proteases in 
peptide-containing dosage forms,(24,25) as a bioadhesive for a 
cervical patch(26) and for intranasally administered microspheres,(
27) in magnetic granules for site-specific drug delivery 
to the esophagus(28) and in oral mucoadhesive controlled drug 
delivery systems.(29,30) Carbomers are also employed as 
emulsifying agents in the preparation of oil-in-water emulsions 
for external use. For this purpose, the carbomer is neutralized 
partly with sodium hydroxide and partly with a long-chain 
amine such as stearylamine. Carbomer 951 has been investigated 
as a viscosity-increasing aid in the preparation of multiple 
emulsion microspheres.(31) Carbomers are also used in cosmetics. 
Therapeutically, carbomer gel formulations have 
proved efficacious in improving symptoms of moderate-tosevere 
dry eye syndrome.(32,33) See Table I. 
Table I: Uses of carbomers. 
Use Concentration (%) 
Emulsifying agent 0.10.5 
Gelling agent 0.52.0 
Suspending agent 0.51.0 
Tablet binder 5.010.0

SEM: 1 
Excipient: Carbomer 971P (Carbopol 971P) 
Manufacturer: BF Goodrich 
Magnification: 2000 Voltage: 25 kV 
8 Description 
Carbomers are white-colored, fluffy, acidic, hygroscopic 
powders with a slight characteristic odor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for carbomers. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Aqueous viscosity (mPa s) 300115 000  
Carbomer 934 (0.5% w/v)  30 50039 400 
Carbomer 934P (0.5% w/v)  29 40039 400 
Carbomer 940 (0.5 w/v)  40 00060 000(a) 
Carbomer 941 (0.5 w/v)  4 00011 000 
Carbomer 1342 (1.0% w/v)  9 50026 500 
Loss on drying 43.0% 42.0% 
Sulfated ash 44.0%  
Heavy metals 420 ppm 40.002% 
Benzene 42 ppm  
Carbomer 910  40.5% 
Carbomer 934  40.5% 
Carbomer 934P  40.01% 
Carbomer 940  40.5% 
Carbomer 941  40.5% 
Carbomer 1342  40.2% 
Free acrylic acid 40.25%  
Organic volatile impurities  . 
Assay (COOH content) 56.068.0% 56.068.0% 
(a) See USPNF 23 Suppl. 1.0 for new method. 
Note that the USPNF 23 has several monographs for 
different carbomer grades, while the BP 2004 and the PhEur 
2005 have only a single monograph. Other grades of carbomer 
SEM: 2 
Excipient: Carbomer 971P (Carbopol 971P) 
Manufacturer: BF Goodrich 
Magnification: 6000 Voltage: 25 kV 
meet the existing USPNF 23 standards as indicated above. 
Carbomer 974P is covered by the monograph for carbomer 
934P in the USPNF 23. Likewise, carbomer 980 meets the 
specifications for carbomer 940; carbomers 971P and 981 meet 
the monograph limits for carbomer 941. Carbomer resins are 
also covered either individually or together in other pharmacopeias. 
Unless otherwise indicated, the test limits shown above 
apply to all grades of carbomer. 
10 Typical Properties 
Acidity/alkalinity: 
pH = 2.73.5 for a 0.5% w/v aqueous dispersion; 
pH = 2.53.0 for a 1% w/v aqueous dispersion. 
Density (bulk): 1.762.08 g/cm3 
Density (tapped): 1.4 g/cm3 
Glass transition temperature: 1001058C 
Melting point: decomposition occurs within 30 minutes at 
2608C. See Section 11. 
Moisture content: normal water content is up to 2% w/w. 
However, carbomers are hygroscopic and a typical equilibrium 
moisture content at 258C and 50% relative humidity 
is 810% w/w. The moisture content of a carbomer does not 
affect its thickening efficiency, but an increase in the 
moisture content makes the carbomer more difficult to 
handle because it is less readily dispersed. 
Particle size distribution: primary particles average about 
0.2 mm in diameter. The flocculated powder particles 
average 27 mm in diameter and cannot be broken down 
into the primary particles. Recently, a granular carbomer 
having a particle size in the range 180425 mm has been 
introduced. Its bulk and tap densities are also higher than 
those of other carbomers. 
Solubility: soluble in water and, after neutralization, in ethanol 
(95%) and glycerin. 
Although they are described as soluble, carbomers do 
not dissolve but merely swell to a remarkable extent, since 
they are three-dimensionally crosslinked microgels. Furthermore, 
the pharmacopeial specifications are unclear, in that 
neutralization with long-chain aliphatic amines or ethoxy- 
112 Carbomer

lated long-chain amines is required for swellability in 
ethanol, and with water-soluble amines for swellability in 
glycerin. 
Specific gravity: 1.41 
Viscosity (dynamic): carbomers disperse in water to form acidic 
colloidal dispersions of low viscosity that, when neutralized, 
produce highly viscous gels. Carbomer powders should first 
be dispersed into vigorously stirred water, taking care to 
avoid the formation of indispersible lumps, then neutralized 
by the addition of a base. The Carbopol ETD and Ultrez 10 
series of carbomers was introduced to overcome some of the 
problems of dispersing the powder into aqueous solvents. 
These carbomer resins wet quickly yet hydrate slowly, while 
possessing a lower unneutralized dispersion viscosity. 
Agents that may be used to neutralize carbomer polymers 
include amino acids, borax, potassium hydroxide, sodium 
bicarbonate, sodium hydroxide, and polar organic amines 
such as triethanolamine. Lauryl and stearyl amines may be 
used as gelling agents in nonpolar systems. One gram of 
carbomer is neutralized by approximately 0.4 g of sodium 
hydroxide. During preparation of the gel, the solution 
should be agitated slowly with a broad, paddlelike stirrer to 
avoid introducing air bubbles. Neutralized aqueous gels are 
more viscous at pH 611. The viscosity is considerably 
reduced at pH values less than 3 or greater than 12 or in the 
presence of strong electrolytes.(23,34) Gels rapidly lose 
viscosity on exposure to ultraviolet light, but this can be 
minimized by the addition of a suitable antioxidant. See also 
Section 11. 
11 Stability and Storage Conditions 
Carbomers are stable, hygroscopic materials that may be 
heated at temperatures below 1048C for up to 2 hours without 
affecting their thickening efficiency. However, exposure to 
excessive temperatures can result in discoloration and reduced 
stability. Complete decomposition occurs with heating for 30 
minutes at 2608C. Dry powder forms of carbomer do not 
support the growth of molds and fungi. In contrast, microorganisms 
grow well in unpreserved aqueous dispersions and 
therefore an antimicrobial preservative such as 0.1% w/v 
chlorocresol, 0.18% w/v methylparaben0.02% w/v propylparaben, 
or 0.1% w/v thimerosal should be added. The 
addition of certain antimicrobials, such as benzalkonium 
chloride or sodium benzoate, in high concentrations (0.1% 
w/v) can cause cloudiness and a reduction in viscosity of 
carbomer dispersions. Aqueous gels may be sterilized by 
autoclaving(7) with minimal changes in viscosity or pH, 
provided care is taken to exclude oxygen from the system, or 
by gamma irradiation, although this technique may increase the 
viscosity of the formulation.(35,36) At room temperature, 
carbomer dispersions maintain their viscosity during storage 
for prolonged periods. Similarly, dispersion viscosity is maintained, 
or only slightly reduced, at elevated storage temperatures 
if an antioxidant is included in the formulation or if the 
dispersion is stored protected from light. Exposure to light 
causes oxidation that is reflected in a decrease in dispersion 
viscosity. Stability to light may be improved by the addition of 
0.050.1% w/v of a water-soluble UV absorber such as 
benzophenone-2 or benzophenone-4 in combination with 
0.050.1% w/v edetic acid. The UV stability of carbomer gels 
may also be improved by using triethanolamine as the 
neutralizing base; see Section 10. 
Carbomer powder should be stored in an airtight, corrosion-
resistant container in a cool, dry place. The use of glass, 
plastic, or resin-lined containers is recommended for the 
storage of formulations containing carbomer. Packaging in 
aluminum tubes usually requires the formulation to have a pH 
less than 6.5, and packaging in other metallic tubes or 
containers necessitates a pH greater than 7.7 to prolong 
carbomer stability. 
12 Incompatibilities 
Carbomers are discolored by resorcinol and are incompatible 
with phenol, cationic polymers, strong acids, and high levels of 
electrolytes. Certain antimicrobial adjuvants should also be 
avoided or used at low levels, see Section 11. Trace levels of iron 
and other transition metals can catalytically degrade carbomer 
dispersions. Intense heat may be generated if a carbomer is in 
contact with a strong basic material such as ammonia, 
potassium or sodium hydroxide, or strongly basic amines. 
Certain amino-functional actives form water-insoluble 
complexes with carbomer; often this can be prevented by 
adjusting the solubility parameter of the fluid phase using 
appropriate alcohols and polyols. 
Carbomers also form pH-dependent complexes with certain 
polymeric excipients. Adjustment of solubility parameter can 
also work in this situation. 
13 Method of Manufacture 
Carbomers are synthetic, high-molecular-weight, crosslinked 
polymers of acrylic acid. These poly(acrylic acid) polymers are 
crosslinked with allyl sucrose or allyl pentaerythritol. The 
polymerization solvent used most commonly was benzene; 
however, some of the newer commercially available grades of 
carbomer are manufactured using either ethyl acetate or a 
cyclohexaneethyl acetate cosolvent mixture. The Carbopol 
ETD resins are produced in the cosolvent mixture with a 
proprietary polymerization aid, and these resins are crosslinked 
with a polyalkenyl polyether. 
14 Safety 
Carbomers are used extensively in nonparenteral products, 
particularly topical liquid and semisolid preparations. They 
may also be used in oral formulations, although only certain 
grades can be used; see Section 18. Acute oral toxicity studies in 
animals indicate that carbomer 934P has a low oral toxicity, 
with doses up to 8 g/kg being administered to dogs without 
fatalities occurring. Carbomers are generally regarded as 
essentially nontoxic and nonirritant materials; there is no 
evidence in humans of hypersensitivity reactions to carbomers 
used topically. In humans, oral doses of 13 g of carbomer have 
been used as a bulk laxative. 
LD50 (guinea pig, oral): 2.5 g/kg for carbomer 934(37) 
LD50 (guinea pig, oral): 2.5 g/kg for carbomer 934P 
LD50 (guinea pig, oral): 2.5 g/kg for carbomer 940 
LD50 (mouse, IP): 0.04 g/kg for carbomer 934P 
LD50 (mouse, IP): 0.04 g/kg for carbomer 940 
LD50 (mouse, IV): 0.07 g/kg for carbomer 934P 
LD50 (mouse, IV): 0.07 g/kg for carbomer 940 
LD50 (mouse, oral): 4.6 g/kg for carbomer 934P 
LD50 (mouse, oral): 4.6 g/kg for carbomer 934 
LD50 (mouse, oral): 4.6 g/kg for carbomer 940 
LD50 (rat, oral): 10.25 g/kg for carbomer 910 
LD50 (rat, oral): 2.5 g/kg for carbomer 934P 
LD50 (rat, oral): 4.1 g/kg for carbomer 934 
LD50 (rat, oral): 2.5 g/kg for carbomer 940 
LD50 (rat, oral): > 1g/kg for carbomer 941 
Carbomer 113

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Excessive dust generation 
should be minimized to avoid the risk of explosion (lowest 
explosive concentration is 100 g/m3). Carbomer dust is irritating 
to the eyes, mucous membranes, and respiratory tract. In 
contact with the eye, carbomer dust is difficult to remove with 
water owing to the gelatinous film that forms; saline should 
therefore be used for irrigation purposes. Gloves, eye protection, 
and a dust respirator are recommended during handling. 
16 Regulatory Acceptance 
Included in the FDA Inactive Ingredients Guide (oral suspensions, 
tablets; ophthalmic, rectal, and topical preparations 
transdermal preparations, vaginal suppositories). Included in 
nonparenteral medicines licensed in Europe. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Polycarbophil. 
18 Comments 
A number of different carbomer grades are commercially 
available that vary in their molecular weight, degree of 
crosslinking, polymer structure, and residual components. 
These differences account for the specific rheological, handling, 
and use characteristics of each grade. Carbomer grades that 
have the polymer backbone modified with long-chain alkyl 
acrylates are used as polymeric emulsifiers or in formulations 
requiring increased resistance to ions. 
Polycarbophil, poly(acrylic acid) polymers crosslinked with 
divinyl glycol, is available for bioadhesive or medicinal 
applications. Carbomers designated with the letter P, e.g. 
carbomer 971P, are the only pharmaceutical grades of polymer 
accepted for oral or mucosal contact products. These resins are 
particularly useful in the production of clear gels. 
19 Specific References 
1 Taylor A, Bagley A. Tailoring closely packed gel-particles systems 
for use as thickening agents. J Appl Polym Sci 1975; 21: 113122. 
2 Taylor A, Bagley A. Rheology of dispersions of swollen gel 
particles. J Polym Sci 1975; 13: 11331144. 
3 Nae HN, Reichert WW. Rheological properties of lightly crosslinked 
carboxy copolymers in aqueous solutions. Rheol Acta 1992; 
31: 351360. 
4 Carnali JO, Naser MS. The use of dilute solution viscosity to 
characterize the network properties of carbopol microgels. Colloid 
Polym Sci 1992; 270: 183193. 
5 Amin PD, Bhogte CP, Deshpande MA. Studies on gel tears. Drug 
Dev Ind Pharm 1996; 22(7): 735739. 
6 U. nlu. N, Ludwig A, van Ooteghem M, et al. Formulation of 
carbopol 940 ophthalmic vehicles, and in vitro evaluation of the 
influence of simulated lacrimal fluid on their physico-chemical 
properties. Pharmazie 1991; 46: 784788. 
7 Deshpande SG, Shirolkar S. Sustained release ophthalmic formulations 
of pilocarpine. J Pharm Pharmacol 1989; 41: 197200. 
8 Dal Zotto M, Realdon N, Ragazzi E, et al. Effect of hydrophilic 
macromolecular substances on the drug release rate from 
suppositories with lipophilic excipient. Part 1: use of polyacrylic 
acids. Farmaco 1991; 46: 14591474. 
9 Morimoto K, Morisaka K. In vitro release and rectal absorption of 
barbital and aminopyrine from aqueous polyacrylic acid gel. Drug 
Dev Ind Pharm 1987; 13(7): 12931305. 
10 Green JT, Rhodes J, Thomas GA, Evans BK, et al. Nicotine 
carbomer enemaspharmacokinetics of a revised formulation. Ital 
J Gastroenterol Hepatol 1998; 30: 260265. 
11 Tamburic S, Craig DQM. Investigation into the rheological, 
dielectric and mucoadhesive properties of poly(acrylic acid) gel 
systems. J Control Release 1995; 37: 5968. 
12 Ferrari F, Bertoni M, Caramella C, et al. Description and validation 
of an apparatus for gel strength measurements. Int J Pharm 1994; 
109: 115124. 
13 Chu JS, Yu DM, Amidon GL, et al. Viscoelastic properties of 
polyacrylic acid gels in mixed solvents. Pharm Res 1992; 9: 1659 
1663. 
14 Amsellem E, Derrien F, Lanquetin M, Paris J, et al. In vitro studies 
on the influence of carbomers on the availability and acceptability 
of estradiol gels. Arzneimittelforschung 1998; 48: 492496. 
15 Jimenez-Kairuz A, Allemandi D, Manzo RH. Mechanism of 
lidocaine release from carbomer-lidocaine hydrogels. J Pharm Sci 
2002; 91: 267272. 
16 Tanna S, Sahota T, Clark J, Taylor MJ. Covalent coupling of 
concanavalin to a carbopol 934P and 941P carrier in glucosesensitive 
gels for delivery of insulin. J Pharm Pharmacol 2002; 54: 
14611469. 
17 Tas C, Ozkan Y, Savaser A, Baykara T. In vitro and ex vivo 
permeation studies of chlorpheniramine maleate gels prepared by 
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18 Meshali MM, El-Sayed GM, El-Said Y, et al. Preparation and 
evaluation of theophylline sustained release tablets. Drug Dev Ind 
Pharm 1996; 22(4): 373376. 
19 Huang LL, Schwartz JB. Studies on drug release from a carbomer 
tablet matrix. Drug Dev Ind Pharm 1995; 21(13): 14871501. 
20 Pe.rez-Marcos B, Iglesias R, Gomez-Amoza JL, et al. Mechanical 
and drug-release properties of atenololcarbomer hydrophilic 
matrix tablets. J Control Release 1991; 17: 267276. 
21 Graf E, Tsaktanis I, Fawzy AA. Studies on the direct compression 
of pharmaceuticals part 20: timed release of tablets of diphenhydramine 
and dexachlorpheniramine. Pharm Ind 1986; 48: 661 
665. 
22 Choulis NH, Papadopoulos H, Choulis M. Long acting methadone. 
Pharmazie 1976; 31: 466470. 
23 Neau SH, ChowMY. Fabrication and characterization of extruded 
and spheronized beads containing Carbopol 974P NF resin. Int J 
Pharm 1996; 131: 4755. 
24 Luessen HL, De-Leeuw BJ, Perard D, et al. Mucoadhesive 
polymers in peroral peptide drug delivery. Part 1: influence of 
mucoadhesive excipients on the proteolytic activity of intestinal 
enzymes. Eur J Pharm Sci 1996; 4: 117128. 
25 Luessen HL, Verhoef JC, Borchard G, et al. Mucoadhesive 
polymers in peroral peptide drug delivery. Part 2: carbomer and 
polycarbophil are potent inhibitors of the intestinal proteolytic 
enzyme trypsin. Pharm Res 1995; 12: 12931298. 
26 Woolfson AD, McCafferty DF, McCarron PA. Bioadhesive patch 
cervical drug delivery system for the administration of 5- 
fluorouracil to cervical tissue. J Control Release 1995; 35: 4958. 
27 Vidgren P, Vidgren M, Arppe J, et al. In vitro evaluation of spraydried 
mucoadhesive microspheres for nasal administration. Drug 
Dev Ind Pharm 1992; 18(5): 581597. 
28 Ito R, Machida Y, Sannan T, et al. Magnetic granules: novel system 
for specific drug delivery to esophageal mucosa in oral administration. 
Int J Pharm 1990; 61: 109117. 
29 Singla AK, Chawla M, Singh A. Potential applications of carbomer 
in oral mucoadhesive controlled drug delivery system: a review. 
Drug Dev Ind Pharm 2000; 26: 913924. 
30 Llabot JM, Manzo RH, Allemandi DA. Drug release from 
carbomer:carbomer sodium salt matrices with potential use as 
mucoadhesive drug delivery system. Int J Pharm 2004; 276: 59 
66. 
31 Wang HT, Schmitt E, Flanagan DR, et al. Influence of formulation 
methods on the in vitro controlled release of protein from 
poly(ester) microspheres. J Control Release 1991; 17: 2332. 
32 Sullivan LJ, McCurrach F, Lee S, Taylor HR, et al. Efficacy and 
safety of 0.3% carbomer gel compared to placebo in patients with 
moderate-to-severe dry eye syndrome. Ophthalmology 1997; 104: 
14021408. 
114 Carbomer

33 Marner K, Mooller PM, Dillon M, Rask-Pedersen E. Viscous 
carbomer eye drops in patients with dry eyes. Efficacy and safety. A 
randomized, open, cross-over, multicentre study. Acta Ophthalmol 
Scand 1996; 74: 249252. 
34 Charman WN, Christy DP, Geunin EP, Monkhouse DC. Interaction 
between calcium, a model divalent cation, and a range of 
poly(acrylic acid) resins as a function of solution pH. Drug Dev 
Ind Pharm 1991; 17(2): 271280. 
35 Adams I, Davis SS. Formulation and sterilization of an original 
lubricant gel base in carboxypolymethylene. J Pharm Pharmacol 
1973; 25: 640646. 
36 Adams I, Davis SS, Kershaw R. Formulation of a sterile surgical 
lubricant. J Pharm Pharmacol 1972; 24(Suppl.): 178P. 
37 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 71. 
20 General References 
Alexander P. Organic rheological additives. Manuf Chem 1986; 57: 81, 
8384. 
BF Goodrich Company. Technical literature: Carbopol, Noveon, 
Pemulen resins handbook, 1995. 
Islam MT, Rodriguez-Hornedo N, Ciotti S, Ackermann C. Rheological 
characterization of topical carbomer gels neutralized to different 
pH. Pharm Res 2004; 21: 11921199. 
Jimenez-Kairuz AF, Llabot JM, Allemandi DA, Manzo RH. Swellable 
drug-polyelectrolyte matrices (SDPM). Characterization and delivery 
properties. Int J Pharm 2005; 288: 8799. 
Pe.rez-Marcos B, Martinez-Pacheco R, Gomez-Amoza JL, et al. Interlot 
variability of carbomer 934. Int J Pharm 1993; 100: 207212. 
Secard DL. Carbopol pharmaceuticals. Drug Cosmet Ind 1962; 90: 28 
30, 113, 115116. 
21 Authors 
JJ Koleng, JW McGinity. 
22 Date of Revision 
25 August 2005. 
Carbomer 115

Carbon Dioxide 
1 Nonproprietary Names 
BP: Carbon dioxide 
JP: Carbon dioxide 
PhEur: Carbonei dioxidum 
USP: Carbon dioxide 
2 Synonyms 
Carbonic acid gas; carbonic anhydride; E290. 
3 Chemical Name and CAS Registry Number 
Carbon dioxide [124-38-9] 
4 Empirical Formula and Molecular Weight 
CO2 44.01 
5 Structural Formula 
CO2 
6 Functional Category 
Aerosol propellant; air displacement. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Carbon dioxide and other compressed gases such as nitrogen 
and nitrous oxide are used as propellants for topical 
pharmaceutical aerosols. They are also used in other aerosol 
products that work satisfactorily with the coarse aerosol spray 
that is produced with compressed gases, e.g., cosmetics, 
furniture polish, and window cleaners.(13) 
The advantages of compressed gases as aerosol propellants 
are that they are inexpensive; are of low toxicity; and are 
practically odorless and tasteless. Also, in comparison to 
liquefied gases, their pressures change relatively little with 
temperature. However, the disadvantages of compressed gases 
are that there is no reservoir of propellant in the aerosol and 
pressure consequently decreases as the product is used. This 
results in a change in spray characteristics. Additionally, if a 
product that contains a compressed gas as a propellant is 
actuated in an inverted position, the vapor phase, rather than 
the liquid phase, is discharged. Most of the propellant is 
contained in the vapor phase and therefore some of the 
propellant will be lost and the spray characteristics will be 
altered. Also, sprays produced using compressed gases are very 
wet. Valves, such as the vapor tap or double dip tube, are 
currently available and will overcome these problems. 
Carbon dioxide is also used to displace air from pharmaceutical 
products by sparging and hence to inhibit oxidation. As 
a food additive it is used to carbonate beverages and to preserve 
foods such as bread from spoilage by mold formation, the gas 
being injected into the space between the product and its 
packaging.(4,5) 
Solid carbon dioxide is also widely used to refrigerate 
products temporarily, while liquid carbon dioxide, which can 
be handled at temperatures up to 318C under high pressure, is 
used as a solvent for flavors and fragrances primarily in the 
perfumery and food manufacturing industries. 
8 Description 
Carbon dioxide occurs naturally as approximately 0.03% v/v 
of the atmosphere. It is a colorless, odorless, noncombustible 
gas with a faint acid taste. Solid carbon dioxide, also known as 
dry ice, is usually encountered as white-colored pellets or 
blocks. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for carbon dioxide. 
Test JP 2001 PhEur 2005 USP 28 
Characters . .  
Production  .  
Total sulfur  41 ppm  
Water  467 ppm 4150mg/m2 
Identification . . . 
Carbon monoxide . 45 ppm 40.001% 
Sulfur dioxide  42 ppm 45 ppm 
Nitrogen monoxide and 
nitrogen dioxide 
 42 ppm 42.5 ppm 
Impurities  .  
Limit of ammonia   40.0025% 
Limit of nitric oxide   42.5 ppm 
Acid .   
Hydrogen phosphide, 
hydrogen sulfide or 
reducing organic 
substances 
. 41 ppm 41 ppm 
Oxygen and nitrogen .   
Assay 499.50% 499.50% 499.00% 
10 Typical Properties 
Boiling point: 56.68C 
Critical pressure: 7.39MPa (72.9 atm) 
Critical temperature: 31.38C 
Density: 
0.714 g/cm3 for liquid at 258C; 
0.742 g/cm3 for vapor at 258C. 
Flammability: nonflammable 
Melting point: sublimes at 78.58C 
Solubility: 1 in about 1 of water by volume at normal 
temperature and pressure. 
Vapor density (absolute): 1.964 g/m3 
Vapor density (relative): 1.53 (air = 1) 
Vapor pressure: 6.436 MPa at 258C 
Viscosity (kinematic): 0.14mm2/s (0.14 cSt) at 17.88C

11 Stability and Storage Conditions 
Extremely stable and chemically nonreactive. Store in a tightly 
sealed cylinder. Avoid exposure to excessive heat. 
12 Incompatibilities 
Carbon dioxide is generally compatible with most materials 
although it may react violently with various metal oxides or 
reducing metals such as aluminum, magnesium, titanium, and 
zirconium. Mixtures with sodium and potassium will explode if 
shocked. 
13 Method of Manufacture 
Carbon dioxide is obtained industrially in large quantities as a 
by-product in the manufacture of lime; by the incineration of 
coke or other carbonaceous material; and by the fermentation 
of glucose by yeast. In the laboratory it may be prepared by 
dropping acid on a carbonate. 
14 Safety 
In formulations, carbon dioxide is generally regarded as an 
essentially nontoxic material. 
See also Section 15. 
15 Handling Precautions 
Handle in accordance with standard procedures for handling 
metal cylinders containing liquefied or compressed gases. 
Carbon dioxide is an asphyxiant and inhalation in large 
quantities is hazardous. It should therefore be handled in a wellventilated 
environment equipped with suitable safety devices 
for monitoring vapor concentration. 
It should be noted that carbon dioxide is classified as a 
greenhouse gas responsible for global warming. At the present 
time there are no restrictions on its use for aerosols and other 
applications. 
In the UK, the occupational exposure limits for carbon 
dioxide are 9150 mg/m3 (5000 ppm) long-term (8-hour TWA) 
and 27 400 mg/m3 (15 000 ppm) short-term (15-minute).(6) In 
the USA, the permissible exposure limits are 9000 mg/m3 
(5000 ppm) long-term and the recommended exposure limits 
are 18 000 mg/m3 (10 000 ppm) short-term and 54 000 mg/m3 
(30 000 ppm) maximum, short-term.(7) 
Solid carbon dioxide can produce severe burns in contact 
with the skin and appropriate precautions, depending on the 
circumstances and quantity of material handled, should be 
taken. A face shield and protective clothing, including thick 
gloves, are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use in Europe as a food additive. 
Included in the FDA Inactive Ingredients Guide (aerosol 
formulation for nasal preparations; IM and IV injections). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Nitrogen; nitrous oxide. 
18 Comments 
Supercritical carbon dioxide has been used in the formation of 
fine powders of stable protein formulations.(8,9) 
Carbon dioxide has also been investigated for its suitability 
in Aerosol Solvent Extraction Systems (ASES), to generate 
microparticles of proteins suitable for aerosol delivery from 
aqueous based solutions.(10) 
A specification for carbon dioxide is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for carbon dioxide is 204-696-9. 
19 Specific References 
1 Haase LW. Application of carbon dioxide in cosmetic aerosols. 
Cosmet Perfum 1975; 90(8): 3132. 
2 Sanders PA. Aerosol packaging of pharmaceuticals. In: Banker GS, 
Rhodes CT, eds. Modern Pharmaceutics. New York: Marcel 
Dekker, 1979; 591626. 
3 Anonymous. CO2/acetone propellant kinder to ozone layer. Manuf 
Chem 1992; 63(1): 14. 
4 King JS, Mabbitt LA. The use of carbon dioxide for the 
preservation of milk. In: Board RG, Allwood MC, Banks JG, 
eds. Preservatives in the Food, Pharmaceutical and Environmental 
Industries. Oxford: Blackwell Scientific, 1987; 3543. 
5 Anonymous. Carbon dioxide breaks the mould. Chem Br 1992; 
28: 506. 
6 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
7 National Institute for Occupational Safety and Health. Recommendations 
for occupational safety and health. MMWR 1988; 
37(Suppl S-7): 129. 
8 Bettini R, Bonassi L, Castoro V, et al. Solubility and conversion of 
carbamazepine polymorphs in supercritical carbon dioxide. Eur J 
Pharm Sci 2001; 13(3): 281286. 
9 Sellers SP, Clark GS, Sievers RE, Carpenter JF. Dry powders of 
stable protein formulations from aqueous solutions prepared using 
supercritical CO2-assisted aerosolization. J Pharm Sci 2001; 90: 
785797. 
10 Bustami RT, Chan HK, Dehghani F, Foster NR. Generation of 
microparticles of proteins for aerosol delivery using high pressure 
modified carbon dioxide. Pharm Res 2000; 17: 13601366. 
20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. Mendham, NJ: WE 
Dorland Co., 1982: 361372. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold Company, 1979: 4454. 
Sciarra JJ, Sciarra CJ. Pharmaceutical and cosmetic aerosols. J Pharm 
Sci 1974; 63: 18151837. 
Sciarra JJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and 
Practice of Pharmacy, 20th edn. Baltimore, MD: Lippincott, 
Williams and Wilkins, 2000: 963979. 
Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhoes CT, eds: 
Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 
547574. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 137145. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Carbon Dioxide 117

Carboxymethylcellulose Calcium 
1 Nonproprietary Names 
BP: Carmellose calcium 
JP: Carmellose calcium 
PhEur: Carmellosum calcicum 
USPNF: Carboxymethylcellulose calcium 
2 Synonyms 
Calcium carboxymethylcellulose; calcium CMC; ECG 505; 
Nymcel ZSC. 
3 Chemical Name and CAS Registry Number 
Cellulose, carboxymethyl ether, calcium salt [9050-04-8] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes carboxymethylcellulose calcium as the 
calcium salt of a polycarboxymethyl ether of cellulose. 
5 Structural Formula 
Structure shown with a degree of substitution (DS) of 1.0. 
6 Functional Category 
Stabilizing agent; suspending agent; tablet and capsule disintegrant; 
viscosity-increasing agent; water-absorbing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
The main use of carboxymethylcellulose calcium is in tablet 
formulations (see Table I), where it is used as a binder, diluent, 
and disintegrant.(14) Although carboxymethylcellulose calcium 
is insoluble in water, it is an effective tablet disintegrant as 
it swells to several times its original bulk on contact with water. 
Concentrations up to 15% w/w may be used in tablet 
formulations; above this concentration, tablet hardness is 
reduced. 
Carboxymethylcellulose calcium is also used in other 
applications similarly to carboxymethylcellulose sodium; for 
example, as a suspending or viscosity-increasing agent in oral 
and topical pharmaceutical formulations. Carboxymethylcellulose 
calcium is also used in modern wound dressings for 
its water absorption, retention and hemostatic properties. 
Table I: Uses of carboxymethylcellulose calcium. 
Use Concentration (%) 
Tablet binder 515 
Tablet disintegrant 115 
8 Description 
Carboxymethylcellulose calcium occurs as a white to yellowishwhite, 
hygroscopic, fine powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for carboxymethylcellulose 
calcium. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters  .  
Alkalinity . . . 
pH 4.56.0   
Loss on drying 410.0% 410.0% 410.0% 
Residue on ignition 10.020.0% 10.020.0% 10.020.0% 
Chloride 40.360% 40.36% 40.36% 
Silicate 40.5% 40.60% 41.5% 
Sulfate 40.960% 41.0% 40.96% 
Arsenic 410 ppm   
Heavy metals 420 ppm 420 ppm 40.002% 
Starch .  . 
Organic volatile 
impurities 
  . 
10 Typical Properties 
Acidity/alkalinity: pH = 4.56.0 for a 1% w/v aqueous 
dispersion. 
Particle size distribution: 95% through a 73.7 mm sieve (#200 
mesh). 
Solubility: practically insoluble in acetone, chloroform, ethanol 
(95%), and ether. Insoluble in water, but swells to twice its 
volume to form a suspension. Insoluble in 0.1 mol/L 
hydrochloric acid, but slightly soluble in 0.1 mol/L sodium 
hydroxide. 
11 Stability and Storage Conditions 
Carboxymethylcellulose calcium is a stable, though hygroscopic 
material. It should be stored in a well-closed container in 
a cool, dry place. 
See also Carboxymethylcellulose sodium.

12 Incompatibilities 
See Carboxymethylcellulose sodium. 
13 Method of Manufacture 
Cellulose, obtained from wood pulp or cotton fibers, is 
carboxymethylated, followed by conversion to the calcium 
salt. It is then graded on the basis of its degree of 
carboxymethylation and pulverized. 
14 Safety 
Carboxymethylcellulose calcium is used in oral and topical 
pharmaceutical formulations, similarly to carboxymethylcellulose 
sodium, and is generally regarded as a nontoxic and 
nonirritant material. However, as with other cellulose derivatives, 
oral consumption of large amounts of carboxymethylcellulose 
calcium may have a laxative effect. 
See also Carboxymethylcellulose sodium. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Carboxymethylcellulose 
calcium may be irritant to the eyes; eye protection is 
recommended. 
16 Regulatory Status 
Accepted for use as a food additive in Japan at concentrations 
up to 2% w/w. Included in the FDA Inactive Ingredients Guide 
(oral, capsules and tablets). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Carboxymethylcellulose sodium; croscarmellose sodium. 
18 Comments 

19 Specific References 
1 Khan KA, Rooke DJ. Effect of disintegrant type upon the 
relationship between compressional pressure and dissolution 
efficiency. J Pharm Pharmacol 1976; 28(8): 633636. 
2 Kitamori N, Makino T. Improvement in pressure-dependent 
dissolution of trepibutone tablets by using intragranular disintegrants. 
Drug Dev Ind Pharm 1982; 8(1): 125139. 
3 Roe TS, Chang KY. The study of Key-Jo clay as a tablet 
disintegrator. Drug Dev Ind Pharm 1986; 12(1113): 15671585. 
4 Ozeki T, Yasuzawa Y, Katsuyama H, et al. Design of rapidly 
disintegrating oral tablets using acid-treated yeast cell wall: a 
technical note. AAPS Pharm Tech Sci 2003; 4(4): E70. 
20 General References 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993 107: 199265. 
21 Authors 
D Parsons. 
22 Date of Revision 
17 August 2005. 
Carboxymethylcellulose Calcium 119

Carboxymethylcellulose Sodium 
1 Nonproprietary Names 
BP: Carmellose sodium 
JP: Carmellose sodium 
PhEur: Carmellosum natricum 
USP: Carboxymethylcellulose sodium 
2 Synonyms 
Akucell; Aquasorb; Blanose; cellulose gum; CMC sodium; 
E466; Finnfix; Nymcel; SCMC; sodium carboxymethylcellulose; 
sodium cellulose glycolate; sodium CMC; Tylose CB. 
3 Chemical Name and CAS Registry Number 
Cellulose, carboxymethyl ether, sodium salt [9004-32-4] 
4 Empirical Formula and Molecular Weight 
The USP 28 describes carboxymethylcellulose sodium as the 
sodium salt of a polycarboxymethyl ether of cellulose. Typical 
molecular weight is 90 000700 000. 
5 Structural Formula 
Structure shown with a degree of substitution (DS) of 1.0. 
6 Functional Category 
Coating agent; stabilizing agent; suspending agent; tablet and 
capsule disintegrant; tablet binder; viscosity-increasing agent; 
water-absorbing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Carboxymethylcellulose sodium is widely used in oral and 
topical pharmaceutical formulations, primarily for its viscosityincreasing 
properties. Viscous aqueous solutions are used to 
suspend powders intended for either topical application or oral 
and parenteral administration.(1,2) Carboxymethylcellulose 
sodium may also be used as a tablet binder and disintegrant,(
36) and to stabilize emulsions.(7,8) 
Higher concentrations, usually 36%, of the mediumviscosity 
grade are used to produce gels that can be used as 
the base for applications and pastes; glycols are often included 
in such gels to prevent them drying out. Carboxymethylcellulose 
sodium is additionally one of the main ingredients of selfadhesive 
ostomy, wound care,(9) and dermatological patches, 
where it is used as a muco-adhesive and to absorb wound 
exudate or transepidermal water and sweat. This mucoadhesive 
property is used in products designed to prevent 
post-surgical tissue adhesions;(1012) and to localize and modify 
the release kinetics of active ingredients applied to mucous 
membranes; and for bone repair. Encapsulation with carboxymethylcellulose 
sodium can affect drug protection and delivery.(
6,13) There have also been reports of its use as a cytoprotective 
agent.(14,15) 
Carboxymethylcellulose sodium is also used in cosmetics, 
toiletries,(16) surgical prosthetics,(17) and incontinence, personal 
hygiene, and food products. 
See Table I. 
Table I: Uses of carboxymethylcellulose sodium. 
Use Concentration (%) 
Emulsifying agent 0.251.0 
Gel-forming agent 3.06.0 
Injections 0.050.75 
Oral solutions 0.11.0 
Tablet binder 1.06.0 
8 Description 
Carboxymethylcellulose sodium occurs as a white to almost 
white, odorless, granular powder. See also Section 18. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for carboxymethylcellulose 
sodium. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . .  
pH (1% w/v solution) 6.08.0 6.08.0 6.58.5 
Appearance of solution . .  
Viscosity . . . 
Loss on drying 410.0% 410.0% 410.0% 
Heavy metals 420 ppm 420 ppm 420 mg/g 
Chloride 40.640% 40.25%  
Arsenic 410 ppm   
Sulfate 40.960%   
Silicate 40.5%   
Sodium glycolate  40.4%  
Starch .   
Sulfated ash  20.033.3%  
Organic volatile impurities   . 
Assay (of sodium) 6.58.5% 6.510.8% 6.59.5%

SEM: 1 
Excipient: Carboxymethylcellulose sodium 
Manufacturer: Buckeye Cellulose Corp. 
Lot No.: 9247 AP 
Magnification: 120 Voltage: 10 kV 
10 Typical Properties 
Density (bulk): 0.52 g/cm3 
Density (tapped): 0.78 g/cm3 
Dissociation constant: pKa = 4.30 
Melting point: browns at approximately 2278C, and chars at 
approximately 2528C. 
Moisture content: typically contains less than 10% water. 
However, carboxymethylcellulose sodium is hygroscopic 
and absorbs significant amounts of water at temperatures 
up to 378C at relative humidities of about 80%. See Section 
11. See also Figure 1. 
Solubility: practically insoluble in acetone, ethanol (95%), ether, 
and toluene. Easily dispersed in water at all temperatures, 
forming clear, colloidal solutions. The aqueous solubility 
varies with the degree of substitution (DS). See Section 18. 
Viscosity: various grades of carboxymethylcellulose sodium are 
commercially available that have differing aqueous viscosities; 
see Table III. Aqueous 1% w/v solutions with 
viscosities of 513 000 mPa s (513 000 cP) may be 
obtained. An increase in concentration results in an increase 
in aqueous solution viscosity.(16) Prolonged heating at high 
temperatures will depolymerize the gum and permanently 
decrease the viscosity. The viscosity of sodium carboxymethylcellulose 
solutions is fairly stable over a pH range of 
410. The optimum pH range is neutral. See Section 11. 
Table III: Viscosity of aqueous carboxymethylcellulose sodium 1% 
w/v solutions. (Measurements made with a Brookfield LVT viscometer at 
258C.) 
Grade Viscosity 
(mPa s) 
Spindle Speed 
Low viscosity Akucell AF 0305 1015 #1 60 rpm 
Medium viscosity Akucell AF 2785 15002500 #3 30 rpm 
High viscosity Akucell AF 3085 800012000 #4 30 rpm 
SEM: 2 
Excipient: Carboxymethylcellulose sodium 
Manufacturer: Hercules Ltd. 
Lot No.: 21 A-1 (44390) 
Magnification: 600 Voltage: 10 kV 
Figure 1: Sorptiondesorption isotherm of carboxymethylcellulose 
sodium. 
*: Sorption 
&: Desorption 
11 Stability and Storage Conditions 
Carboxymethylcellulose sodium is a stable, though hygroscopic 
material. Under high-humidity conditions, carboxymethylcellulose 
sodium can absorb a large quantity (>50%) of water. 
Carboxymethylcellulose Sodium 121

In tablets, this has been associated with a decrease in tablet 
hardness and an increase in disintegration time.(18) 
Aqueous solutions are stable at pH 210; precipitation can 
occur below pH 2, and solution viscosity decreases rapidly 
above pH 10. Generally, solutions exhibit maximum viscosity 
and stability at pH 79. 
Carboxymethylcellulose sodium may be sterilized in the dry 
state by maintaining it at a temperature of 1608C for 1 hour. 
However, this process results in a significant decrease in 
viscosity and some deterioration in the properties of solutions 
prepared from the sterilized material. 
Aqueous solutions may similarly be sterilized by heating, 
although this also results in some reduction in viscosity. After 
autoclaving, viscosity is reduced by about 25%, but this 
reduction is less marked than for solutions prepared from 
material sterilized in the dry state. The extent of the reduction is 
dependent on the molecular weight and degree of substitution; 
higher molecular weight grades generally undergo a greater 
percentage reduction in viscosity.(19) Sterilization of solutions 
by gamma irradiation also results in a reduction in viscosity. 
Aqueous solutions stored for prolonged periods should 
contain an antimicrobial preservative.(20) 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Carboxymethylcellulose sodium is incompatible with strongly 
acidic solutions and with the soluble salts of iron and some 
other metals, such as aluminum, mercury, and zinc. Precipitation 
may occur at pH <2, and also when it is mixed with 
ethanol (95%). 
Carboxymethylcellulose sodium forms complex coacervates 
with gelatin and pectin. It also forms a complex with collagen 
and is capable of precipitating certain positively charged 
proteins. 
13 Method of Manufacture 
Alkali cellulose is prepared by steeping cellulose obtained from 
wood pulp or cotton fibers in sodium hydroxide solution. The 
alkaline cellulose is then reacted with sodium monochloroacetate 
to produce carboxymethylcellulose sodium. Sodium 
chloride and sodium glycolate are obtained as by-products of 
this etherification. 
14 Safety 
Carboxymethylcellulose sodium is used in oral, topical, and 
some parenteral formulations. It is also widely used in 
cosmetics, toiletries, and food products, and is generally 
regarded as a nontoxic and nonirritant material. However, 
oral consumption of large amounts of carboxymethylcellulose 
sodium can have a laxative effect; therapeutically, 410 g in 
daily divided doses of the medium- and high-viscosity grades of 
carboxymethylcellulose sodium have been used as bulk 
laxatives.(21) 
The WHO has not specified an acceptable daily intake for 
carboxymethylcellulose sodium as a food additive since the 
levels necessary to achieve a desired effect were not considered 
to be a hazard to health.(2225) However, in animal studies, 
subcutaneous administration of carboxymethylcellulose 
sodium has been found to cause inflammation, and in some 
cases of repeated injection fibrosarcomas have been found at 
the site of injection.(26) 
Hypersensitivity and anaphylactic reactions have occurred 
in cattle and horses, which have been attributed to carboxymethylcellulose 
sodium in parenteral formulations such as 
vaccines and penicillins.(2730) 
LD50 (guinea pig, oral): 16 g/kg(31) 
LD50 (rat, oral): 27 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Carboxymethylcellulose 
sodium may be irritant to the eyes. Eye protection is 
recommended. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (dental preparations; 
inhalations; intra-articular, intrabursal, intradermal, intralesional, 
IM, intrasynovial and SC injections; oral capsules, 
drops, solutions, suspensions, syrups and tablets; topical and 
vaginal preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Carboxymethylcellulose calcium. 
18 Comments 
A number of grades of carboxymethylcellulose sodium are 
commercially available, such as Accelerate. These have a degree 
of substitution (DS) in the range 0.71.2. The DS is defined as 
the average number of hydroxyl groups substituted per 
anhydroglucose unit and it is this that determines the aqueous 
solubility of the polymer. Thermal crosslinking reduces 
solubility while retaining water absorption, therefore producing 
materials suitable for water absorption. 
Grades are typically classified as being of low, medium, or 
high viscosity. The degree of substitution and the maximum 
viscosity of an aqueous solution of stated concentration should 
be indicated on any carboxymethylcellulose sodium labeling. 
Carboxymethylcellulose sodium has been reported to give 
false positive results in the LAL test for endotoxins.(32) 
19 Specific References 
1 Hussain MA, Aungst BJ, Maurin MB, Wu LS. Injectable 
suspensions for prolonged release nalbuphine. Drug Dev Ind 
Pharm 1991; 17(1): 6776. 
2 Chang JH, Lee KC, Choi HJ, et al. Radiographic contrast study of 
the upper gastrointestinal tract of eight dogs using carboxymethylcellulose 
mixed with a low concentration of barium sulphate. Vet 
Rec 2004; 154(7): 201204. 
3 Khan KA, Rhodes CT. Evaluation of different viscosity grades of 
sodium carboxymethylcellulose as tablet disintegrants. Pharm 
Acta Helv 1975; 50: 99102. 
4 Shah NH, Lazarus JH, Sheth PR, Jarowski CI. Carboxymethylcellulose: 
effect of degree of polymerization and substitution on 
tablet disintegration and dissolution. J Pharm Sci 1981; 70(6): 
611613. 
5 Singh J. Effect of sodium carboxymethylcelluloses on the disintegration, 
dissolution and bioavailability of lorazepam from 
tablets. Drug Dev Ind Pharm 1992; 18(3): 375383. 
6 Dabbagh MA, Ford JL, Rubinstein MH, et al. Release of 
propanolol hydrochloride from matrix tablets containing sodium 
122 Carboxymethylcellulose Sodium

carboxymethylcellulose and hydroxypropylmethylcellulose. 
Pharm Dev Technol 1999; 4(3): 313324. 
7 Oza KP, Frank SG. Microcrystalline cellulose stabilized emulsions. 
J Disper Sci Technol 1986; 7(5): 543561. 
8 Adeyeye MC, Jain AC, Ghorab MK, Reilly WJ Jr. Viscoelastic 
evaluation of topical creams containing microcrystalline cellulose/ 
sodium carboxymethylcellulose as stabilizer. AAPS PharmSciTech 
2002; 3(2): E8. 
9 Fletcher J. The benefits if using hydrocolloids. Nurs Times 2003; 
99(21): 57. 
10 Yelimlies B, Alponat A, Cubukcu A, et al. Carboxymethylcellulose 
coated on visceral face of polypropylene mesh prevents adhesion 
without impairing wound healing in incisional hernia model in 
rats. Hernia 2003; 7(3): 130133. 
11 Hay WP, Mueller PO, Harmon B, Amoroso L. One percent sodium 
carboxymethylcellulose prevents experimentally induced adhesions 
in horses. Vet Surg 2001; 673(3): 223227. 
12 Liu LS, Berg RA. Adhesion barriers of carboxymethylcellulose and 
polyethylene oxide composite gels. J Biomed Mater Res 2002; 
63(3): 326332. 
13 Marschutz MK, Caliceti P, Bernkop-Schnurch A. Design and in 
vivo evaluation of an oral delivery system for insulin. Pharm Res 
2000; 17(12): 14681474. 
14 Ahee JA, Kaufman SC, Samuel MA, et al. Decreased incidence of 
epithelial defects during laser in situ keratomileusis using 
intraoperative nonpreserved carboxymethylcellulose sodium 
0.5% solution. J Cateract Refract Surg 2002; 28(9): 16511654. 
15 Vehige JG, Simmons PA, Anger C, et al. Cytoprotective properties 
of carboxymethylcellulose (CMC) when used prior to wearing 
contact lenses treated with cationic disinfecting agents. Eye 
Contact Lens 2003; 29(3): 177180. 
16 Mombellet H, Bale P. Sodium carboxymethylcellulose toothpaste. 
Manuf Chem 1988; 59(11): 47, 49, 52. 
17 Valeriani M, Mezzana P, Madonna Terracina FS. Carboxymethylcellulose 
hydrogel mammary implants: our experience. Acta Chir 
Plast 2002; 44(3): 7779. 
18 Khan KA, Rhodes CT. Water-sorption properties of tablet 
disintegrants. J Pharm Sci 1975; 64(6): 447451. 
19 Chu PI, Doyle D. Development and evaluation of a laboratoryscale 
apparatus to simulate the scale-up of a sterile semisolid and 
effects of manufacturing parameters on product viscosity. Pharm 
Dev Technol 1999; 4(4): 553559. 
20 Banker G, Peck G, Williams E, et al. Microbiological considerations 
of polymer solutions used in aqueous film coating. Drug Dev 
Ind Pharm 1982; 8(1): 4151. 
21 Wapnir RA, Wingertzahn MA, Teichberg S. Cellulose derivatives 
and intestinal absorption of water and electrolytes: potential role 
in oral rehydration solutions. Proc Soc Exp Biol Med 1997; 
215(3): 275280. 
22 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990: No. 
789. 
23 Til HP, Bar A. Subchronic (13-week) oral toxicity study of gammacyclodextrin 
in dogs. Regul Toxicol Pharmacol 1998; 27(2): 159 
165. 
24 Diebold Y, Herreras JM, , Callejo S, et al. Carbomer- versus 
cellulose-based artificial-tear formulations: morphological and 
toxicologic effects on a corneal cell line. Cornea 1998; 17(4): 
433440. 
25 Ugwoke MI, Agu RU, Jorissen M, et al. Toxicological investigations 
of the effects of carboxymethylcellulose on ciliary beat 
frequency of human nasal epithelial cells in primary suspension 
culture and in vivo on rabbit nasal mucosa. Int J Pharm 2000; 
205(12): 4351. 
26 Teller MN, Brown GB. Carcinogenicity of carboxymethylcellulose 
in rats. Proc Am Assoc Cancer Res 1977; 18: 225. 
27 Schneider CH, de Weck AL, Sta. uble E. Carboxymethylcellulose 
additives in penicillins and the elucidation of anaphylactic 
reactions. Experentia 1971; 27: 167168. 
28 Aitken MM. Induction of hypersensitivity to carboxymethylcellulose 
in cattle. Res Vet Sci 1975; 19: 110113. 
29 Bigliardi PL, Izakovic J,Weber JM, Bircher AJ. Anaphylaxis to the 
carbohydrate carboxymethylcellulose in parenteral corticosteroid 
preparations. Dermatology 2003; 207(1): 100103. 
30 Montoro J, Valero A, Elices A, et al. Anaphylactic shock after 
intra-articular injection of carboxymethylcellulose. Allergol 
Immunopathol 2000; 28(6): 332333. 
31 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3236. 
32 Tanaka S, Aketagawa J, Takahashi S, et al. Activation of a limulus 
coagulation factor G by (1!3)-b-D-glucans. Carbohydr Res 1991; 
218: 167174. 
20 General References 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199265. 
21 Authors 
D Parsons. 
22 Date of Revision 
17 August 2005. 
Carboxymethylcellulose Sodium 123

Carrageenan 
1 Nonproprietary Names 
USPNF: Carrageenan 
2 Synonyms 
Chondrus extract; E407; Gelcarin; Genu; Hygum TP-1; Irish 
moss extract; Marine Colloids; SeaSpen PF; Viscarin. 
3 Chemical Name and CAS Registry Number 
Carrageenan [9000-07-1] 
k-Carrageenan [11114-20-8] 
l-Carrageenan [9064-57-7] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes carrageenan as the hydrocolloid 
obtained by extraction with water or aqueous alkali from some 
members of the class Rhodophyceae (red seaweed). It consists 
chiefly of potassium, sodium, calcium, magnesium, and 
ammonium sulfate esters of galactose and 3,6-anhydrogalactose 
copolymers. These hexoses are alternately linked at the 
a-1,3 and b-1,4 sites in the polymer. 
5 Structural Formula 
The carrageenans are divided into three families according to 
the position of sulfate groups and the presence or absence of 
anhydrogalactose. 
l-Carrageenan (lambda-carrageenan) is a nongelling polymer 
containing about 35% ester sulfate by weight and no 3,6- 
anhydrogalactose. 
i-Carrageenan (iota-carrageenan) is a gelling polymer 
containing about 32% ester sulfate by weight and approximately 
30% 3,6-anhydrogalactose. 
k-Carrageenan (kappa-carrageenan) is a strongly gelling 
polymer which has a helical tertiary structure that allows 
gelling.(1) It contains 25% ester sulfate by weight and 
approximately 34% 3,6-anhydrogalactose. 
6 Functional Category 
Emulsifying agent; gel base; stabilizing agent; suspending agent; 
sustained release tablet matrix; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Carrageenan is used in a variety of nonparenteral dosage forms, 
including suspensions (wet and reconstitutable), emulsions, 
gels, creams, lotions, eye drops, suppositories, and tablets and 
capsules. In suspension formulations, usually only the icarrageenen 
and l-carrageenan fractions are used. l-Carrageenan 
is generally used at levels of 0.7% w/v or less, and provides 
viscosity to the liquid. Carrageenan has been shown to mask 
the chalkiness of antacid suspensions when used as a 
suspending agent in these preparations.(2) When used in 
concentrations of 0.10.5%, carrageenan gives stable emulsions. 
Carrageenan is used in hand lotions and creams to 
provide slip and improved rub out. 
i-Carrageenan develops a shear-thinning thixotropic gel, 
which can be easily poured after shaking. When i-carrageenan 
is used, the presence of calcium ions is required for the gel 
network to become established. With pure i-carrageenan, 
about 0.4% w/v is required for most suspensions plus the 
addition of calcium. However, if SeaSpen PF is used, it must be 
at about 0.75% w/v level, although no additional calcium is 
required as this is already present in the product to control the 
rate of gelation. 
Studies on the effect of carrageenan and other colloids on 
muco-adhesion of drugs to the oropharyngeal areas(3,4) have 
shown that carrageenan had the greatest propensity for 
adhesion and can be used in formulations for oral and buccal 
drug delivery. 
The application of carrageenan in both topical gel bases and 
suppository bases has been examined,(5,6) and the findings 
indicate that the use of carrageenan in these dosage forms is 
most likely to be dependent on the active drug, owing to the 
potential for ionic interactions. 
In the case of topical gels, a combination of i, k-, and lcarrageenans 
produces a spreadable gel with acceptable tactile 
sensation, resulting in drug release that is more likely to follow 
diffusion kinetics.

In the case of suppository dosage forms, a greater amount of 
k-carrageenan is required in the presence of potassium to form 
a more rigid structure. 
Incorporation of carrageenan into tablet matrices with 
various drugs and other excipients to alter release profiles has 
been studied, illustrating that the carrageenans have good 
tablet-binding properties.(710) Furthermore, the inclusion of 
calcium or potassium salts into the tablet creates a microenvironment 
for gelation to occur, which further controls drug 
release. 
There have also been several references to the use of 
carrageenan in chewable tablets having a confectionary 
texture.(11,12) This approach to creating a novel dosage form 
requires the use of both i-carrageenan and k-carrageenan, to 
prevent moisture loss and texture changes that occur over time. 
See also Section 10. Carrageenan has been used for the 
microencapsulation of proteins(13) and probiotic bacteria.(14) It 
has also been used as beads in the preparation of controlled 
release systems.(15,16) Studies have shown that carrageenan 
compounds block infections by the herpes simplex virus;(17) 
human cytomegalovirus; human papilloma virus; Sindbis virus; 
vesicular stomatitis virus; and HIV.(18) A combined k- and lcarrageenan 
formulation is currently being investigated as the 
active ingredient in a topical microbicide used to prevent the 
sexual transmission of HIV.(1921) In combination with 
chitosan, agar and polyvinyl pyrrolidone, carrageenan forms 
a water-insoluble complex which is able to absorb large 
amounts of body fluids, and is used as an effective wound 
dressing.(2224) Carrageenan is used in the preparation of hard 
and soft capsule shells.(25) It is also used in toothpastes and 
cosmetic preparations such as conditioners and shampoos.(
26,27) 
8 Description 
Carrageenan, when extracted from the appropriate seaweed 
source, is a yellow-brown to white colored, coarse to fine 
powder that is odorless and tasteless. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for carrageenan. 
Test USPNF 23 
Identification . 
Acid insoluble matter 42.0% 
Arsenic 43 ppm 
Heavy metals 40.004% 
Lead 40.001% 
Loss on drying 412.5% 
Total ash 435.0% 
Viscosity (at 758C) 45 mPa s 
Microbial limits 4200 /g 
10 Typical Properties 
Because of the vast differences in the material that can be 
referred to as carrageenan, it is difficult to give descriptions of 
typical properties. See Table II. 
Solubility: soluble in water at 808C. See Tables II and III. 
Viscosity (dynamic): 5 mPa s (5 cP) at 758C. See Table II. 
11 Stability and Storage Conditions 
Carrageenan is a stable, though hygroscopic, polysaccharide 
and should be stored in a cool, dry place. 
12 Incompatibilities 
Carrageenan can react with cationic materials. If complexation 
of cationic materials, with associated modification of the active 
compounds solubility, is undesirable, the use of carrageenan is 
not recommended. 
Table III: Solubililty and gelation properties of i-, k-, and lcarrageenans. 
Kappa Iota Lambda 
Solubility in water 
208C Na salt only Na salt only Yes 
808C Yes Yes Yes 
Gelation 
Ions necessary K. Ca2. No gel 
Texture Brittle Elastic No gel 
Re-gelation after shear No Yes  
Acid stability >pH 3.8 >pH 3.8  
Table II: Typical properties of different grades of carrageenan (FMC Biopolymer). 
Trade name Carrageenan 
type 
Gel type Solubility in water Viscosity Use concentration 
(%) 
Use examples 
Gelcarin GP-379 Iota Elastic, medium 
strength 
Hot High, 
thixotropic 
0.31.0 Creams, suspensions 
Gelcarin GP-812 Kappa Brittle, strong Hot Low 0.31.0 Gels 
Gelcarin GP-911 Kappa Brittle, firm Hot, partial in cold Low 0.252.0 Encapsulation 
SeaSpen PF Iota Elastic, weak Cold, delayed gel 
formation 
Medium, 
thixotropic 
0.51.0 Creams, suspensions, 
lotions 
Viscarin GP-109 Lambda Non-gelling Partial cold, full in hot Medium 0.11.0 Creams, lotions 
Viscarin GP-209 Lambda Non-gelling Partial cold, full in hot High 0.11.0 Creams, lotions 
Viscarin GP-328 Kappa/lambda Weak Hot Mediumhigh 0.71.2 Creams, emulsions, 
lotions 
Carrageenan 125

13 Method of Manufacture 
The main species of seaweed from which carrageenan is 
manufactured are Eucheuma, Chondrus, and Gigartina. The 
weed is dried quickly to prevent degradation, and is then baled 
for shipment to processing facilities. The seaweed is repeatedly 
washed to remove gross impurities such as sand, salt and 
marine life. The weed undergoes a hot alkali extraction process, 
releasing the carrageenan from the cell. Once it is in a hot 
solution, carrageenan undergoes clarification and concentration 
in solution and is converted to powder. 
Three processes can be used to remove the carrageenan from 
solution. The first is a freezethaw technique. The solution is 
gelled with various salts, then the gels are frozen. Upon 
thawing, the water is removed and the resultant mass, primarily 
carrageenan and salt, is ground to the desired particle size. 
The second method, referred to as the alcohol precipitation 
method takes the concentrated solution of carrageenan and 
places it in alcohol. This causes the carrageenan to precipitate 
out of solution. The cosolvents are evaporated and the 
precipitated carrageenan is dried and ground to the desired 
particle size. 
The third method is the KCl precipitation process, where 
after hot extraction, the filtrate is evaporated to reduce the 
filtrate volume. The filtrate is then extruded through spinnerets 
into a cold 1.01.5% solution of potassium chloride. The 
resulting gel threads are washed with KCl solution and are 
pressed, dried and milled to carrageenan powder.(2) Commercial 
carrageenan is usually standardized by blending different 
batches of carrageenan and adding sugar or salt to obtain the 
desired gelling or thickening properties.(28) 
14 Safety 
Carrageenan is widely used in numerous food applications and 
is increasingly being used in pharmaceutical formulations. 
Carrageenan is generally regarded as a relatively nontoxic and 
nonirritating material when used in nonparenteral pharmaceutical 
formulations. 
However, carrageenan is known to induce inflammatory 
responses in laboratory animals, and for this reason it is 
frequently used in experiments for the investigation of antiinflammatory 
drugs.(29,30) Animal studies suggest that 
degraded carrageenan (which is not approved for use in food 
products) may be associated with cancer in the intestinal tract, 
although comparable evidence does not exist in humans.(31) 
The WHO has set an acceptable daily intake of carrageenan 
of not specified as the total daily intake was not considered to 
represent a hazard to health.(32) In the UK, the Food Advisory 
Committee has recommended that carrageenan should not be 
used as an additive for infant formulas.(33) 
LD50 (rat, oral): >5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
GRAS listed. Accepted as a food additive in Europe. Included in 
the FDA Inactive Ingredients Guide (dental; oral granules, 
powders and syrups, topical; and transdermal preparations). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 

18 Comments 
The EINECS number for carrageenan is 232-524-2. 
19 Specific References 
1 The Merck Index: an Encyclopedia of Chemicals, Drugs and 
Biologicals, 13th edn. Whitehouse Station, NJ: Merck, 2001: 316. 
2 Chaoyuan W, ed. Training Manual on Gracilaria Culture and 
Seaweed Processing in China. China: Depratment of Aquatic 
Products, Ministry of Agriculture, 1990. 
3 Brannon-Peppas L, Reilly W. In vitro testing of bioadhesion of 
solutions for buccal administration and drug delivery. Proceedings 
of the 23rd International Symposium on Controlled Release of 
Bioactive Materials, 1996: 513. 
4 Hanawa T, Masuda N, Mohri K, et al. Development of patientfriendly 
preparations: preparation of a new allopurinol 
mouthwash containing polyethylene(oxide) and carrageenan. 
Drug Dev Ind Pharm 2004; 30(2): 151161. 
5 Lev R, Long R, Mallonga L, et al. Evaluation of carrageenan as a 
base for topical gels. Pharm Res 1997; 14(11): 42. 
6 Lui Y, Schnaare R, Reilly W. Evaluation of carrageenan as a 
suppository base. Pharm Res 1997; 14(11): 41. 
7 Hariharan M, Wheatley TA, Price JC. Controlled-release tablet 
matrices from carrageenans: compression and dissolution studies. 
Pharm Dev Technol 1997; 2(4): 383393. 
8 Picker KM. Matrix tablets of carrageenans I: a compaction study. 
Drug Dev Ind Pharm 1999; 25(3): 329337. 
9 Picker KM. Matrix tablets of carrageenans II: release behavior and 
effect of added cations. Drug Dev Ind Pharm 1999; 25(3): 339 
346. 
10 Gursoy A, Cevik S. Sustained release properties of alginate 
microspheres and tabletted microspheres of diclofenac sodium. J 
Microencapsul 2000; 17(5): 565575. 
11 Bubnis W, OHare K, Reilly W. A novel soft chewable gel delivery 
system. Proceedings of the 24th International Symposium on 
Controlled Release of Bioactive Materials, 1997: 653. 
12 Bubnis W, OHare K, Reilly W. A low moisture hydrocolloid soft 
chewable gel delivery system. Pharm Res 1997; 14(11): 525. 
13 Patil RT, Speaker TJ.Water-based microsphere delivery system for 
proteins. J Pharm Sci 2000; 89(1): 915. 
14 Kailasapathy K. Microencapsulation of probiotic bacteria: technology 
and potential applications. Curr Issues Intest Microbiol 
2002; 3(2): 3948. 
15 Ozsoy Y, Bergisadi N. Preparation of mefenamic acid sustained 
release beads based om kappa-carrageenan. Boll Chim Farm 2000; 
139(3): 120123. 
16 Sipahigil O, Dortunc B. Preparation and in vitro evaluation of 
verapamil hydrochloride and ibuprofen containing carrageenan 
beads. Int J Pharm 2001; 228(12): 119128. 
17 Carlucci MJ, Scolaro LA, Damonte EB. Inhibitory action of 
natural carrageenans on herpes simplex virus infection of mouse 
astrocytes. Chemotherapy 1999; 45(6): 429436. 
18 Gonzalez ME, Alarcon B, Carrasco L. Polysaccharides as antiviral 
agents: antiviral activity of carrageenan. Antimicrob Agents 
Chemother 1987; 31(9): 13881393. 
19 Population Council. Biomedicine: Population Council Microbicide 
Programme. The Population Councils Head Candidate Microbicide: 
Carraguard. http://www.popcouncil.org/biomed/ 
carraguard.html (accessed 29 December 2004). 
20 Pearce-Pratt R, Phillips DM. Sulfated polysaccharides inhibit 
lymphocyte-to-epithelial transmission of human immunodeficiency 
virus-1. Biol Reprod 1996; 53(1): 173182. 
21 Perotti ME, Pirovano A, Phillips DM. Carrageenan formulation 
prevents macrophage trafficking from vagina: implications for 
microbicide development. Biol Reprod 2003; 69(3): 933939. 
126 Carrageenan

22 Varshney L. Hydrogel: A new radiation processed surgical 
dressing. Nuclear Medicine. India: Press Information Bureau, 
2003. 
23 Wu M, Bao B, Yoshii F, Makuuchi K. Irradiation of cross-linked 
polyvinyl alcohol blended hydrogel for wound dressing. J Radioanal 
Nuclear Chem 2001; 250(2): 391395. 
24 Radiation studies of carrageenan. Manila, Phillipines: Food and 
Nutrition Research Institute, 2003. 
25 Briones AV. Carrageenan capsules (hard type). Manila, Phillipines: 
Industrial Technology Development Institute, Department of 
Science and Technology, 2003. 
26 Stanley N. In: McHugh DJ, ed. Production, Properties and Uses of 
Carrageenan in Production and Utilization of Products from 
Commercial Seaweeds. Rome: Food and Agriculture Organisation 
of United Nations, 1987. 
27 Profile of Key Industries: Seaweeds/Carrageenan Industry Profile. 
Manila, Philippines: Department of Trade and Industry, 1998. 
28 Marcel Trading Corporation. Technical Literature: Marcel Carrageenan, 
1999. 
29 Cuzzocrea S, Mazzon E, Sautebin L, et al. Protective effects of 
Celecoxib on lung injury and red blood cells modification induced 
by carrageenan in the rat. Biochem Pharmacol 2002; 63(4): 785 
795. 
30 Manni L, Lundeberg T, Tirassa P, Aloe L. Role of cholecystokinin- 
8 in nerve growth factor and nerve growth factor in mRNA 
expression in carrageenan-induced joint inflammation in adult 
rats. Rheumatology (Oxford) 2002; 41(7): 787792. 
31 Tobacman JK. Review of harmful gastrointestinal effects of 
carrageenan in animal experiments. Environ Health Perspect 
2001; 109(10): 983994. 
32 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-eighth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1984; No 710. 
33 MAFF. Food Advisory Committee: report on the review of the use 
of additives in foods specially prepared for infants and young 
children. FdAC/REP/12. London: HMSO, 1992. 
20 General References 
FMC Biopolymer. Technical literature: Marine colloids, carrageenan 
application bulletins, 2004. 
Whistler RL, BeMiller JN, eds. Industrial Gums, Polysaccharides and 
Their Derivatives, 3rd edn. San Diego: Academic Press, 1993. 
21 Authors 
KK Singh. 
22 Date of Revision 
26 August 2005. 
Carrageenan 127

Castor Oil 
1 Nonproprietary Names 
BP: Virgin castor oil 
JP: Castor oil 
PhEur: Ricini oleum virginale 
USP: Castor oil 
2 Synonyms 
EmCon CO; Lipovol CO; oleum ricini; ricinoleum; ricinus 
communis; ricinus oil; tangantangan. 
3 Chemical Name and CAS Registry Number 
Castor oil [8001-79-4] 
4 Empirical Formula and Molecular Weight 
Castor oil is a triglyceride of fatty acids. The fatty acid 
composition is approximately ricinoleic acid (87%); oleic acid 
(7%); linoleic acid (3%); palmitic acid (2%); stearic acid (1%) 
and trace amounts of dihydroxystearic acid. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emollient; oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Castor oil is widely used in cosmetics, food products, and 
pharmaceutical formulations. In pharmaceutical formulations, 
castor oil is most commonly used in topical creams and 
ointments at concentrations of 512.5%. However, it is also 
used in oral tablet and capsule formulations and as a solvent in 
intramuscular injections.(1,2) 
Therapeutically, castor oil has been administered orally for 
its laxative action, but such use is now obsolete. 
8 Description 
Castor oil is a clear, almost colorless or pale yellow-colored 
viscous oil. It has a slight odor and a taste that is initially bland 
but afterwards slightly acrid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for castor oil. 
Test JP 2001 PhEur 2005 USP 28 
Identification . .  
Characters . .  
Specific gravity 0.9530.965 0.958 0.9570.961 
Heavy metals   40.001% 
Iodine value 8090 8290 8388 
Saponification value 176187  176182 
Hydroxyl value 155177 5150 160168 
Acid value 41.5 42.0  
Peroxide value  410.0  
Refractive index  1.479  
Optical rotation  .3.58 to .6.08  
Water  40.3%  
Absorbance . 41.5  
Composition of fatty 
acids 
 .  
Purity .   
Distinction from most 
other fixed oils 
  . 
Free fatty acids   . 
Unsaponifiable 
matter 
 40.8%  
10 Typical Properties 
Autoignition temperature: 4498C 
Boiling point: 3138C 
Density: 0.9550.968 g/cm3 at 258C 
Flash point: 2298C 
Melting point: 128C 
Moisture content: 40.25% 
Refractive index: 
nD
25 = 1.4731.477; 
nD
40 = 1.4661.473. 
Solubility: miscible with chloroform, diethyl ether, ethanol, 
glacial acetic acid, and methanol; freely soluble in ethanol 
(95%) and petroleum ether; practically insoluble in water; 
practically insoluble in mineral oil unless mixed with 
another vegetable oil. See also Section 11. 
Surface tension: 
39.0mN/m at 208C; 
35.2mN/m at 808C. 
Viscosity (dynamic): 
1000 mPa s (1000 cP) at 208C; 
200 mPa s (200 cP) at 408C. 
11 Stability and Storage Conditions 
Castor oil is stable and does not turn rancid unless subjected to 
excessive heat. On heating at 3008C for several hours, castor oil 
polymerizes and becomes soluble in mineral oil. When cooled 
to 08C, it becomes more viscous. 
Castor oil should be stored at a temperature not exceeding 
258C in well-filled airtight containers protected from light.

12 Incompatibilities 
Castor oil is incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Castor oil is the fixed oil obtained by cold-expression of the 
seeds of Ricinus communis Linne. (Fam. Euphorbiaceae). No 
other substances are added to the oil. 
14 Safety 
Castor oil is used in cosmetics and foods and orally, 
parenterally, and topically in pharmaceutical formulations. It 
is generally regarded as a relatively nontoxic and nonirritant 
material when used as an excipient.(3) 
Castor oil has been used therapeutically as a laxative and 
oral administration of large quantities may cause nausea, 
vomiting, colic, and severe purgation. It should not be given 
when intestinal obstruction is present. 
Although widely used in topical preparations, including 
ophthalmic formulations, castor oil has been associated with 
some reports of allergic contact dermatitis, mainly to cosmetics 
such as lipsticks.(47) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Castor oil may cause mild 
irritation to the skin and eyes. Castor oil is flammable when 
exposed to heat. Spillages are slippery and should be covered 
with an inert absorbant before collection and disposal. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(IM injections; oral capsules and tablets; topical creams, 
emulsions, ointments, and solutions). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Castor oil, hydrogenated. 
18 Comments 
A specification for castor oil is contained in the Food Chemicals 
Codex (FCC). 
The EINECS number for castor oil is 232-293-8. 
19 Specific References 
1 Rifkin C, Huber R, Keysser CH. Castor oil as a vehicle for 
parenteral administration of steroid hormones. J Pharm Sci 1964; 
53: 891895. 
2 Jumaa M, Mu. ller BW. Development of a novel parenteral 
formulation for tetrazepam using a lipid emulsion. Drug Dev 
Ind Pharm 2001; 27(10): 11151121. 
3 Irwin R. NTP technical report on the toxicity studies of castor oil 
(CAS no 8001-79-4) in F344/N rats and B6C3F1 mice (dosed feed 
studies). Toxic Rep Ser 1982; 12: 1B5. 
4 Fisher LB, Berman B. Contact allergy to sulfonated castor oil. 
Contact Dermatitis 1981; 7(6): 339340. 
5 Sai S. Lipstick dermatitis caused by castor oil. Contact Dermatitis 
1983; 9(1): 75. 
6 Andersen KE, Nielsen R. Lipstick dermatitis related to castor oil. 
Contact Dermatitis 1984; 11(4): 253254. 
7 Smolinske SC. CRC Handbook of Food, Drug and Cosmetic 
Excipients. Boca Raton, FL: CRC Press, 1992: 6970. 
20 General References 

21 Authors 
LME McIndoe. 
22 Date of Revision 
7 August 2005. 
Castor Oil 129

Castor Oil, Hydrogenated 
1 Nonproprietary Names 
BP: Hydrogenated castor oil 
PhEur: Ricini oleum hydrogenatum 
USPNF: Hydrogenated castor oil 
2 Synonyms 
Castorwax; Castorwax MP 70; Castorwax MP 80; Croduret; 
Cutina HR; Fancol; Simulsol 1293. 
3 Chemical Name and CAS Registry Number 
Glyceryl-tri-(12-hydroxystearate) [8001-78-3] 
4 Empirical Formula and Molecular Weight 
C57O9H110 939.50 
The USPNF 23 describes hydrogenated castor oil as the 
refined, bleached, hydrogenated, and deodorized castor oil, 
consisting mainly of the triglyceride of hydroxystearic acid. 
5 Structural Formula 
6 Functional Category 
Extended release agent; stiffening agent; tablet and capsule 
lubricant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Hydrogenated castor oil is a hard wax with a high melting 
point used in oral and topical pharmaceutical formulations; see 
Table I. 
In topical formulations, hydrogenated castor oil is used to 
provide stiffness to creams and emulsions.(1) In oral formulations, 
hydrogenated castor oil is used to prepare sustainedrelease 
tablet and capsule preparations;(25) the hydrogenated 
castor oil may be used as a coat or to form a solid matrix. 
Hydrogenated castor oil is additionally used to lubricate the 
die walls of tablet presses;(6,7) and is similarly used as a 
lubricant in food processing. 
Hydrogenated castor oil is also used in cosmetics. 
Table I: Uses of hydrogenated castor oil. 
Use Concentration (%) 
Coating agent (delayed release) 5.020.0 
Delayed release drug matrix 5.010.0 
Tablet die lubricant 0.12.0 
8 Description 
Hydrogenated castor oil occurs as a fine, almost white or pale 
yellow powder or flakes. The PhEur 2005 describes hydrogenated 
castor oil as the oil obtained by hydrogenation of virgin 
castor oil. It consists mainly of the triglyceride of 12- 
hydroxystearic acid. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for hydrogenated castor oil. 
Test PhEur 2005 USPNF 23 
Characters .  
Identification .  
Acid value 44.0  
Hydroxyl value 145165 154162 
Iodine value 45.0 45.0 
Saponification value  176182 
Alkaline impurities .  
Composition of fatty acids . . 
Palmitic acid 42.0%  
Stearic acid 7.014%  
Arachidic acid 41.0%  
12-Oxostearic acid 45.0%  
12-Hydroxystearic acid 78.091.0%  
Any other fatty acid 43.0%  
Nickel 41 ppm  
Heavy metals  40.001% 
Melting range 83888C 85888C 
10 Typical Properties 
Acid value: 45 
Density: 0.981.10 g/cm3 
Flash point: 3168C (open cup) 
Moisture content: 40.1% 
Particle size distribution: 97.7% 51000 mm in size for flakes. 
Solubility: practically insoluble in water; soluble in acetone, 
chloroform, and methylene chloride. 
11 Stability and Storage Conditions 
Hydrogenated castor oil is stable at temperatures up to 1508C. 
Clear, stable, chloroform solutions containing up to 15% 
w/v of hydrogenated castor oil may be produced. Hydrogenated 
castor oil may also be dissolved at temperatures greater

than 908C in polar solvents and mixtures of aromatic and polar 
solvents, although the hydrogenated castor oil precipitates out 
on cooling below 908C. 
Hydrogenated castor oil should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Hydrogenated castor oil is compatible with most natural 
vegetable and animal waxes. 
13 Method of Manufacture 
Hydrogenated castor oil is prepared by the hydrogenation of 
castor oil using a catalyst. 
14 Safety 
Hydrogenated castor oil is used in oral and topical pharmaceutical 
formulations and is generally regarded as an essentially 
nontoxic and nonirritant material. 
Acute oral toxicity studies in animals have shown that 
hydrogenated castor oil is a relatively nontoxic material. 
Irritation tests with rabbits show that hydrogenated castor oil 
causes mild, transient irritation to the eye. 
LD50 (rat, oral): >10 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Accepted in the USA as an indirect food additive. Included in 
the FDA Inactive Ingredients Guide (oral capsules, tablets, and 
sublingual tablets). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Castor oil; vegetable oil, hydrogenated. 
18 Comments 
Various different grades of hydrogenated castor oil are 
commercially available, the composition of which may vary 
considerably. Sterotex K (Karlshamns Lipid Specialities), for 
example, is a mixture of hydrogenated castor oil and 
hydrogenated cottonseed oil. See Vegetable Oil, hydrogenated 
for further information. The EINECS number for hydrogenated 
castor oil is 232-292-2. 
19 Specific References 
1 Kline CH. Thixcin R-thixotrope. Drug Cosmet Ind 1964; 95(6): 
895897, 960, 963, 973, 976. 
2 Yonezawa Y, Ishida S, Suzuki S, Sunada H. Release from or 
through a wax matrix system. III: basic properties of release 
through the wax matrix layer. Chem Pharm Bull (Tokyo) 2002; 
50(6): 814817. 
3 Pommier AM, Brossard C, Ser J, Duche.ne D. Optimization of a 
prolonged release tablet formulation of diphylline by retention in a 
lipid matrix [in French]. STP Pharma 1988; 4: 384391. 
4 Boles MG, Deasy PB, Donnellan MF. Design and evaluation of a 
sustained-release aminophylline tablet. Drug Dev Ind Pharm 
1993; 19: 349370. 
5 Vergote GJ, Verraet C, Van-Driessche I, et al. Oral controlled 
release matrix pellet formulation containing microcrystalline 
ketoprofen. Int J Pharm 2002; 219: 8187. 
6 Danish FQ, Parrott EL. Effect of concentration and size of 
lubricant on flow rate of granules. J Pharm Sci 1971; 60: 752754. 
7 Ho. lzer AW, Sjo. gren J. Evaluation of some lubricants by the 
comparison of friction coefficients and tablet properties. Acta 
Pharm Suec 1981; 18: 139148. 
20 General References 

21 Authors 
RT Guest. 
22 Date of Revision 
21 August 2005. 
Castor Oil, Hydrogenated 131

Cellulose, Microcrystalline 
1 Nonproprietary Names 
BP: Microcrystalline cellulose 
JP: Microcrystalline cellulose 
PhEur: Cellulosum microcristallinum 
USPNF: Microcrystalline cellulose 
2 Synonyms 
Avicel PH; Celex; cellulose gel; Celphere; Ceolus KG; crystalline 
cellulose; E460; Emcocel; Ethispheres; Fibrocel; Pharmacel; 
Tabulose; Vivapur. 
3 Chemical Name and CAS Registry Number 
Cellulose [9004-34-6] 
4 Empirical Formula and Molecular Weight 
(C6H10O5)n 36 000 
where n  220. 
5 Structural Formula 
6 Functional Category 
Adsorbent; suspending agent; tablet and capsule diluent; tablet 
disintegrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Microcrystalline cellulose is widely used in pharmaceuticals, 
primarily as a binder/diluent in oral tablet and capsule 
formulations where it is used in both wet-granulation and 
direct-compression processes.(17) In addition to its use as a 
binder/diluent, microcrystalline cellulose also has some lubricant(
8) and disintegrant properties that make it useful in 
tableting. 
Microcrystalline cellulose is also used in cosmetics and food 
products; see Table I. 
8 Description 
Microcrystalline cellulose is a purified, partially depolymerized 
cellulose that occurs as a white, odorless, tasteless, crystalline 
powder composed of porous particles. It is commercially 
available in different particle sizes and moisture grades that 
have different properties and applications. 
Table I: Uses of microcrystalline cellulose. 
Use Concentration (%) 
Adsorbent 2090 
Antiadherent 520 
Capsule binder/diluent 2090 
Tablet disintegrant 515 
Tablet binder/diluent 2090 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for microcrystalline cellulose. 
Test JP 2001 PhEur 2005 
(Suppl 5.1) 
USPNF 23 
Identification . . . 
Characters . .  
pH 5.07.0 5.07.5 5.07.5 
Bulk density .  . 
Loss on drying 47.0% 47.0% 47.0% 
Residue on ignition 40.05%  40.1% 
Conductivity . . . 
Sulfated ash  40.1%  
Ether-soluble substances 40.05% 40.05% 40.05% 
Water-soluble substances . 40.25% 40.25% 
Heavy metals 410 ppm 410 ppm 40.001% 
Organic volatile impurities   . 
Microbial limits . . . 
Aerobic  4103/g 41000 cfu/g 
Molds and yeasts  4102/g 4100 cfu/g 
Solubility  .  
Particle size distribution   . 
10 Typical Properties 
Angle of repose: 
498 for Ceolus KG; 
34.48 for Emcocel 90M.(9) 
Density (bulk): 
0.337 g/cm3; 
0.32 g/cm3 for Avicel PH-101;(10) 
0.29 g/cm3 for Emcocel 90M;(9) 
0.29 g/cm3 for VivaPur 101. 
Density (tapped): 
0.478 g/cm3; 
0.45 g/cm3 for Avicel PH-101; 
0.35 g/cm3 for Emcocel 90M.(9) 
Density (true): 1.5121.668 g/cm3 
Flowability: 1.41 g/s for Emcocel 90M.(9) 
Melting point: chars at 2602708C. 
Moisture content: typically less than 5% w/w. However, 
different grades may contain varying amounts of water. 
Microcrystalline cellulose is hygroscopic.(11) See Table III.

SEM: 1 
Excipient: Microcrystalline cellulose 
Manufacturer: JRS Pharma LP. 
Lot No.: 98662 
Magnification: 100 
SEM: 2 
Excipient: Microcrystalline cellulose 
Manufacturer: JRS Pharma LP. 
Lot No.: 98662 
Magnification: 300 
Particle size distribution: typical mean particle size is 
20200 mm. Different grades may have a different nominal 
mean particle size; see Table III. 
SEM: 3 
Excipient: Microcrystalline cellulose 
Manufacturer: FMC Biopolymer 
Magnification: 100 
Solubility: slightly soluble in 5% w/v sodium hydroxide 
solution; practically insoluble in water, dilute acids, and 
most organic solvents. 
Specific surface area: 
1.061.12m2/g for Avicel PH-101; 
1.211.30m2/g for Avicel PH-102; 
0.781.18m2/g for Avicel PH-200. 
11 Stability and Storage Conditions 
Microcrystalline cellulose is a stable though hygroscopic 
material. The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Microcrystalline cellulose is incompatible with strong oxidizing 
agents. 
13 Method of Manufacture 
Microcrystalline cellulose is manufactured by controlled 
hydrolysis with dilute mineral acid solutions of a-cellulose, 
obtained as a pulp from fibrous plant materials. Following 
hydrolysis, the hydrocellulose is purified by filtration and the 
aqueous slurry is spray-dried to form dry, porous particles of a 
broad size distribution. 
14 Safety 
Microcrystalline cellulose is widely used in oral pharmaceutical 
formulations and food products and is generally regarded as a 
relatively nontoxic and nonirritant material. 
Microcrystalline cellulose is not absorbed systemically 
following oral administration and thus has little toxic potential. 
Consumption of large quantities of cellulose may have a 
laxative effect, although this is unlikely to be a problem when 
cellulose is used as an excipient in pharmaceutical formulations. 
Cellulose, Microcrystalline 133

Deliberate abuse of formulations containing cellulose, either 
by inhalation or by injection, has resulted in the formation of 
cellulose granulomas.(12) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Microcrystalline cellulose 
may be irritant to the eyes. Gloves, eye protection, and a dust 
mask are recommended. In the UK, the occupational exposure 
limits for cellulose have been set at 10 mg/m3 long-term (8-hour 
TWA) for total inhalable dust and 4 mg/m3 for respirable dust; 
the short-term limit for total inhalable dust has been set at 
20 mg/m3.(13) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (inhalations; 
oral capsules, powders, suspensions, syrups, and tablets; 
topical and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Microcrystalline cellulose and carrageenan; microcrystalline 
cellulose and carboxymethylcellulose sodium; microcrystalline 
cellulose and guar gum; powdered cellulose; silicified microcrystalline 
cellulose. 
Microcrystalline cellulose and carrageenan 
Synonyms: Lustre Clear. 
Comments: Lustre Clear (FMC Biopolymer) is an aqueous film 
coating combining microcrystalline cellulose and carrageenan. 
Microcrystalline cellulose and carboxymethylcellulose sodium 
Synonyms: Avicel CL-611; Avicel RC-581; Avicel RC-591; 
colloidal cellulose; dispersible cellulose. 
Appearance: white, odorless and tasteless, hygroscopic powder. 
Acidity/alkalinity: pH = 68 for a 1.2% w/v aqueous 
dispersion. 
Moisture content: not more than 6.0% w/w. 
Particle size distribution: 
Avicel CL-611:40.1% retained on a #60 mesh and450% 
retained on a #325 mesh; 
Avicel RC-581:40.1% retained on a #60 mesh and435% 
retained on a #200 mesh; 
Avicel RC-591:40.1% retained on a #60 mesh and445% 
retained on a #325 mesh. 
Solubility: practically insoluble in dilute acids and organic 
solvents. Partially soluble in dilute alkali and water 
(carboxymethylcellulose sodium fraction). 
Viscosity (dynamic): 
520 mPa s (520 cP) for a 1.2% w/v aqueous dispersion of 
Avicel CL-611; 
72168 mPa s (72168 cP) for Avicel RC-581 at the same 
concentration; 
3991 mPa s (3991 cP) for Avicel RC-591 at the same 
concentration. 
Comments: mixtures of microcrystalline cellulose and carboxymethylcellulose 
sodium that are dispersible in water and 
produce thixotropic gels are suitable as suspending vehicles 
in pharmaceutical formulations. The amount of carboxymethylcellulose 
present can vary between 8.3% and 18.8% 
w/w depending upon the grade of material. 
Microcrystalline cellulose and guar gum 
Synonyms: Avicel CE-15. 
Comments: Avicel CE-15 (FMC Biopolymer) is a coprocessed 
mixture of microcrystalline cellulose and guar gum used in 
chewable tablet formulations. 
18 Comments 
Several different grades of microcrystalline cellulose are 
commercially available that differ in their method of manufacture,(
14,15) particle size, moisture, flow, and other physical 
properties.(1628) The larger-particle-size grades generally provide 
better flow properties in pharmaceutical machinery. Lowmoisture 
grades are used with moisture-sensitive materials. 
Higher-density grades have improved flowability. 
Several coprocessed mixtures of microcrystalline cellulose 
with other excipients such as carrageenan, carboxymethylcellulose 
sodium, and guar gum are commercially available; see 
Section 17. 
Table III: Properties of selected commercially available grades of 
microcrystalline cellulose. 
Grade Nominal mean 
particle size (mm) 
Particle size analysis Moisture 
content (%) 
Mesh 
size 
Amount 
retained (%) 
Avicel PH-101(a) 50 60 41.0 45.0 
200 430.0 
Avicel PH-102(a) 100 60 48.0 45.0 
200 545.0 
Avicel PH-103(a) 50 60 41.0 43.0 
200 430.0 
Avicel PH-105(a) 20 400 41.0 45.0 
Avicel PH-112(a) 100 60 48.0 41.5 
Avicel PH-113(a) 50 60 41.0 41.5 
200 430.0 
Avicel PH-200(a) 180 60 510.0 45.0 
100 550.0 
Avicel PH-301(a) 50 60 41.0 45.0 
200 430.0 
Avicel PH-302(a) 100 60 48.0 45.0 
200 545.0 
Celex 101(b) 75 60 41.0 45.0 
200 530.0 
Ceolus KG-802(c) 50 60 40.5 46.0 
200 430.0 
Emcocel 50M(d) 50 60 40.25 45.0 
200 430.0 
Emcocel 90M(d) 91 60 48.0 45.0 
200 545.0 
Vivapur 101(d) 50 60 41.0 45.0 
200 430.0 
Vivapur 102(d) 90 60 48.0 45.0 
200 545.0 
Vivapur 12(d) 160 38 41.0 45.0 
94 450.0 
Suppliers: 
(a)FMC Biopolymer 
(b) International Specialty Products 
(c) Asahi Kasei Corporation 
(d) J Rettenmaier & So.hne GmbH 
134 Cellulose, Microcrystalline

Celphere (Asahi Kasei Corporation) is a pure spheronized 
microcrystalline cellulose available in several different particle 
size ranges. 
A specification for microcrystalline cellulose is contained in 
the Food Chemicals Codex (FCC). 
19 Specific References 
1 Ene.zian GM. Direct compression of tablets using microcrystalline 
cellulose [in French]. Pharm Acta Helv 1972; 47: 321363. 
2 Lerk CF, Bolhuis GK. Comparative evaluation of excipients for 
direct compression I. Pharm Weekbl 1973; 108: 469481. 
3 Lerk CF, Bolhuis GK, de Boer AH. Comparative evaluation of 
excipients for direct compression II. Pharm Weekbl 1974; 109: 
945955. 
4 Lamberson RF, Raynor GE. Tableting properties of microcrystalline 
cellulose. Manuf Chem Aerosol News 1976; 47(6): 5561. 
5 Lerk CF, Bolhuis GK, de Boer AH. Effect of microcrystalline 
cellulose on liquid penetration in and disintegration of directly 
compressed tablets. J Pharm Sci 1979; 68: 205211. 
6 Chilamkurti RN, Rhodes CT, Schwartz JB. Some studies on 
compression properties of tablet matrices using a computerized 
instrumented press. Drug Dev Ind Pharm 1982; 8: 6386. 
7 Wallace JW, Capozzi JT, Shangraw RF. Performance of pharmaceutical 
filler/binders as related to methods of powder characterization. 
Pharm Technol 1983; 7(9): 94104. 
8 Omray A, Omray P. Evaluation of microcrystalline cellulose as a 
glidant. Indian J Pharm Sci 1986; 48: 2022. 
9 Celik M, Okutgen E. A feasibility study for the development of a 
prospective compaction functionality test and the establishment of 
a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309 
2334. 
10 Parker MD, York P, Rowe RC. Bindersubstrate interactions in 
wet granulation 3: the effect of excipient source variation. Int J 
Pharm 1992; 80: 179190. 
11 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355369. 
12 Cooper CB, Bai TR, Heyderman E, Corrin B. Cellulose granulomas 
in the lungs of a cocaine sniffer. Br Med J 1983; 286: 2021 
2022. 
13 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
14 Jain JK, Dixit VK, Varma KC. Preparation of microcrystalline 
cellulose from cereal straw and its evaluation as a tablet excipient. 
Indian J Pharm Sci 1983; 45: 8385. 
15 Singla AK, Sakhuja A, Malik A. Evaluation of microcrystalline 
cellulose prepared from absorbent cotton as a direct compression 
carrier. Drug Dev Ind Pharm 1988; 14: 11311136. 
16 Doelker E, Mordier D, Iten H, Humbert-Droz P. Comparative 
tableting properties of sixteen microcrystalline celluloses. Drug 
Dev Ind Pharm 1987; 13: 18471875. 
17 Bassam F, York P, Rowe RC, Roberts RJ. Effect of particle size and 
source on variability of Youngs modulus of microcrystalline 
cellulose powders. J Pharm Pharmacol 1988; 40: 68P. 
18 Dittgen M, Fricke S, Gerecke H. Microcrystalline cellulose in direct 
tabletting. Manuf Chem 1993; 64(7): 17, 19, 21. 
19 Landin M, Martinez-Pacheco R, Go.mez-Amoza JL, et al. Effect of 
country of origin on the properties of microcrystalline cellulose. Int 
J Pharm 1993; 91: 123131. 
20 Landin M, Martinez-Pacheco R, Go.mez-Amoza JL, et al. Effect of 
batch variation and source of pulp on the properties of 
microcrystalline cellulose. Int J Pharm 1993; 91: 133141. 
21 Landin M, Martinez-Pacheco R, Go.mez-Amoza JL, et al. Influence 
of microcrystalline cellulose source and batch variation on 
tabletting behavior and stability of prednisone formulations. Int 
J Pharm 1993; 91: 143149. 
22 Podczeck F, Re.ve.sz P. Evaluation of the properties of microcrystalline 
and microfine cellulose powders. Int J Pharm 1993; 91: 183 
193. 
23 Rowe RC, McKillop AG, Bray D. The effect of batch and source 
variation on the crystallinity of microcrystalline cellulose. Int J 
Pharm 1994; 101: 169172. 
24 HasegawaM. Direct compression: microcrystalline cellulose grade 
12 versus classic grade 102. Pharm Technol 2002; 26(5): 50, 52, 
54, 56, 58, 60. 
25 Kothari SH, Kumar V, Banker GS. Comparative evaluations of 
powder and mechanical properties of low crystallinity celluloses, 
microcrystalline celluloses, and powdered celluloses. Int J Pharm 
2002; 232: 6980. 
26 Levis SR, Deasy PB. Production and evaluation of size-reduced 
grades of microcrystalline cellulose. Int J Pharm 2001; 213: 1324. 
27 Wu JS, Ho HO, Sheu MT. A statistical design to evaluate the 
influence of manufacturing factors on the material properties and 
functionalities of microcrystalline cellulose. Eur J Pharm Sci 2001; 
12: 417425. 
28 Suzuki T, Nakagami H. Effect of crystallinity of microcrystalline 
cellulose on the compactability and dissolution of tablets. Eur J 
Pharm Biopharm 1999; 47: 225230. 
20 General References 
Asahi Kasei Corporation. Technical literature: Ceolus KG microcrystalline 
cellulose, 2001. 
Asahi Kasei Corporation. Technical literature: Celphere microcrystalline 
cellulose spheres, 2001. 
DMV Pharma. Technical literature: Pharmacel microcrystalline cellulose, 
1998. 
Doelker E. Comparative compaction properties of various microcrystalline 
cellulose types and generic products. Drug Dev Ind Pharm 
1993; 19: 23992471. 
FMC Biopolymer. Technical literature: Avicel PH microcrystalline 
cellulose, 1998. 
International Specialty Products. Technical literature: Celex 101 
microcrystalline cellulose, 1997. 
JRS Pharma LP. Technical literature: Emcocel microcrystalline cellulose, 
2003. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 7174. 
Staniforth JN, Baichwal AR, Hart JP, Heng PWS. Effect of addition of 
water on the rheological and mechanical properties of microcrystalline 
celluloses. Int J Pharm 1988; 41: 231236. 
21 Authors 
LY Galichet. 
22 Date of Revision 
20 August 2005. 
Cellulose, Microcrystalline 135

Cellulose, Powdered 
1 Nonproprietary Names 
BP: Powdered cellulose 
JP: Powdered cellulose 
PhEur: Cellulosi pulvis 
USPNF: Powdered cellulose 
2 Synonyms 
Arbocel; E460; Elcema; Sanacel; Solka-Floc. 
3 Chemical Name and CAS Registry Number 
Cellulose [9004-34-6] 
4 Empirical Formula and Molecular Weight 
(C6H10O5)n 243 000 where n  500. 
Since cellulose is derived from a natural polymer, it has 
variable chain length and thus variable molecular weight. See 
also Sections 8 and 13. 
5 Structural Formula 
6 Functional Category 
Adsorbent; glidant; suspending agent; tablet and capsule 
diluent; tablet disintegrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Powdered cellulose is used as a tablet diluent and a hard gelatin 
capsule filler; see Table I. In both contexts it acts as a bulking 
agent to increase the physical size of the dosage form for 
formulations containing a small amount of active substance. 
Powdered cellulose has acceptable compression properties, 
although its flow properties are poor. However, low-crystallinity 
powdered cellulose has exhibited properties that are 
different from standard powdered cellulose materials, and has 
shown potential as a direct-compression excipient.(1) 
In soft gelatin capsules, powdered cellulose may be used to 
reduce the sedimentation rate of oily suspension fills. It is also 
used as the powder base material of powder dosage forms, and 
as a suspending agent in aqueous suspensions for peroral 
delivery. It may also be used to reduce sedimentation during the 
manufacture of suppositories. 
Powdered cellulose has been investigated as an alternative to 
microcrystalline cellulose as an agent to assist the manufacture 
of pellets by extrusion/spheronization.(2,3) 
Powdered cellulose is also used widely in cosmetics and food 
products. 
Table I: Uses of powdered cellulose. 
Use Concentration (%) 
Capsule filler 0100 
Tablet binder 525 
Tablet disintegrant 515 
Tablet glidant 12 
8 Description 
Powdered cellulose occurs as a white or almost white, odorless 
and tasteless powder of various particle sizes, ranging from a 
free-flowing fine or granular dense powder, to a coarse, fluffy, 
nonflowing material. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for powdered cellulose. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . .  
Microbial limits 
Aerobic 4103/g 4103/g 4103/g 
Fungi and yeast 4102/g 4102/g 4102/g 
pH (10% w/w suspension) 5.07.5 5.07.5 5.07.5 
Loss on drying 46.0% 46.5% 46.0% 
Residue on ignition 40.3% 40.3% 40.3% 
Solubility  .  
Ether-soluble substances 415.0mg 40.15% 40.15% 
Water-soluble substances 415.0mg 41.5% 41.5% 
Heavy metals 410 ppm 410 ppm 40.001% 
Organic volatile impurities   . 
10 Typical Properties 
Angle of repose: 
<628 for Arbocel M80; 
<498 for Arbocel P 290; 
<368 for Arbocel A 300 (J. Rettenmaier and So. hne). 
Density (bulk): 0.1390.391 g/cm3, depending on the source. 
Density (tapped): 0.2100.481 g/cm3, depending on the source. 
Density (true): 1.5 g/cm3 
Moisture content: powdered cellulose is slightly hygroscopic;(4) 
see Figures 1 and 2. 
Particle size distribution: powdered cellulose is commercially 
available in several different particle sizes.

Arbocel M80: average particle size 60 mm; 
Arbocel P 290: average particle size 70 mm; 
Arbocel A 300: average particle size 200 mm. 
Solubility: practically insoluble in water, dilute acids, and most 
organic solvents although it disperses in most liquids. 
Slightly soluble in 5% w/v sodium hydroxide solution. 
Powdered cellulose does not swell in water, but does so in 
dilute sodium hypochlorite (bleach). 
11 Stability and Storage Conditions 
Powdered cellulose is a stable, slightly hygroscopic material. 
The bulk material should be stored in a well-closed container in 
a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Powdered cellulose is manufactured by the purification and 
mechanical size reduction of a-cellulose obtained as a pulp 
from fibrous plant materials. 
14 Safety 
Powdered cellulose is widely used in oral pharmaceutical 
formulations and food products and is generally regarded as a 
nontoxic and nonirritant material. 
Powdered cellulose is not absorbed systemically following 
peroral administration and thus has little toxic potential. 
Figure 1: Equilibrium moisture content of powdered cellulose at 
258C. 
*: Powdered cellulose (Solka-Floc BW-40, Lot no. 8-10- 
30A) 
~: Powdered cellulose (Solka-Floc BW-20, Lot no. 22A- 
19) 
!: Powdered cellulose (Solka-Floc Fine Granular, Lot no. 
9-10-8) 
Consumption of large quantities of cellulose may, however, 
have a laxative effect, although this is unlikely to be a problem 
when cellulose is used as an excipient in pharmaceutical 
formulations. 
Deliberate abuse of formulations containing cellulose, either 
by inhalation or by injection, has resulted in the formation of 
cellulose granulomas.(5) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Powdered cellulose may be 
irritant to the eyes. Gloves, eye protection, and a dust mask are 
recommended. In the UK, the occupational exposure limits for 
cellulose have been set at 10 mg/m3 long-term (8-hour TWA) 
for total inhalable dust and 4 mg/m3 for respirable dust; the 
short-term limit for total inhalable dust has been set at 
20 mg/m3.(6) 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Cellulose, microcrystalline. 
Figure 2: Equilibrium moisture content of powdered cellulose at 
258C. 
*: Powdered cellulose (Solka-Floc BW-100, Lot no. 9-7- 
18B) 
~: Powdered cellulose (Solka-Floc BW-200, Lot no. 22A- 
20) 
!: Powdered cellulose (Solka-Floc Fine BW-2030, Lot no. 
240) 
Cellulose, Powdered 137

18 Comments 
A specification for powdered cellulose is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for powdered cellulose is 232-674-9. 
19 Specific References 
1 Kothari SH, Kumar V, Banker GS. Comparative evaluations of 
powder and mechanical properties of low crystallinity celluloses, 
microcrystalline celluloses, and powdered celluloses. Int J Pharm 
2002; 232(12): 6980. 
2 Alvarez L, Concheiro A, Gomez Amoza JL, et al. Powdered 
cellulose as excipient for extrusion-spheronization pellets of a 
cohesive hydrophobic drug. Eur J Pharm Biopharm 2003; 55(3): 
291295. 
3 Lindner H, Kleinebudde P. Use of powdered cellulose for the 
production of pellets by extrusion spheronization. J Pharm 
Pharmacol 1994; 46: 27. 
4 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355369. 
5 Cooper CB, Bai TR, Heyderman E, Corrin B. Cellulose granulomas 
in the lungs of a cocaine sniffer. Br Med J 1983; 286: 2021 
2022. 
6 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
See also Cellulose, microcrystalline. 
20 General References 
Allen LV. Featured excipient: capsule and tablet diluents. Int J Pharm 
Compound 2000; 4(4): 306310, 324325. 
Belda PM, Mielck JB. The tabletting behavior of cellactose compared 
with mixtures of celluloses with lactoses. Eur J Pharm Biopharm 
1996; 42(5): 325330. 
Kimura M, Shimada Y, Oshima T, et al. The evaluation of powdered 
cellulose as a pharmaceutical excipient. J Pharm Sci Tech 
Yakuzaigaku 2002; 62(3): 113123. 
Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 7174. 
21 Authors 
ME Aulton. 
22 Date of Revision 
21 August 2005. 
138 Cellulose, Powdered

Cellulose, Silicified Microcrystalline 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
ProSolv. 
3 Chemical Name and CAS Registry Number 
See Section 8. 
4 Empirical Formula and Molecular Weight 
See Section 8. 
5 Structural Formula 
See Section 8. 
6 Functional Category 
Tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Silicified microcrystalline cellulose is used as a filler in the 
formulation of capsules and tablets. It has improved compaction 
properties in both wet granulation and direct compression 
compared to conventional microcrystalline cellulose.(15) Silicified 
microcrystalline cellulose was specifically developed to 
address the loss of compaction that occurs with microcrystalline 
cellulose after wet granulation. 
8 Description 
Silicified microcrystalline cellulose is a synergistic, intimate 
physical mixture of two components: microcrystalline cellulose 
and colloidal silicon dioxide (for further information see 
Cellulose, Microcrystalline and Colloidal Silicon Dioxide). 
Silicified microcrystalline cellulose contains 2% w/w colloidal 
silicon dioxide. 
9 Pharmacopeial Specifications 

10 Typical properties 
Acidity/alkalinity: pH = 5.07.5 (10% w/v suspension) 
Density: 1.58 g/cm(5) 
Density (bulk): 0.31 g/cm3 
Density (tapped): 0.39 g/cm(5) 
Melting point: the microcrystalline cellulose component chars 
at 2602708C. 
Moisture content: typically less than 6% w/w. 
Particle size distribution: typical particle size is 20200 mm. 
Different grades may have a different normal mean particle 
size. 
Solubility: practically insoluble in water, dilute acids, and most 
organic solvents. The microcrystalline cellulose component 
is slightly soluble in 5% w/w sodium hydroxide solution. 
SEM: 1 
Excipient: Silicified microcrystalline cellulose 
Manufacturer: JRS Pharma LP 
Lot No.: CSD5866 
Magnification: 100 
SEM: 2 
Excipient: Silicified microcrystalline cellulose 
Manufacturer: JRS Pharma LP 
Lot No.: CSD5866 
Magnification: 300

SEM: 3 
Excipient: Silicified microcrystalline cellulose 
Manufacturer: JRS Pharma LP 
Lot No.: CSD5866 
Magnification: 500 
11 Stability and Storage Conditions 
Silicified microcrystalline cellulose is stable when stored in a 
well-closed container in a cool, dry place. 
12 Incompatibilities 
See Cellulose, Microcrystalline and Colloidal Silicon Dioxide. 
13 Method of Manufacture 
Silicified microcrystalline cellulose is manufactured by codrying 
a suspension of microcrystalline cellulose particles and 
colloidal silicon dioxide so that the dried finished product 
contains 2% w/w colloidal silicon dioxide. 
The colloidal silicon dioxide appears physically bound onto 
the surface and inside the silicified microcrystalline cellulose 
particles. Extensive studies using different spectroscopic 
methods have failed to show any form of chemical interaction.(
4,6,7) 
14 Safety 
See Cellulose, Microcrystalline and Colloidal Silicon Dioxide. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Handling of silicified 
microcrystalline cellulose can generate nuisance dusts and the 
use of a respirator or dust mask may be necessary. 
Microcrystalline cellulose may be irritant to the eyes. 
Gloves, eye protection, and a dust mask are recommended. In 
the UK the long-term occupational exposure limits (8-hour 
TWA) have been set at 10 mg/m3 for total inhalable dust and 
4 mg/m3 for respirable dust; short-term limit for total inhalable 
dust has been set at 20 mg/m3.(8) 
Since the colloidal silicon dioxide is physically bound to the 
microcrystalline cellulose the general recommendations of 
gloves, eye protection, and a dust mask should be followed 
when handling silicified microcrystalline cellulose. 
16 Regulatory Status 
Silicified microcrystalline cellulose is a physical mixture of two 
materials both of which are generally regarded as nontoxic: 
Microcrystalline cellulose: GRAS listed. Included in the FDA 
Inactive Ingredients Guide (inhalations, oral capsules, 
powders, suspensions, syrups, and tablets). Included in 
nonparenteral medicines licensed in Europe and the US. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
Colloidal silicon dioxide: GRAS listed. Included in the FDA 
Inactive Ingredients Guide (oral capsules and tablets). 
Included in nonparenteral medicines licensed in Europe 
and the US. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Cellulose, microcrystalline; colloidal silicon dioxide. 
18 Comments 
Silicified microcrystalline cellulose has greater tensile strength 
and requires lower compression pressures than regular grades 
of microcrystalline cellulose. Furthermore, silicified microcrystalline 
cellulose maintains its compactability when wet granulated; 
the compacts exhibit greater stiffness and they require 
considerably more energy for tensile failure to occur.(4,9) 
19 Specific References 
1 Sherwood BE, Hunter EA, Staniforth JN. Silicified microcrystalline 
cellulose (SMCC): a new class of high functionality binders for 
direct compression. Pharm Res 1996; 13(9): S197. 
2 Staniforth JN, Sherwood BE, Hunter EA. Towards a new class of 
high functionality tablet binders. II: silicified microcrystalline 
cellulose (SMCC). Pharm Res 1996; 13(9): S197. 
3 Tobyn MJ, Staniforth JN, Hunter EA. Compaction studies on a 
new class of high functionality binders: silicified microcrystalline 
cellulose (SMCC). Pharm Res 1996; 13(9): S198. 
4 Habib SY, Abramowitz R, Jerzewski RL, et al. Is silicified wetgranulated 
microcrystalline cellulose better than original wetgranulated 
microcrystalline cellulose? Pharm Dev Technol 1999; 
4(3): 431437. 
5 Tobyn MJ, McCarthy AP, Staniforth JN, Edge S. Physiochemical 
comparison between microcrystalline cellulose and silicified 
microcrystalline cellulose. Int J Pharm 1998; 169: 183194. 
6 Edge S, Steele DF, Chen A, et al. The mechanical properties of 
compacts of microcrystalline cellulose and silicified microcrystalline 
cellulose. Int J Pharm 2000; 200: 6772. 
7 Buckton G, Yoremochi E. Near IR spectroscopy to quantify the 
silica content and differences between silicified miicrocrystalline 
cellulose and physical mixtures of microcrystalline cellulose and 
silica. Int J Pharm 1998; 169: 183194. 
8 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
9 Buckton G, Yoremochi E, Yoon NL, Moffat AC. Water sorption 
and near IR spectroscopy to study the differences between 
microcrystalline cellulose and silicified miicrocrystalline cellulose 
after wet granulation. Int J Pharm 1999; 181: 4147. 
140 Cellulose, Silicified Microcrystalline

20 General References 
Li JX, Zhou Y, Wu XY, et al. Characterization of wet masses of 
pharmaceutical powders by triaxial compression test. J Pharm Sci 
2000; 89(2): 178190. 
Staniforth JN, Hunter EA, Sherwood BE. Pharmaceutical excipient 
having improved compressability. US Patent 5,585,115, 1996. 
21 Authors 
RC Moreton. 
22 Date of Revision 
26 August 2005. 
Cellulose, Silicified Microcrystalline 141

Cellulose Acetate 
1 Nonproprietary Names 
BP: Cellulose acetate 
PhEur: Cellulosi acetas 
USPNF: Cellulose acetate 
2 Synonyms 
Acetyl cellulose; cellulose diacetate; cellulose triacetate. 
3 Chemical Name and CAS Registry Number 
Cellulose acetate [9004-35-7] 
Cellulose diacetate [9035-69-2] 
Cellulose triacetate [9012-09-3] 
4 Empirical Formula and Molecular Weight 
Cellulose acetate is cellulose in which a portion or all of the 
hydroxyl groups are acetylated. Cellulose acetate is available in 
a wide range of acetyl levels and chain lengths and thus 
molecular weights; see Table I. 
5 Structural Formula 
6 Functional Category 
Coating agent; extended release agent; tablet and capsule 
diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cellulose acetate is widely used in pharmaceutical formulations 
both in sustained-release applications and for taste masking. 
Cellulose acetate is used as a semipermeable coating on 
tablets, especially on osmotic pump-type tablets and implants. 
This allows for controlled, extended release of actives.(15) 
Cellulose acetate films, in conjunction with other materials, 
also offer sustained release without the necessity of drilling a 
hole in the coating as is typical with osmotic pump systems. 
Cellulose acetate and other cellulose esters have also been used 
to form drug-loaded microparticles with controlled-release 
characteristics.(6,7) 
Cellulose acetate films are used in transdermal drug delivery 
systems(8,9) and also as film coatings on tablets or granules for 
taste masking. For example, acetaminophen granules have been 
coated with a cellulose acetate-based coating before being 
processed to provide chewable tablets. Extended-release tablets 
can also be formulated with cellulose acetate as a directly 
compressible matrix former.(10) The release profile can be 
modified by changing the ratio of active to cellulose acetate and 
by incorporation of plasticizer, but was shown to be insensitive 
to cellulose acetate molecular weight and particle size distribution. 
Therapeutically, cellulose acetate has been used to treat 
cerebral aneurysms, and also for spinal perimedullary arteriovenous 
fistulas.(11) 
8 Description 
Cellulose acetate occurs as a white to off-white powder, freeflowing 
pellets, or flakes. It is tasteless and odorless, or may 
have a slight odor of acetic acid. 
Table I: Comparison of different types of cellulose acetate.(2) 
Type Acetyl (%) Viscosity (mPa s) Hydroxyl (%) Melting range (8C) Tg
(a) (8C) Density(b) (g/cm3) MWn(c) 
CA-320S 32.0 210.0 8.7 230250 180 0.4 38 000 
CA-398-3 39.8 11.4 3.5 230250 180 0.4 30 000 
CA-398-6 39.8 22.8 3.5 230250 182 0.4 35 000 
CA-398-10NF 39.8 38.0 3.5 230250 185 0.4 40 000 
CA-398-30 39.7 114.0 3.5 230250 189 0.4 50 000 
CA-394-60S 39.5 228.0 4.0 240260 186  60 000 
CA-435-75 43.5  0.9 280300 185 0.7 122 000 
(a) Glass transition temperature. 
(b) Tapped. 
(c) Number average molecular weight in polystyrene equivalents. 
Supplier: Eastman Chemical Company.

SEM: 1 
Excipient: Cellulose acetate, CA-398-10NF 
Manufacturer: Eastman Chemical Co. 
Lot No.: AC65280NF 
Magnification: 60 Voltage: 3kV 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for cellulose acetate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Loss on drying 45.0% 45.0% 
Residue on ignition 40.1% 40.1% 
Free acid 40.1% 40.1% 
Heavy metals 410 ppm 40.001% 
Microbial contamination .  
Aerobic 4103/g  
Fungi and yeast 4102/g  
Organic volatile impurities  . 
Assay (of acetyl groups) 29.044.8% 29.044.8% 
10 Typical Properties 
Density (bulk): typically 0.4 g/cm3 for powders 
Glass transition temperature: 1701908C 
Melting point: melting range 2303008C 
Solubility: the solubility of cellulose acetate is greatly influenced 
by the level of acetyl groups present. In general, cellulose 
acetates are soluble in acetonewater blends of varying 
ratios, dichloromethaneethanol blends, dimethyl formamide, 
and dioxane. The cellulose acetates of higher acetyl 
level are generally more limited in solvent choice than are the 
lower-acetyl materials. 
Viscosity (dynamic): various grades of cellulose acetate are 
commercially available that differ in their acetyl content and 
degree of polymerization. They can be used to produce 10% 
SEM 2 
Excipient: Cellulose acetate, CA-398-10NF 
Manufacturer: Eastman Chemical Co. 
Lot No.: AC65280NF 
Magnification: 600 Voltage: 2kV 
w/v solutions in organic solvents with viscosities of 
10230 mPa s. Blends of cellulose acetates may also be 
prepared with intermediate viscosity values. See also Table I. 
11 Stability and Storage Conditions 
Cellulose acetate is stable if stored in a well-closed container in 
a cool, dry place. Cellulose acetate hydrolyzes slowly under 
prolonged adverse conditions such as high temperature and 
humidity, with a resultant increase in free acid content and odor 
of acetic acid. 
12 Incompatibilities 
Cellulose acetate is incompatible with strongly acidic or 
alkaline substances. Cellulose acetate is compatible with the 
following plasticizers: diethyl phthalate, polyethylene glycol, 
triacetin, and triethyl citrate. 
13 Method of Manufacture 
Cellulose acetate is prepared from highly purified cellulose by 
treatment with acid catalysis and acetic anhydride. 
14 Safety 
Cellulose acetate is widely used in oral pharmaceutical products 
and is generally regarded as a nontoxic and nonirritant 
material. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Dust may be irritant to the 
eyes and eye protection should be worn. Like most organic 
Cellulose Acetate 143

materials in powder form, these materials are capable of 
creating dust explosions. Cellulose acetate is combustible. 
16 Regulatory Acceptance 
Included in the FDA Inactive Ingredients Guide (oral tablets). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Cellulose acetate phthalate. 
18 Comments 
When solutions are being prepared, cellulose acetate should 
always be added to the solvent, not the reverse. Various grades 
of cellulose acetate are available with varying physical properties; 
see Table I. 
19 Specific References 
1 Meier MA, Kanis LA, Soldi V. Characterization and drugpermeation 
profiles of microporous and dense cellulose acetate 
membranes: influence of plasticizer and pre-forming agent. Int J 
Pharm 2004; 278(1): 99110. 
2 Eastman Chemical Company. Technical literature: Cellulose Esters 
for Pharmaceutical Drug Delivery, 1997. 
3 Theeuwes F. Elementary osmotic pump. J Pharm Sci 1975; 64(12): 
19871991. 
4 Santus G, Baker RW. Osmotic drug delivery: review of the patent 
literature. J Control Release 1995; 35: 121. 
5 Van Savage G, Rhodes CT. The sustained release coating of solid 
dosage forms: a historical review. Drug Dev Ind Pharm 1995; 
21(1): 93118. 
6 Soppimath KS, Kulkarni AR, Aminabhavi TM. Development of 
hollow microspheres as floating controlled-release systems for 
cardiovascular drugs: preparation and release characteristics. 
Drug Dev Ind Pharm 2001; 27(6): 507515. 
7 Soppimath KS, Kulkarni AR, Aminabhavi TM, Bhaskar C. 
Cellulose acetate microspheres prepared by o/w emulsification 
and solvent evaporation method. J Microencapsul 2001; 18(6): 
811817. 
8 Rao PR, Diwan PV. Drug diffusion from cellulose acetatepolyvinyl 
pyrrolidine free films for transdermal administration. 
Indian J Pharm Sci 1996; 58(6): 246250. 
9 Rao PR, Diwan PV. Permeability studies of cellulose acetate free 
films for transdermal use: influences of plasticizers. Pharm Acta 
Helv 1997; 72: 4751. 
10 Yuan J,Wu SHW. Sustained-release tablets via direct compression: 
a feasibility study using cellulose acetate and cellulose acetate 
butyrate. Pharm Technol 2000; 24(10): 92, 94, 96, 98, 100, 102, 
104, 106. 
11 Sugiu K, Meguro T, Nakashiama H, Ohmoto T. Successful 
embolization of a spinal perimedullary arteriovenous fistula with 
cellulose acetate polymer solution: technical case report. Neurosurgery 
2001; 49(5): 12571260. 
20 General References 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199265. 
21 Authors 
LA Miller. 
22 Date of Revision 
15 August 2005. 
144 Cellulose Acetate

Cellulose Acetate Phthalate 
1 Nonproprietary Names 
BP: Cellacefate 
JP: Cellulose acetate phthalate 
PhEur: Cellulosi acetas phthalas 
USPNF: Cellacefate 
2 Synonyms 
Acetyl phthalyl cellulose; Aquacoat cPD; CAP; cellacephate; 
cellulose acetate benzene-1,2-dicarboxylate; cellulose acetate 
hydrogen 1,2-benzenedicarboxylate; cellulose acetate hydrogen 
phthalate; cellulose acetate monophthalate; cellulose acetophthalate; 
cellulose acetylphthalate. 
3 Chemical Name and CAS Registry Number 
Cellulose, acetate, 1,2-benzenedicarboxylate [9004-38-0] 
4 Empirical Formula and Molecular Weight 
Cellulose acetate phthalate is a cellulose in which about half the 
hydroxyl groups are acetylated, and about a quarter are 
esterified with one of two acid groups being phthalic acid, 
where the remaining acid group is free. See Section 5. 
5 Structural Formula 
The PhEur 2005 and USPNF 23 describe cellulose acetate 
phthalate as a reaction product of phthalic anhydride and a 
partial acetate ester of cellulose containing 21.526.0% of 
acetyl (C2H3O) groups, and 30.036.0% of phthalyl(ocarboxybenzoyl, 
C8H5O3) groups. 
6 Functional Category 
Coating agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cellulose acetate phthalate (CAP) is used as an enteric film 
coating material, or as a matrix binder for tablets and 
capsules.(18) Such coatings resist prolonged contact with the 
strongly acidic gastric fluid, but dissolve in the mildly acidic or 
neutral intestinal environment. 
Cellulose acetate phthalate is commonly applied to soliddosage 
forms either by coating from organic or aqueous solvent 
systems or by direct compression. Concentrations generally 
used are 0.59.0% of the core weight. The addition of 
plasticizers improves the water resistance of this coating 
material, and formulations using such plasticizers are more 
effective than when cellulose acetate phthalate is used alone. 
Cellulose acetate phthalate is compatible with many 
plasticizers, including acetylated monoglyceride; butyl phthalybutyl 
glycolate; dibutyl tartrate; diethyl phthalate; dimethyl 
phthalate; ethyl phthalylethyl glycolate; glycerin; propylene 
glycol; triacetin; triacetin citrate; and tripropionin. It is also 
used in combination with other coating agents such as ethyl 
cellulose, in drug controlled-release preparations. 
Therapeutically, cellulose acetate phthalate has recently 
been reported to exhibit experimental microbicidal activity 
against sexually transmitted disease pathogens, such as the 
HIV-1 retrovirus.(9,10) 
8 Description 
Cellulose acetate phthalate is a hygroscopic, white to off-white, 
free-flowing powder, granule, or flake. It is tasteless and 
odorless, or might have a slight odor of acetic acid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cellulose acetate phthalate. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . .  
Free acid 43.0% 43.0% 43.0% 
Heavy metals 410 ppm 410 ppm 40.001% 
Organic volatile 
impurities 
  . 
Phthaloyl groups  . . 
Residue on ignition 40.1% 40.1% 40.1% 
Viscosity (15% w/v 
solution) 
4590mPa s 45.090.0 mPa s 45.090.0 mPa s 
Water 45.0% 45.0% 45.0% 
Assay . . . 
Acetyl groups 21.526.0% 21.526.0% 21.526.0% 
Carboxybenzoyl 
groups 
30.040.0% 30.036.0% 30.036.0% 
10 Typical Properties 
Density (bulk): 0.260 g/cm3 
Density (tapped): 0.266 g/cm3 
Melting point: 1928C. Glass transition temperature is 
1601708C.(11) 
Moisture content: 2.2%. Cellulose acetate phthalate is hygroscopic 
and precautions are necessary to avoid excessive 
absorption of moisture.(12) See also Figure 1.

Figure 1: Sorptiondesorption isotherm of cellulose acetate phthlate. 
Table II: Examples of solvents with which cellulose acetate phthalate 
has 410% w/w solubility. 
Acetone 
Diacetone alcohol 
Dioxane 
Ethoxyethyl acetate 
Ethyl glycol monoacetate 
Ethyl lactate 
Methoxyethyl acetate 
b-Methoxyethylene alcohol 
Methyl acetate 
Methyl ethyl ketone 
Table III: Examples of solvent mixtures with which cellulose acetate 
phthalate has 410% w/w solubility. 
Acetone : ethanol (1 : 1) 
Acetone : water (97 : 3) 
Benzene : methanol (1 : 1) 
Ethyl acetate : ethanol (1 : 1) 
Methylene chloride : ethanol (3 : 1) 
Solubility: practically insoluble in water, alcohols, and chlorinated 
and nonchlorinated hydrocarbons. Soluble in a 
number of ketones, esters, ether alcohols, cyclic ethers, 
and in certain solvent mixtures. It can be soluble in certain 
buffered aqueous solutions as low as pH 6.0. Cellulose 
acetate phthalate has a solubility of 410% w/w in a wide 
range of solvents and solvent mixtures; see Table II and 
Table III. 
Viscosity (dynamic): a 15% w/w solution in acetone with a 
moisture content of 0.4% has a viscosity of 5090 mPa s 
(5090 cP). This is a good coating solution with a honey-like 
consistency, but the viscosity is influenced by the purity of 
the solvent. 
11 Stability and Storage Conditions 
Slow hydrolysis of cellulose acetate phthalate will occur under 
prolonged adverse conditions such as high temperatures and 
high humidity, with a resultant increase in free acid content, 
viscosity, and odor of acetic acid. However, cellulose acetate 
phthalate is stable if stored in a well-closed container in a cool, 
dry place. 
12 Incompatibilities 
Cellulose acetate phthalate is incompatible with ferrous sulfate, 
ferric chloride, silver nitrate, sodium citrate, aluminum sulfate, 
calcium chloride, mercuric chloride, barium nitrate, basic lead 
acetate, and strong oxidizing agents such as strong alkalis and 
acids. 
13 Method of Manufacture 
Cellulose acetate phthalate is produced by reacting the partial 
acetate ester of cellulose with phthalic anhydride in the presence 
of a tertiary organic base such as pyridine, or a strong acid such 
as sulfuric acid. 
14 Safety 
Cellulose acetate phthalate is widely used in oral pharmaceutical 
products and is generally regarded as a nontoxic material, 
free of adverse effects. 
Results of long-term feeding in rats and dogs have indicated 
a low oral toxicity. Rats survived daily feedings of up to 30% in 
the diet for up to 1 year without showing a depression in 
growth. Dogs fed 16 g daily in the diet for 1 year remained 
normal. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Cellulose acetate phthalate 
may be irritant to the eyes, mucous membranes, and upper 
respiratory tract. Eye protection and gloves are recommended. 
Cellulose acetate phthalate should be handled in a wellventilated 
environment; use of a respirator is recommended 
when handling large quantities. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral tablets). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Cellulose acetate; hypromellose phthalate; polyvinyl acetate 
phthalate. 
18 Comments 
Any plasticizers that are used with cellulose acetate phthalate to 
improve performance should be chosen on the basis of 
experimental evidence. The same plasticizer used in a different 
tablet base coating may not yield a satisfactory product. 
In using mixed solvents, it is important to dissolve the 
cellulose acetate phthalate in the solvent with the greater 
dissolving power, and then to add the second solvent. Cellulose 
146 Cellulose Acetate Phthalate

acetate phthalate should always be added to the solvent, not the 
reverse. 
Cellulose acetate phthalate films are permeable to certain 
ionic substances, such as potassium iodide and ammonium 
chloride. In such cases, an appropriate sealer subcoat should be 
used. 
A reconstituted colloidal dispersion of latex particles rather 
than solvent solution coating material of cellulose acetate 
phthalate is also available. This white, water-insoluble powder 
is composed of solid or semisolid submicrometer-sized polymer 
spheres with an average particle size of 0.2 mm. A typical 
coating system made from this latex powder is a 1030% solidcontent 
aqueous dispersion with a viscosity in the 
50100 mPa s range. 
19 Specific References 
1 Spitael J, Kinget R, Naessens K. Dissolution rate of cellulose 
acetate phthalate and Bro. nsted catalysis law. Pharm Ind 1980; 42: 
846849. 
2 Takenaka H, Kawashima Y, Lin SY. Preparation of enteric-coated 
microcapsules for tableting by spray-drying technique and in vitro 
simulation of drug release from the tablet in GI tract. J Pharm Sci 
1980; 69: 13881392. 
3 Takenaka H, Kawashima Y, Lin SY. Polymorphism of spray-dried 
microencapsulated sulfamethoxazole with cellulose acetate phthalate 
and colloidal silica, montmorillonite, or talc. J Pharm Sci 
1981; 70: 12561260. 
4 Stricker H, Kulke H. Rate of disintegration and passage of entericcoated 
tablets in gastrointestinal tract [in German]. Pharm Ind 
1981; 43: 10181021. 
5 Maharaj I, Nairn JG, Campbell JB. Simple rapid method for the 
preparation of enteric-coated microspheres. J Pharm Sci 1984; 73: 
3942. 
6 Beyger JW, Nairn JG. Some factors affecting the microencapsulation 
of pharmaceuticals with cellulose acetate phthalate. J Pharm 
Sci 1986; 75: 573578. 
7 Lin SY, Kawashima Y. Drug release from tablets containing 
cellulose acetate phthalate as an additive or enteric-coating 
material. Pharm Res 1987; 4: 7074. 
8 Thoma K, Heckenmu. ller H. Effect of film formers and plasticizers 
on stability of resistance and disintegration behaviour. Part 4: 
pharmaceutical-technological and analytical studies of gastric juice 
resistant commercial preparations [in German]. Pharmazie 1987; 
42: 837841. 
9 Neurath AR, Strick N, Li YY, Debnath AK. Cellulose acetate 
phthalate, a common pharmaceutical excipient, inactivates HIV-1 
and blocks the coreceptor binding site on the virus envelope 
glycoprotein gp120. BMC Infect Dis 2001; 1(1): 17. 
10 Neurath AR, Strick N, Jiang S, et al. Anti-HIV-1 activity of 
cellulose acetate phthalate: synergy with soluble CD4 and 
induction of dead-end gp41 six-helix bundles. BMC Infect Dis 
2002; 2(1): 6. 
11 Sakellariou P, Rowe RC, White EFT. The thermomechanical 
properties and glass transition temperatures of some cellulose 
derivatives used in film coating. Int J Pharm 1985; 27: 267277. 
12 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355369. 
20 General References 
Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199265. 
Obara S, Mcginty JW. Influence of processing variables on the 
properties of free films prepared from aqueous polymeric dispersions 
by a spray technique. Int J Pharm 1995; 126: 110. 
OConnor RE, Berryman WH. Evaluation of enteric film permeability: 
tablet swelling method and capillary rise method. Drug Dev Ind 
Pharm 1992; 18: 21232133. 
Raffin F, Duru C, Jacob M, et al. Physico-chemical characterization of 
the ionic permeability of an enteric coating polymer. Int J Pharm 
1995; 120(2): 205214. 
Wyatt DM. Cellulose esters as direct compression matrices. Manuf 
Chem 1991; 62(12): 20, 21, 23. 
21 Authors 
LA Miller. 
22 Date of Revision 
15 August 2005. 
Cellulose Acetate Phthalate 147

Ceratonia 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Algaroba; carob bean gum; carob flour; ceratonia gum; 
ceratonia siliqua; ceratonia siliqua gum; Cheshire gum; E410; 
gomme de caroube; locust bean gum; Meyprofleur; St. Johns 
bread. 
3 Chemical Name and CAS Registry Number 
Carob gum [9000-40-2] 
4 Empirical Formula and Molecular Weight 
Ceratonia is a naturally occurring plant material that consists 
chiefly of a high molecular weight hydrocolloidal polysaccharide, 
composed of D-galactose and D-mannose units combined 
through glycosidic linkages, which may be described chemically 
as galactomannan. The molecular weight is approximately 
310 000. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Controlled-release vehicle; stabilizing agent; suspending agent; 
tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ceratonia is a naturally occurring material generally used as a 
substitute for tragacanth or other similar gums. A ceratonia 
mucilage that is slightly more viscous than tragacanth mucilage 
may be prepared by boiling 1.01.5% of powdered ceratonia 
with water. As a viscosity-increasing agent, ceratonia is said to 
be five times as effective as starch and twice as effective as 
tragacanth. Ceratonia has also been used as a tablet binder(1) 
and is used in oral controlled-release drug delivery systems 
approved in Europe and the USA. 
Ceratonia is widely used as a binder, thickening agent, and 
stabilizing agent in the cosmetics and food industry. In foods, 
0.150.75% is used. Therapeutically, ceratonia mucilage is 
used orally in adults and children to regulate intestinal 
function; see Section 14. 
8 Description 
Ceratonia occurs as a yellow-green or white colored powder. 
Although odorless and tasteless in the dry powder form, 
ceratonia acquires a leguminous taste when boiled in water. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Acidity/alkalinity: pH = 5.3 (1% w/v aqueous solution) 
Solubility: ceratonia is dispersible in hot water, forming a sol 
having a pH 5.47.0 that may be converted to a gel by the 
addition of small amounts of sodium borate. In cold water, 
ceratonia hydrates very slowly and incompletely. Ceratonia 
is practically insoluble in ethanol. 
Viscosity (dynamic): 12002500 mPa s (12002500 cP) for a 
1% w/v aqueous dispersion at 258C. Viscosity is unaffected 
by pH within the range pH 311. Viscosity is increased by 
heating: if heated to 958C then cooled, practically clear 
solutions may be obtained that are more viscous than prior 
to heating. 
11 Stability and Storage Conditions 
The bulk material should be stored in a well-closed container in 
a cool, dry place. Ceratonia loses not more than 15% of its 
weight on drying. 
12 Incompatibilities 
The viscosity of xanthan gum solutions is increased in the 
presence of ceratonia.(2) This interaction is used synergistically 
in controlled-release drug delivery systems. 
13 Method of Manufacture 
Ceratonia is a naturally occurring material obtained from the 
ground endosperms separated from the seeds of the locust bean 
tree, Ceratonia siliqua (Leguminosae). The tree is indigenous to 
southern Europe and the Mediterranean region. 
14 Safety 
Ceratonia is generally regarded as an essentially noncarcinogenic,(
3) nontoxic and nonirritant material. Therapeutically, it 
has been used in oral formulations for the control of vomiting 
and diarrhea in adults and children; 2040 g daily in adults has 
been used dispersed in liquid.(4) As an excipient, ceratonia is 
used in oral controlled-release formulations approved in 
Europe and the USA. 
Ceratonia is also widely used in food products. The WHO 
has not specified an acceptable total daily intake for ceratonia 
as the total daily intake arising from its use at the levels 
necessary to achieve the desired effect, and from its acceptable 
background in food, was not considered to represent a hazard 
to health.(5) Ceratonia hypersensitivity has been reported, in a 
single case report, in an infant.(6) However, ceratonia is said to 
be nonallergenic in children with known allergy to peanuts.(7) 
LD50 (hamster, oral): 10.0 g/kg(8) 
LD50 (mouse, oral): 13.0 g/kg 
LD50 (rabbit, oral): 9.1 g/kg 
LD50 (rat, oral): 13.0 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition 
ceratonia emits acrid smoke and irritating fumes. 
16 Regulatory Status 
GRAS listed. Accepted for use in Europe as a food additive. In 
Europe and the USA, ceratonia has been used in oral tablet 
formulations. 
17 Related Substances 
Acacia; ceratonia extract; tragacanth; xanthan gum. 
Ceratonia extract 
Synonyms: ceratonia siliqua extract; extract of carob; locust 
tree extract. 
CAS number: [84961-45-5] 
Comments: ceratonia extract is used as an emollient. The 
EINECS number for ceratonia extract is 284-634-5. 
18 Comments 
The EINECS number for ceratonia is 232-541-5. 
Although not included in any pharmacopeias, a specification 
for ceratonia is contained in the Food Chemicals Codex 
(FCC), see Table I.(9) However, ceratonia (locust bean gum) is 
described under reagent specifications in the USP 28, where the 
reader is directed to the FCC specifications. Ceratonia (carob 
bean gum) is mentioned in the BP 2004 under general reagents 
and is described as a white powder containing 7080% of a 
water-soluble gum consisting mainly of galactomannoglycone. 
Table I: Food Chemicals Codex specifications for ceratonia.(9) 
Test FCC 1996 
Identification . 
Acid-insoluble matter 44.0% 
Arsenic 43 mg/kg 
Ash 41.2% 
Galactomannans 575% 
Heavy metals (as Pb) 40.002% 
Lead 45 mg/kg 
Loss on drying 414.0% 
Protein 47.0% 
Starch . 
19 Specific References 
1 Georgakopoulos PP, Malamataris S. Locust bean gum as 
granulating and binding agent for tablets. Pharm Ind 1980; 
42(6): 642646. 
2 Kovacs P. Useful incompatibility of xanthan gum with galactomannans. 
Food Technol 1973; 27(3): 2630. 
3 National Toxicology Program. Carcinogenesis bioassay of locust 
bean gum (CAS No. 9000-40-2) in F344 rats and B6C3F1 mice 
(feed study). Natl Toxicol Program Tech Rep Ser 1982; 221 (Feb): 
199. 
4 Wade A, ed. Martindale: The Extra Pharmacopoeia, 27th edn. 
London: Pharmaceutical Press, 1977: 921. 
5 FAO/WHO. Evaluation of certain food additives. Twenty-fifth 
report of the FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1981; No. 669. 
6 Savino F, Muratore MC, Silvestro L, Oggero R, Mostert M. 
Allergy to carob gum in an infant. J Pediatr Gastroenterol Nutr 
1999; 29(4): 475476. 
7 Fiocchi A, Restaini P, Travaini M, et al. Carob is not allergenic in 
peanut-allergic subjects. Clin Exp Allergy 1999; 29(3): 402406. 
8 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2247. 
9 Food Chemicals Codex, 4th edn. Washington DC: National 
Academy of Sciences, 1996: 228. 
20 General References 
Bhardwaj TR, Kanwar M, Lal R. Natural gums and modified gums as 
sustained-release carriers. Drug Dev Ind Pharm 2000; 26(10): 
10251038. 
Griffiths C. Locust bean gum: a modern thickening agent from a 
biblical fruit. Manuf Chem 1949; 20: 321324. 
Hoepfner E, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of 
Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th 
edn. Aulendorf: Editio Cantor Verlag, 2002: 358359. 
Knight WA, Dowsett MM. Ceratoniae gummi: carob gum. An 
inexpensive substitute for gum tragacanth. Pharm J 1936; 82: 35 
36. 
Sujja-areevath J, Munday DL, Cox PJ, Khan KA. Release characteristics 
of diclofenac sodium from encapsulated natural gum minimatrix 
formulations. Int J Pharm 1996; 139: 5362. 
Woodruff J. Ingredients for success in thickening. Manuf Chem 1998; 
69(9): 49, 50, 52. 
Yousif AK, Alghzawi HM. Processing and characterization of carob 
powder. Food Chem 2000; 69: 283287. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
Ceratonia 149

Cetostearyl Alcohol 
1 Nonproprietary Names 
BP: Cetostearyl alcohol 
PhEur: Alcohol cetylicus et stearylicus 
USPNF: Cetostearyl alcohol 
2 Synonyms 
Cetearyl alcohol; Crodacol CS90; Lanette O; Tego Alkanol 
1618; Tego Alkanol 6855. 
3 Chemical Name and CAS Registry Number 
Cetostearyl alcohol [67762-27-0] and [8005-44-5] 
4 Empirical Formula and Molecular Weight 
Cetostearyl alcohol is a mixture of solid aliphatic alcohols 
consisting mainly of stearyl (C18H38O) and cetyl (C16H34O) 
alcohols. The proportion of stearyl to cetyl alcohol varies 
considerably, but the material usually consists of about 
5070% stearyl alcohol and 2035% cetyl alcohol, with limits 
specified in pharmacopeias. The combined stearyl alcohol and 
cetyl alcohol comprise at least 90% of the material. Small 
quantities of other alcohols, chiefly myristyl alcohol, make up 
the remainder of the material. Two emulsifying grades of 
ceteostearyl alcohol are recognized by the PhEur 2005 and 
contain at least 7% surfactant, with Type A containing sodium 
cetostearyl sulfate and Type B containing sodium lauryl sulfate. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Emollient; emulsifying agent; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cetostearyl alcohol is used in cosmetics and topical pharmaceutical 
preparations. In topical pharmaceutical formulations, 
cetostearyl alcohol will increase the viscosity and impart body 
in both water-in-oil and oil-in-water emulsions. Cetostearyl 
alcohol will stablize an emulsion and also act as a co-emulsifier, 
thus decreasing the amount of surfactant required to form a 
stable emulsion. Cetostearyl alcohol is also used in the 
preparation of nonaqueous creams and sticks. Research articles 
have been published in which cetostearyl alcohol has been used 
to slow the dissolution of water-soluble drugs.(14) In combination 
with surfactants, cetostearyl alcohol forms emulsions with 
very complex microstructures. These microstructures can 
include liquid crystals, lamellar structures, and gel phases.(516) 
8 Description 
Cetostearyl alcohol occurs as white or cream-colored unctuous 
masses, or almost white flakes or granules. It has a faint, 
characteristic sweet odor. On heating, cetostearyl alcohol melts 
to a clear, colorless or pale yellow-colored liquid free of 
suspended matter. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cetostearyl alcohol. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Appearance of solution .  
Melting range 49568C 48558C 
Acid value 41.0 42.0 
Iodine value 42.0 44 
Hydroxyl value 208228 208228 
Saponification value 42.0  
Assay 
of C18H38O 540.0% 540.0% 
of C16H34O and C18H38O 590.0% 590.0% 
10 Typical Properties 
Solubility: soluble in ethanol (95%), ether, and oil; practically 
insoluble in water. 
11 Stability and Storage Conditions 
Cetostearyl alcohol is stable under normal storage conditions. 
Cetostearyl alcohol should be stored in a well-closed container 
in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents and metal salts. 
13 Method of Manufacture 
Cetostearyl alcohol is prepared by the reduction of the 
appropriate fatty acids from vegetable and animal sources. 
Cetostearyl alcohol can also be prepared directly from 
hydrocarbon sources. 
14 Safety 
Cetostearyl alcohol is mainly used in topical pharmaceutical 
formulations and topical cosmetic formulations. 
Cetostearyl alcohol is generally regarded as a nontoxic 
material.(17) Although it is essentially nonirritating, sensitization 
reactions to cetostearyl, cetyl, and stearyl alcohols(1823) 
have been reported.

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Cetostearyl alcohol is flammable and on 
combustion may produce fumes containing carbon monoxide. 
16 Regulatory Status 
Accepted as an indirect food additive and as an adhesive and a 
component of packaging coatings in the USA. Included in the 
FDA Inactive Ingredients Guide (oral tablets and topical 
emulsions, lotions, ointments, vaginal suppositories). Included 
in nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Anionic emulsifying wax; cetyl alcohol; sodium lauryl sulfate; 
stearyl alcohol. 
18 Comments 
The composition of cetostearyl alcohol from different sources 
may vary considerably. The composition of the minor 
components, typically straight-chain and branched-chain alcohols, 
varies greatly depending upon the source, which may be 
animal, vegetable, or synthetic. This has been reported in the 
literature to impart differences in emulsification behavior, 
particularly with respect to emulsion consistency or stability.(
1416) 
The PhEur 2005 also contains specifications for cetostearyl 
alcohol, emulsifying Type A, and Type B, respectively. 
19 Specific References 
1 Al-Kassas RS, Gilligan CA, Li Wan Po A. Processing factors 
affecting particle size and in vitro drug release of sustained-release 
ibuprofen microspheres. Int J Pharm 1993; 94: 5967. 
2 Lashmar UT, Beesley J. Correlation of rheological properties of an 
oil-in-water emulsion with manufacturing procedures and stability. 
Int J Pharm 1993; 91: 5967. 
3 Wong LP, Gilligan CA, Li Wan Po A. Preparation and characterization 
of sustained-release ibuprofen-cetostearyl alcohol spheres. 
Int J Pharm 1992; 83: 95114. 
4 Ahmed M, Enever RP. Formulation and evaluation of sustained 
release paracetamol tablets. J Clin Hosp Pharm 1981; 6: 2738. 
5 Forster T, Schambil F, von RybinskiW. Production of fine disperse 
and long-term stable oil-in-water emulsions by the phase inversion 
temperature method. Disper Sci Technol 1992; 13(2): 183193. 
6 Niemi L, Laine E. Effect of water content on the microstructure of 
an O/W cream. Int J Pharm 1991; 68: 205214. 
7 Eccleston GM, Beattie L. Microstructural changes during the 
storage of systems containing cetostearyl alcohol; polyoxyethylene 
alkyl ether surfactants. In: Rubinstein MH, ed. Pharmaceutical 
Technology: Drug Stability. Chichester: Ellis Horwood, 1989: 76 
87. 
8 Schambil F, Jost F, Schwuger MJ. Interfacial and colloidal 
properties of cosmetic emulsions containing fatty alcohol and 
fatty alcohol polygylcol ethers. Progr Colloid Polym Sci 1987; 73: 

3747. 
9 Rowe RC, Bray D. Water distribution in creams prepared using 
cetostearyl alcohol and cetrimide. J Pharm Pharmacol 1987; 39: 
642643. 
10 Eros I, Kedvessy G. Applied rheological research on ointment 
bases. Acta Chim Hung 1984; 115(4): 363375. 
11 Tsugita A, Nishijima Y, Sasaki T. Stable emulsion regions of 
surfactant-oil-water and surfactant-oil-water-long chain alcohol 
systems. Yukagaku 1980; 29(4): 227234. 
12 Eccleston GM. Structure and rheology of cetomacrogol creams: 
The influence of alcohol chain length and homologue composition. 
J Pharm Pharmacol 1997; 29: 157162. 
13 Fukushima S, Yamaguchi M, Harusawa F. Effect of cetostearyl 
alcohol on stabilization of oil-in-water emulsion, II. Relation 
between crystal form of the alcohol and stability of the emulsion. J 
Colloid Interface Sci 1977; 59(1): 159165. 
14 Rowe RC, McMahon J. The stability of oil-in-water emulsions 
containing cetrimide and cetostearyl alcohol. Int J Pharm 1986; 
31: 281282. 
15 Patel HK, Rowe RC, McMahon J, Stewart RF. A comparison of 
the structure and properties of ternary gels containing cetrimide 
and cetostearyl alcohol obtained from both natural and synthethic 
sources. Acta Pharm Technol 1985; 31(4): 243247. 
16 Fukushim S, Yamaguchi M. The effect of cetostearyl alcohol in 
cosmetic emulsions. Cosmet Toilet 1983; 98: 89102. 
17 Anonymous. Final report on the safety assessment of ceteryl 
alcohol, cetyl alcohol, isostearyl alcohol, myristyl alcohol, and 
behenyl alcohol. J Am Coll Toxicol 1988; 7(3): 359413. 
18 Tosti A, Guerra L, Morelli R, Bardazzi F. Prevalence and sources of 
sensitization to emulsifiers: A clinical study. Contact Dermatitis 
1990; 23: 6872. 
19 Pasche-Koo F, Piletta PA, Hunziker N, Hauser C. High sensitization 
rate to emulsifiers in patients with chronic leg ulcers. Contact 
Dermatitis 1994; 31: 226228. 
20 Wilson CL, Cameron J, Powell SM, et al. High incidence of contact 
dermatitis in leg-ulcer patients  implications for management. 
Clin Exp Dermatol 1991; 16: 250253. 
21 Pecegueiro M, Brandao M, Pinto J, Concal S. Contact dermatitis to 
hirudoid cream. Contact Dermatitis 1987; 17: 290293. 
22 Hannuksela M. Skin contact allergy to emulsifiers. Int J Cosmet Sci 
1988; 10: 914. 
23 Hannuksela M. Skin reactions to emulsifiers. Cosmet Toilet 1988; 
10: 8186. 
20 General References 

21 Authors 
G Frunzi, B Sarsfield. 
22 Date of Revision 
12 August 2005. 
Cetostearyl Alcohol 151

Cetrimide 
1 Nonproprietary Names 
BP: Cetrimide 
PhEur: Cetrimidum 
2 Synonyms 
Bromat; Cetab; Cetavlon; Cetraol; Lissolamine V; Micol; 
Morpan CHSA; Morphans; Quammonium; Sucticide. 
3 Chemical Name and CAS Registry Number 
Cetrimide [8044-71-1] 
Note that the above name, CAS Registry Number, and 
synonyms refer to the PhEur 2005 material which, although it 
consists predominantly of trimethyltetradecylammonium bromide, 
may also contain other bromides; see Section 4. 
There is some confusion in the literature regarding the 
synonyms, CAS Registry Number, and molecular weight 
applied to cetrimide. It is most common to find the molecular 
weight and CAS Registry Number of trimethyltetradecylammonium 
bromide used, as this is the principal component 
of cetrimide. It should be noted however, that in the original BP 
1953 material the principal component of cetrimide was 
hexadecyltrimethylammonium bromide. 
The CAS Registry Number for hexadecyltrimethylammonium 
hydroxide [505-86-2] has also been widely applied to 
cetrimide. 
See Section 17 for further information. 
4 Empirical Formula and Molecular Weight 
Cetrimide consists mainly of trimethyltetradecylammonium 
bromide (C17H38BrN), and may contain smaller amounts of 
dodecyltrimethylammonium bromide (C15H34BrN) and hexadecyltrimethylammonium 
bromide (C19H42BrN). 
C17H38BrN 336.40 
See also Section 17. 
5 Structural Formula 
where 
n = 11 for dodecyltrimethylammonium bromide 
n = 13 for trimethyltetradecylammonium bromide 
n = 15 for hexadecyltrimethylammonium bromide 
6 Functional Category 
Antimicrobial preservative; antiseptic; cationic surfactant; 
disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cetrimide is a quaternary ammonium compound that is used in 
cosmetics and pharmaceutical formulations as an antimicrobial 
preservative; see Section 10. It may also be used as a cationic 
surfactant. In eye-drops, it is used as a preservative at a 
concentration of 0.005% w/v. 
Therapeutically, cetrimide is used in relatively high concentrations, 
generally as 0.11.0% w/v aqueous solutions, as a 
topical antiseptic for skin, burns, and wounds. Solutions 
containing 13% w/v cetrimide are used as shampoos to 
remove the scales in seborrhea. 
Cetrimide is also used as a cleanser and disinfectant for hard 
contact lenses, although it should not be used on soft lenses; as 
an ingredient of cetrimide emulsifying wax, and in o/w creams 
(e.g. cetrimide cream). 
8 Description 
Cetrimide is a white to creamy white, free-flowing powder, with 
a faint but characteristic odor and a bitter, soapy taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cetrimide. 
Test PhEur 2005 
Identification . 
Characters . 
Acidity or alkalinity . 
Appearance of solution . 
Amines and amine salts . 
Loss on drying 42.0% 
Sulfated ash 40.5% 
Assay (as C17H38BrN, dried basis) 96.0101.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.07.5 (1% w/v aqueous solution) 
Antimicrobial activity: cetrimide has good bactericidal activity 
against Gram-positive species but is less active against 
Gram-negative species. Pseudomonas species, particularly 
Pseudomonas aeruginosa, may exhibit resistance. Cetrimide 
is most effective at neutral or slightly alkaline pH values, 
with activity appreciably reduced in acidic media and in the 
presence of organic matter. The activity of cetrimide is 
enhanced in the presence of alcohols. Cetrimide has variable 
antifungal activity, is effective against some viruses, and is 
inactive against bacterial spores. Typical minimum inhibitory 
concentrations (MICs) are shown in Table II.

Table II: Minimum inhibitory concentrations (MIC) of cetrimide. 
Microorganism MIC (mg/mL) 
Escherichia coli 30 
Pseudomonas aeruginosa 300 
Staphylococcus aureus 10 
Critical micelle concentration: 0.01% 
Melting point: 2322478C 
Moisture content: at 4050% relative humidity and 208C, 
cetrimide absorbs sufficient moisture to cause caking and 
retard flow properties. 
Partition coefficients: 
Liquid paraffin : water = <1; 
Vegetable oil : water = <1. 
Solubility: freely soluble in chloroform, ethanol (95%), and 
water; practically insoluble in ether. A 2% w/v aqueous 
solution foams strongly on shaking. 
11 Stability and Storage Conditions 
Cetrimide is chemically stable in the dry state, and also in 
aqueous solution at ambient temperatures. Aqueous solutions 
may be sterilized by autoclaving. Water containing metal ions 
and organic matter may reduce the antimicrobial activity of 
cetrimide. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with soaps, anionic surfactants, high concentrations 
of nonionic surfactants, bentonite, iodine, phenylmercuric 
nitrate, alkali hydroxides, and acid dyes. Aqueous solutions 
react with metals. 
13 Method of Manufacture 
Cetrimide is prepared by the condensation of suitable alkyl 
bromides and trimethylamine. 
14 Safety 
Most adverse effects reported relate to the therapeutic use of 
cetrimide. If ingested orally, cetrimide and other quaternary 
ammonium compounds can cause nausea, vomiting, muscle 
paralysis, CNS depression, and hypotension; concentrated 
solutions may cause esophageal damage and necrosis. The 
fatal oral human dose is estimated to be 1.03.0 g.(1) 
At the concentrations used topically, solutions do not 
generally cause irritation, although concentrated solutions 
have occasionally been reported to cause burns. Cases of 
hypersensitivity have been reported following repeated application.(
2) 
Adverse effects that have been reported following irrigation 
of hydatid cysts with cetrimide solution include chemical 
peritonitis,(3) methemoglobinemia with cyanosis,(4) and metabolic 
disorders.(5) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Cetrimide powder and 
concentrated cetrimide solutions are irritant; avoid inhalation, 
ingestion, and skin and eye contact. Eye protection, gloves, and 
a respirator are recommended.(6) 
16 Regulatory Status 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Benzalkonium chloride; benzethonium chloride; dodecyltrimethylammonium 
bromide; hexadecyltrimethylammonium 
bromide; trimethyltetradecylammonium bromide. 
Dodecyltrimethylammonium bromide 
Empirical formula: C15H34BrN 
Molecular weight: 308.35 
CAS number: [1119-94-4] 
Synonyms: DTAB; N-lauryl-N,N,N-trimethylammonium bromide; 
N,N,N-trimethyldodecylammonium bromide. 
Safety:
LD50 (mouse, IV): 5.2 mg/kg(7) 
LD50 (rat, IV): 6.8 mg/kg 
Hexadecyltrimethylammonium bromide 
Empirical formula: C19H42BrN 
Molecular weight: 364.48 
CAS number: [57-09-0] 
Synonyms: cetrimide BP 1953; cetrimonium bromide; cetyltrimethylammonium 
bromide; CTAB; N,N,N-trimethylhexadecylammonium 
bromide. 
Appearance: a white to creamy-white, voluminous, freeflowing 
powder, with a characteristic faint odor and bitter, 
soapy taste. 
Melting point: 2372438C 
Safety:
LD50 (guinea pig, SC): 100 mg/kg(8) 
LD50 (mouse, IP): 106 mg/kg 
LD50 (mouse, IV): 32 mg/kg 
LD50 (rabbit, IP): 125 mg/kg 
LD50 (rabbit, SC): 125 mg/kg 
LD50 (rat, IV): 44 mg/kg 
LD50 (rat, oral): 410 mg/kg 
Solubility: freely soluble in ethanol (95%); soluble 1 in 10 parts 
of water. 
Comments: the original cetrimide BP 1953 consisted largely of 
hexadecyltrimethylammonium bromide, with smaller 
amounts of analogous alkyltrimethylammonium bromides. 
It contained a considerable proportion of inorganic salts, 
chiefly sodium bromide, and was less soluble than the 
present product. 
Trimethyltetradecylammonium bromide 
Empirical formula: C17H38BrN 
Molecular weight: 336.40 
CAS number: [1119-97-7] 
Synonyms: myristyltrimethylammonium bromide; tetradecyltrimethylammonium 
bromide; N,N,N-trimethyl-1-tetradecanaminium 
bromide. 
Safety:
LD50 (mouse, IV): 12 mg/kg(9) 
LD50 (rat, IV): 15 mg/kg 
Cetrimide 153

18 Comments 
As a precaution against contamination with Pseudomonas 
species resistant to cetrimide, stock solutions may be further 
protected by adding at least 7% v/v ethanol or 4% v/v propan- 
2-ol. 
The EINECS number for cetrimide is 214-291-9. 
19 Specific References 
1 Arena JM. Poisonings and other health hazards associated with the 
use of detergents. J Am Med Assoc 1964; 190: 5658. 
2 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: A Handbook of Excipients. New York: Marcel Dekker, 
1989. 
3 Gilchrist DS. Chemical peritonitis after cetrimide washout in 
hydatid-cyst surgery [letter]. Lancet 1979; ii: 1374. 
4 Baraka A, Yamut F, Wakid N. Cetrimide-induced methaemoglobinaemia 
after surgical excision of hydatid cyst [letter]. Lancet 
1980; ii: 8889. 
5 Momblano P, Pradere B, Jarrige N, et al. Metabolic acidosis 
induced by cetrimonium bromide [letter]. Lancet 1984; ii: 1045. 
6 Jacobs JY. Work hazards from drug handling. Pharm J 1984; 233: 
195196. 
7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1550. 
8 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1925. 
9 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 33853386. 
20 General References 
August PJ. Cutaneous necrosis due to cetrimide application. Br Med J 
1975; 1: 70. 
Eccleston GM. Phase transitions in ternary systems and oil-in-water 
emulsions containing cetrimide and fatty alcohols. Int J Pharm 
1985; 27: 311323. 
Evans BK, Harding KG, Marks J, Ribeiro CD. The disinfection of 
silicone-foam dressings. J Clin Hosp Pharm 1985; 10: 289295. 
Louden JD, Rowe RC. A quantitative examination of the structure of 
emulsions prepared using cetostearyl alcohol and cetrimide using 
Fourier transform infrared microscopy. Int J Pharm 1990; 63: 219 
225. 
Rowe RC, Patel HK. The effect of temperature on the conductivity of 
gels and emulsions prepared from cetrimide and cetostearyl alcohol. 
J Pharm Pharmacol 1985; 37: 564567. 
Rowe RC, McMahon J, Stewart RF. The stability of oil-in-water 
emulsions containing cetrimide and cetostearyl alcohol. Int J Pharm 
1986; 31: 281282. 
Smith ARW, Lambert PA, Hammond SM, Jessup C. The differing 
effects of cetyltrimethylammonium bromide and cetrimide BP upon 
growing cultures of Escherichia coli NCIB 8277. J Appl Bacteriol 
1975; 38: 143149. 
21 Authors 
SC Owen. 
22 Date of Revision 
15 August 2005. 
154 Cetrimide

Cetyl Alcohol 
1 Nonproprietary Names 
BP: Cetyl alcohol 
JP: Cetanol 
PhEur: Alcohol cetylicus 
USPNF: Cetyl alcohol 
2 Synonyms 
Avol; Cachalot; Crodacol C70; Crodacol C90; Crodacol C95; 
ethal; ethol; 1-hexadecanol; n-hexadecyl alcohol; Hyfatol 16- 
95; Hyfatol 16-98; Kessco CA; Lanette 16; Lipocol C; palmityl 
alcohol; Rita CA; Tego Alkanol 16. 
3 Chemical Name and CAS Registry Number 
Hexadecan-1-ol [36653-82-4] 
4 Empirical Formula and Molecular Weight 
C16H34O 242.44 (for pure material) 
Cetyl alcohol, used in pharmaceutical preparations, is a 
mixture of solid aliphatic alcohols comprising mainly 
1-hexadecanol (C16H34O). The USPNF 23 specifies not less 
than 90.0% of cetyl alcohol, the remainder consisting chiefly of 
related alcohols. 
Commercially, many grades of cetyl alcohol are available as 
mixtures of cetyl alcohol (6070%) and stearyl alcohol 
(2030%), the remainder being related alcohols. 
5 Structural Formula 
6 Functional Category 
Coating agent; emulsifying agent; stiffening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cetyl alcohol is widely used in cosmetics and pharmaceutical 
formulations such as suppositories, modified-release solid 
dosage forms, emulsions, lotions, creams, and ointments. 
In suppositories cetyl alcohol is used to raise the melting 
point of the base, and in modified-release dosage forms it may 
be used to form a permeable barrier coating. In lotions, creams, 
and ointments cetyl alcohol is used because of its emollient, 
water-absorptive, and emulsifying properties. It enhances 
stability, improves texture, and increases consistency. The 
emollient properties are due to absorption and retention of 
cetyl alcohol in the epidermis, where it lubricates and softens 
the skin while imparting a characteristic velvety texture. 
Cetyl alcohol is also used for its water absorption properties 
in water-in-oil emulsions. For example, a mixture of petrolatum 
and cetyl alcohol (19:1) will absorb 4050% of its weight of 
water. Cetyl alcohol acts as a weak emulsifier of the water-in-oil 
type, thus allowing a reduction of the quantity of other 
emulsifying agents used in a formulation. Cetyl alcohol has also 
been reported to increase the consistency of water-in-oil 
emulsions. 
In oil-in-water emulsions, cetyl alcohol is reported to 
improve stability by combining with the water-soluble emulsifying 
agent. The combined mixed emulsifier produces a close 
packed, monomolecular barrier at the oilwater interface 
which forms a mechanical barrier against droplet coalescence. 
In semisolid emulsions, excess cetyl alcohol combines with 
the aqueous emulsifier solution to form a viscoelastic continuous 
phase that imparts semisolid properties to the emulsion 
and also prevents droplet coalescence. Therefore, cetyl alcohol 
is sometimes referred to as a consistency improver or a 
bodying agent, although it may be necessary to mix cetyl 

alcohol with a hydrophilic emulsifier to impart this property. 
It should be noted that pure or pharmacopeial grades of 
cetyl alcohol may not form stable semisolid emulsions and may 
not show the same physical properties as grades of cetyl alcohol 
that contain significant amounts of other similar alcohols. See 
Section 4. 
See Table I. 
Table I: Uses of cetyl alcohol. 
Use Concentration (%) 
Emollient 25 
Emulsifying agent 25 
Stiffening agent 210 
Water absorption 5 
8 Description 
Cetyl alcohol occurs as waxy, white flakes, granules, cubes, or 
castings. It has a faint characteristic odor and bland taste. 
9 Pharmacopeial Specifications 
See Table II. 
10 Typical Properties 
Boiling point: 
3163448C; 
3448C for pure material. 
Density: 0.908 g/cm3 
Flash point: 1658C 
Melting point: 
45528C; 
498C for pure material. 
Refractive index: nD
79 = 1.4283 for pure material. 
Solubility: freely soluble in ethanol (95%) and ether, solubility 
increasing with increasing temperature; practically insoluble

in water. Miscible when melted with fats, liquid and solid 
paraffins, and isopropyl myristate. 
Specific gravity:  0.81 g/cm3 at 508C 
Viscosity (dynamic):  7 mPa s (7 cP) at 508C 
11 Stability and Storage Conditions 
Cetyl alcohol is stable in the presence of acids, alkalis, light, and 
air; it does not become rancid. It should be stored in a wellclosed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents. Cetyl alcohol is 
responsible for lowering the melting point of ibuprofen, which 
results in sticking tendencies during the process of film coating 
ibuprofen crystals.(1) 
13 Method of Manufacture 
Cetyl alcohol may be manufactured by a number of methods 
such as esterification and hydrogenolysis of fatty acids or by 
catalytic hydrogenation of the triglycerides obtained from 
coconut oil or tallow. Cetyl alcohol may be purified by 
crystallization and distillation. 
14 Safety 
Cetyl alcohol is mainly used in topical formulations, although it 
has also been used in oral and rectal preparations. 
Cetyl alcohol has been associated with allergic delayed-type 
hypersensitivity reactions in patients with stasis dermatitis.(2) 
Cross-sensitization with cetostearyl alcohol, lanolin, and 
stearyl alcohol has also been reported.(3,4) It has been suggested 
that hypersensitivity may be caused by impurities in commercial 
grades of cetyl alcohol since highly refined cetyl alcohol 
(99.5%) has not been associated with hypersensitivity reactions.(
5) 
LD50 (mouse, IP): 1.6 g/kg(6) 
LD50 (mouse, oral): 3.2 g/kg 
LD50 (rat, IP): 1.6 g/kg 
LD50 (rat, oral): 5 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (ophthalmic 
preparations, oral capsules and tablets, otic and rectal 
preparations, topical aerosols, creams, emulsions, ointments 
and solutions, and vaginal preparations). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cetostearyl alcohol; stearyl alcohol. 
18 Comments 
The EINECS number for cetyl alcohol is 253-149-0. 
19 Specific References 
1 Schmid S, Mu. ller-Goymann CC, Schmidt PC. Interactions during 
aqueous film coating of ibuprofen with Aquacoat ECD. Int J 
Pharm 2000; 197: 3539. 
2 Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 7577. 
3 van Ketel WG, Wemer J. Allergy to lanolin and lanolin-free 
creams. Contact Dermatitis 1983; 9(5): 420. 
4 Degreef H, Dooms-Goossens A. Patch testing with silver sulfadiazine 
cream. Contact Dermatitis 1985; 12: 3337. 
5 Hannuksela M, Salo H. The repeated open application test 
(ROAT). Contact Dermatitis 1986; 14(4): 221227. 
6 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1923. 
20 General References 
Eccleston GM. Properties of fatty alcohol mixed emulsifiers and 
emulsifying waxes. In: Florence AT, ed. Materials Used in 
Pharmaceutical Formulation: Critical Reports on Applied Chemistry, 
volume 6. Oxford: Blackwell Scientific, 1984: 124156. 
Mapstone GE. Crystallization of cetyl alcohol from cosmetic emulsions. 
Cosmet Perfum 1974; 89(11): 3133. 
21 Authors 
HM Unvala. 
22 Date of Revision 
12 April 2005. 
Table II: Pharmacopeial specifications for cetyl alcohol. 
Test JP 2001 PhEur 2005 USPNF 
23 
Identification  . . 
Characters  .  
Melting range 47538C 46528C  
Residue on ignition 40.05%   
Ester value 42.0   
Alkali .   
Acid value 41.0 41.0 42 
Iodine value 42.0 42.0 45 
Hydroxyl value 210232 218238 
218238 
Saponification value  42.0  
Clarity and color of 
solution 
. .  
Assay   590.0% 
156 Cetyl Alcohol

Cetylpyridinium Chloride 
1 Nonproprietary Names 
BP: Cetylpyridinium chloride 
PhEur: Cetylpridinii chloridum 
USP: Cetylpyridinium chloride 
2 Synonyms 
C16-alkylpyridinium chloride; Cepacol; Cepacol chloride; 
Cetamiun; cetyl pyridium chloride; Dobendan; hexadecylpyridinium 
chloride; 1-hexadecylpyridinium chloride; Medilave; 
Pristacin; Pyrisept. 
3 Chemical Name and CAS Registry Number 
1-Hexadecylpyridinium chloride [123-03-5] 
1-Hexadecylpyridinium chloride monohydrate [6004-24-6] 
4 Empirical Formula and Molecular Weight 
C21H38ClN 339.9 (for anhydrous) 
C21H38ClNH2O 358.1 (for monohydrate) 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic; cationic surfactant; 
disinfectant; solubilizing agent; wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cetylpyridinium chloride is a quaternary ammonium cationic 
surfactant, used in pharmaceutical and cosmetic formulations 
as an antimicrobial preservative; see Section 10. It is used 
therapeutically as an antiseptic agent; used alone or in 
combination with other drugs for oral and throat care; used 
in nonparenteral formulations licensed in the UK; and used in 
oral and inhalation preparations at concentrations of 
0.021.5mg (see Section 16). 
Mouthwashes containing cetylpyridinium chloride have 
been shown to inhibit plaque formation,(13) although efficacy 
is variable owing to limited published data.(4,5) 
8 Description 
Cetylypyridinium chloride is a white powder with a characteristic 
odor. It is slightly soapy to the touch. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cetylpyridinium chloride. 
Test PhEur 2005 USP 28 
Absorbance . . 
Acidity . . 
Amines and amine salts .  
Appearance of solution .  
Characters .  
Heavy metals  40.002% 
Identification . . 
Melting range  80.084.08C 
Organic volatile impurities  . 
Pyridine  . 
Residue on ignition 40.2% 40.2% 
Water 4.55.5% 4.55.5% 
Assay 96.0101.0% 99.0102.0% 
10 Typical Properties 
Antibacterial activity: bactericidal to Gram-positive bacteria; 
relatively ineffective against some Gram-negative bacteria.(6) 
Cetylpyridinium chloride is also antibacterial against a 
number of oral bacteria;(7) see Table II.(8) 
Melting point: 80838C 
Solubility: freely soluble in water; very soluble in chloroform; 
very slightly soluble in ether; insoluble in acetone, acetic 
acid, and ethanol. 
Table II: Minimum inhibitory concentrations (MICs) for 
cetylpyridinium chloride.(8) 
Microorganism MIC (mg/mL) 
Staphylococcus aureus <2.0 
Bacillus subtilis <2.0 
Salmonella typhimurium 8.0 
Pseudomonas aeruginosa 16.0 
Streptococcus pyogenes <2.0 
Critical micelle concentration: 0.34 g/L (water, 258C).(9,10) 
11 Stability and Storage Conditions 
Cetylpyridinium chloride is stable under normal conditions. It 
should be stored in well-closed containers. 
12 Incompatibilities 
Incompatible with strong oxidizing agents and bases. It is also 
incompatible with methylcellulose. 
Magnesium stearate suspensions in cetylpyridinium chloride 
have been shown to significantly reduce its antimicrobial 
activity. This is due to the absorption of cetylpyridinium chloride 
on magnesium stearate.(11) The cetylpyridinium chloride ion 
also interacts with gelatin, resulting in reduced bioavailability.(
12)

13 Method of Manufacture 
Cetylpyridinium chloride is prepared from cetyl chloride by 
treatment with pyridine. 
14 Safety 
Cetylpyridinium chloride is used widely in mouthwashes as a 
bactericidal antiseptic. It is generally regarded as a relatively 
nontoxic material when used at a concentration of 0.05% w/v, 
although minor side effects such as mild burning sensations on 
the tongue have been reported.(13) 
At higher concentrations, cetylpyridinium chloride may 
damage the mucous membranes in the mouth. It is harmful 
when ingested or inhaled. It can cause eye irritation, and is 
irritant to the respiratory system and the skin. 
LD50 (rat, IP): 0.006 g/kg(14) 
LD50 (rat, IV): 0.03 g/kg 
LD50 (rat, oral): 0.2 g/kg 
LD50 (rat, SC): 0.25 g/kg 
LD50 (mouse, IP): 0.01 g/kg 
LD50 (mouse, oral): 0.108 g/kg 
LD50 (rabbit, oral): 0.4 g/kg 
LD50 (rabbit, IV): 0.036 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. When significant 
quantities are being handled, the use of a respirator with an 
appropriate gas filter is advised. When heated to decomposition, 
cetylpyridinium chloride emits very toxic fumes of NOx 
and Cl. Eye protection, gloves and adequate ventilation are 
recommended. 
16 Regulatory Status 
Included in nonparenteral formulations licensed in the UK. 
Included in the FDA Inactive Ingredients Guide, for use in 
inhalation and oral preparations. Reported in the EPA TSCA 
Inventory. It is not approved for use in Japan. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cetylpyridinium bromide. 
Cetylpyridinium bromide 
Empirical formula: C21H38BrN 
Molecular weight: 384.45 
CAS number: [140-72-7] 
Synonyms: Aceloquat CPB; Bromocet; Cetapharm; Cetasol; 
N-cetylpyridinium bromide; hexadexylpyridinium bromide; 
Nitrogenol; Seprison; Sterogenol. 
18 Comments 
Cetylpyridinium chloride has also been studied for use as an 
antimicrobial preservative for meat(15) and vegetables.(16) 
However, the residual levels after treatment are considered 
excessive for human consumption; see Section 14. 
The EINECS number for cetylpyridinium chloride is 204- 
593-9. 
19 Specific References 
1 Volpe AR, Kupczak LJ, Brant JH, et al. Antimicrobial control of 
bacterial plaque and calculus, and the effects of these agents on 
oral flora. J Dent Res 1969; 48: 832841. 
2 Holbeche JD, Ruljancich MK, Reade PC. A clinical trial of the 
efficacy of a cetylpyridinium chloride-based mouth-wash. 1. Effect 
on plaque accumulation and gingival condition. Aust Dent J 1975; 
20: 397404. 
3 Ashley FP, Skinner A, Jackson P, Woods A, Wilson RF. The effects 
of a 0.1% cetylpyridinium chloride mouth-rinse on plaque and 
gingivitis in adult subjects. Br Dent J 1984; 157: 191196. 
4 Bonosvoll P, Gjermo P. A comparison between chlorhexedine and 
some quaternary ammonium compounds with regard to retention, 
salivary concentration and plaque-inhibiting effect in the human 
mouth after mouth rinses. Arch Oral Biol 1978; 23: 289294. 
5 Sheen S, Addy M. An in vitro evaluation of the availability of 
cetylpyridinium chloride and chlorhexidine in some commercially 
available mouthrinse products. Br Dent J 2003; 194(4): 207210. 
6 Baker Z, Harrison RW, Miller BF. The bacterial action of synthetic 
detergents. J Exp Med 1941; 74: 611620. 
7 Smith RN, Anderson RN, Kolenbrander PE. Inhibition of 
intergeneric coaggregation among oral bacteria by cetylpyridinium 
chloride, chlorhexidine digluconate and octenidine dihydrochloride. 
J Periodontal Res 1991; 26(5): 422428. 
8 Bodor N, Kaminski JJ, Selk S. Soft drugs. 1. Labile quaternary 
ammonium salts as soft antimicrobials. J Med Chem 1980; 23: 
469474. 
9 Harada T, Nishikido N, Moroi Y, Matuura R. Effect of surfactant 
micelles on the rate of reaction of tetranitromethane with 
hydroxide ion. Bull Chem Soc Jpn 1981; 54: 25922597. 
10 Wang K, Karlson G, Almgren M, Asakawa T. Aggregation 
behaviour of cationic fluorosurfactants in water and salt solutions. 
A cryoTEM survey. J Phys Chem B 1999; 103(43): 92379246. 
11 Richards RM, Xing JZ, Mackay KM. Excipient interaction with 
cetylpyridinium chloride activity in tablet based lozenges. Pharm 
Res 2003: 13(8): 12581264. 
12 Ofner CM3d, Schott H. Swelling studies of gelatin. II: Effect of 
additives. J Pharm Sci 1987; 76(9): 715723. 
13 Ciano SG, Mather ML, Bunnell HL. Clinical evaluation of a 
quaternary ammonium containing mouthrinse. J Periodontol 
1975; 46: 397401. 
14 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 737. 
15 Cutter CN, Dorsa WJ, Handie A, et al. Antimicrobial activity of 
cetylpyridinium chloride washes against pathogenic bacteria on 
beef surfaces. J Food Prot 2000; 63(5): 593600. 
16 Wang H, Li Y, Slavik MF. Efficacy of cetylpyridinium chloride in 
immersion treatment reducing populations of pathogenic bacteria 
on fresh-cut vegetables. J Food Prot 2001; 64(12): 20712074. 
20 General References 
Huyck CL. Cetylpyridinium chloride. Am J Pharm 1944; 116: 5059. 
Radford JR, Beighton D, Nugent Z, Jackson RJ. Effect of use of 
0.005% cetylpyridinium chloride mouthwash on normal oral flora. 
J Dent 1997; 25(1): 3540. 
21 Authors 
JL Gray, CP McCoy. 
22 Date of Revision 
1 September 2005. 
158 Cetylpyridinium Chloride

Chitosan 
1 Nonproprietary Names 
BP: Chitosan hydrochloride 
PhEur: Chitosani hydrochloridum 
2 Synonyms 
2-Amino-2-deoxy-(1,4)-b-D-glucopyranan; deacetylated chitin; 
deacetylchitin; b-1,4-poly-D-glucosamine; poly-D-glucosamine; 
poly-(1,4-b-D-glucopyranosamine). 
3 Chemical Name and CAS Registry Number 
Poly-b-(1,4)-2-Amino-2-deoxy-D-glucose [9012-76-4] 
4 Empirical Formula and Molecular Weight 
Partial deacetylation of chitin results in the production of 
chitosan, which is a polysaccharide comprising copolymers of 
glucosamine and N-acetylglucosamine. Chitosan is the term 
applied to deacetylated chitins in various stages of deacetylation 
and depolymerization and it is therefore not easily defined 
in terms of its exact chemical composition. A clear nomenclature 
with respect to the different degrees of N-deacetylation 
between chitin and chitosan has not been defined,(13) and as 
such chitosan is not one chemical entity but varies in 
composition depending on the manufacturer. In essence, 
chitosan is chitin sufficiently deacetylated to form soluble 
amine salts. The degree of deacetylation necessary to obtain a 
soluble product must be greater than 8085%. Chitosan is 
commercially available in several types and grades that vary in 
molecular weight by 10 0001 000 000, and vary in degree of 
deacetylation and viscosity.(4) 
5 Structural Formula 
6 Functional Category 
Coating agent; disintegrant; film-forming agent; mucoadhesive; 
tablet binder; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chitosan is used in cosmetics and is under investigation for use 
in a number of pharmaceutical formulations. The suitability 
and performance of chitosan as a component of pharmaceutical 
formulations for drug delivery applications has been investigated 
in numerous studies.(3,58) These include controlled drug 
delivery applications,(914) use as a component of mucoadhesive 
dosage forms,(15,16) rapid release dosage forms,(17,18) 
improved peptide delivery,(19,20) colonic drug delivery systems,(
21,22) and use for gene delivery.(23) Chitosan has been 
processed into several pharmaceutical forms including 
gels,(24,25) films,(11,12,26,27) beads,(28,29) microspheres,(30,31) 
tablets,(32,33) and coatings for liposomes.(34) Furthermore, 
chitosan may be processed into drug delivery systems using 
several techniques including spray-drying,(15,16) coacervation,(
35) direct compression,(32) and conventional granulation 
processes.(36) 
8 Description 
Chitosan occurs as odorless, white or creamy-white powder or 
flakes. Fiber formation is quite common during precipitation 
and the chitosan may look cottonlike. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for chitosan. 
Test PhEur 2005 
Identification . 
Characters . 
Appearance of solution . 
Matter insoluble in water 40.5% 
pH (1% w/v solution) 4.06.0 
Viscosity . 
Degree of deacetylation . 
Chlorides 10.020.0% 
Heavy metals 440 ppm 
Loss on drying 410% 
Sulfated ash 41.0% 
10 Typical Properties 
Chitosan is a cationic polyamine with a high charge density at 
pH <6.5; and so adheres to negatively charged surfaces and 
chelates metal ions. It is a linear polyelectrolyte with reactive 
hydroxyl and amino groups (available for chemical reaction 
and salt formation).(7) The properties of chitosan relate to its 
polyelectrolyte and polymeric carbohydrate character. The 
presence of a number of amino groups allows chitosan to react 
chemically with anionic systems, which results in alteration of 
physicochemical characteristics of such combinations. The 
nitrogen in chitosan is mostly in the form of primary aliphatic 
amino groups. Chitosan therefore undergoes reactions typical

of amines: for example, N-acylation and Schiff reactions.(3) 
Almost all functional properties of chitosan depend on the 
chain length, charge density, and charge distribution.(8) 
Numerous studies have demonstrated that the salt form, 
molecular weight, and degree of deacetylation as well as pH 
at which the chitosan is used all influence how this polymer is 
utilized in pharmaceutical applications.(7) 
Acidity/alkalinity: pH = 4.06.0 (1% w/v aqueous solution) 
Density: 1.351.40 g/cm3 
Glass transition temperature: 2038C(37) 
Moisture content: chitosan adsorbs moisture from the atmosphere, 
the amount of water adsorbed depending upon the 
initial moisture content and the temperature and relative 
humidity of the surrounding air.(38) 
Particle size distribution: <30 mm 
Solubility: sparingly soluble in water; practically insoluble in 
ethanol (95%), other organic solvents, and neutral or alkali 
solutions at pH above approximately 6.5. Chitosan 
dissolves readily in dilute and concentrated solutions of 
most organic acids and to some extent in mineral inorganic 
acids (except phosphoric and sulfuric acids). Upon dissolution, 
amine groups of the polymer become protonated, 
resulting in a positively charged polysaccharide (RNH3.) 
and chitosan salts (chloride, glutamate, etc.) that are soluble 
in water; the solubility is affected by the degree of 
deacetylation.(7) Solubility is also greatly influenced by the 
addition of salt to the solution. The higher the ionic strength, 
the lower the solubility as a result of a salting-out effect, 
which leads to the precipitation of chitosan in solution.(39) 
When chitosan is in solution, the repulsions between the 
deacetylated units and their neighboring glucosamine units 
cause it to exist in an extended conformation. Addition of an 
electrolyte reduces this effect and the molecule possesses a 
more random, coil-like conformation.(40) 
Viscosity (dynamic): a wide range of viscosity types is 
commercially available. Owing to its high molecular weight 
and linear, unbranched structure, chitosan is an excellent 
viscosity-enhancing agent in an acidic environment. It acts 
as a pseudo-plastic material, exhibiting a decrease in 
viscosity with increasing rates of shear.(7) The viscosity of 
chitosan solutions increases with increasing chitosan concentration, 
decreasing temperature, and increasing degree of 
deacetylation; see Table II.(40) 
Table II: Typical viscosity (dynamic) values for chitosan 1% w/v 
solutions in different acids.(40) 
Acid 1% acid 
concentration 
5% acid 
concentration 
10% acid 
concentration 
Viscosity 
(mPa s) 
pH Viscosity 
(mPa s) 
pH Viscosity 
(mPa s) 
pH 
Acetic 260 4.1 260 3.3 260 2.9 
Adipic 190 4.1     
Citric 35 3.0 195 2.3 215 2.0 
Formic 240 2.6 185 2.0 185 1.7 
Lactic 235 3.3 235 2.7 270 2.1 
Malic 180 3.3 205 2.3 220 2.1 
Malonic 195 2.5     
Oxalic 12 1.8 100 1.1 100 0.8 
Tartaric 52 2.8 135 2.0 160 1.7 
11 Stability and Storage Conditions 
Chitosan powder is a stable material at room temperature, 
although it is hygroscopic after drying. Chitosan should be 
stored in a tightly closed container in a cool, dry place. The 
PhEur 2005 specifies that chitosan should be stored at a 
temperature of 288C. 
12 Incompatibilities 
Chitosan is incompatible with strong oxidizing agents. 
13 Method of Manufacture 
Chitosan is manufactured commercially by chemically treating 
the shells of crustaceans such as shrimps and crabs. The basic 
manufacturing process involves the removal of proteins by 
treatment with alkali and of minerals such as calcium carbonate 
and calcium phosphate by treatment with acid.(3,40) Before 
these treatments, the shells are ground to make them more 
accessible. The shells are initially deproteinized by treatment 
with an aqueous sodium hydroxide 35% solution. The 
resulting product is neutralized and calcium is removed by 
treatment with an aqueous hydrochloric acid 35% solution at 
room temperature to precipitate chitin. The chitin is dried so 
that it can be stored as a stable intermediate for deacetylation to 
chitosan at a later stage. N-deacetylation of chitin is achieved 
by treatment with an aqueous sodium hydroxide 4045% 
solution at elevated temperature (1108C), and the precipitate is 
washed with water. The crude sample is dissolved in acetic acid 
2% and the insoluble material is removed. The resulting clear 
supernatant solution is neutralized with aqueous sodium 
hydroxide solution to give a purified white precipitate of 
chitosan. The product can then be further purified and ground 
to a fine uniform powder or granules.(1) The animals from 
which chitosan is derived must fulfil the requirements for the 
health of animals suitable for human consumption to the 
satisfaction of the competent authority. The method of 
production must consider inactivation or removal of any 
contamination by viruses or other infectious agents. 
14 Safety 
Chitosan is being investigated widely for use as an excipient in 
oral and other pharmaceutical formulations. It is also used in 
cosmetics. Chitosan is generally regarded as a nontoxic and 
nonirritant material. It is biocompatible(41) with both healthy 
and infected skin.(42) Chitosan has been shown to be 
biodegradable.(3,41) 
LD50 (mouse, oral): >16 g/kg(43) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Chitosan is combustible; 
open flames should be avoided. Chitosan is temperaturesensitive 
and should not be heated above 2008C. Airborne 
chitosan dust may explode in the presence of a source of 
ignition, depending on its moisture content and particle size. 
Water, dry chemicals, carbon dioxide, sand, or foam firefighting 
media should be used. 
160 Chitosan

Chitosan may cause skin or eye irritation. It may be harmful 
if absorbed through the skin or if inhaled and may be irritating 
to mucous membranes and the upper respiratory tract. Eye and 
skin protection and protective clothing are recommended; wash 
thoroughly after handling. Prolonged or repeated exposure 
(inhalation) should be avoided by handling in a well-ventilated 
area and wearing a respirator. 
16 Regulatory Status 
Chitosan is registered as a food supplement in some countries. 
17 Related Substances 
See Section 18. 
18 Comments 
Chitosan derivatives are easily obtained under mild conditions 
and can be considered as substituted glucens.(3) 
19 Specific References 
1 Muzzarelli RAA, ed. Natural Chelating Polymers. New York: 
Pergamon Press, 1973: 83227. 
2 Zikakis JP, ed. Chitin, Chitosan and Related Enzymes. New York: 
Academic Press, 1974. 
3 Kumar MNVR. A review of chitin and chitosan applications. 
React Funct Polym 2000; 46: 127. 
4 Genta I, Perugini P, Pavanetto F. Different molecular weight 
chitosan microspheres: influence on drug loading and drug release. 
Drug Dev Ind Pharm 1998; 24: 779784. 
5 Illum L. Chitosan and its use as a pharmaceutical excipient. Pharm 
Res 1998; 15: 13261331. 
6 PaulW, Sharma CP. Chitosan, a drug carrier for the 21st century: a 
review. STP Pharma Sci 2000; 10: 522. 
7 Singla AK, Chawla M. Chitosan: some pharmaceutical and 
biological aspects  an update. J Pharm Pharmacol 2001; 53: 
10471067. 
8 Dodane V, Vilivalam VD. Pharmaceutical applications of chitosan. 
PSTT1998; 1: 246253. 
9 Muzzarelli RAA, ed. Chitin. London: Pergamon Press, 1977: 69. 
10 Nakatsuka S, Andrady LA. Permeability of vitamin-B-12 in 
chitosan membranes: effect of crosslinking and blending with 
poly(vinyl alcohol) on permeability. J Appl Polym Sci 1992; 44: 7 
28. 
11 Kubota N, Ohga K, Moriguchi M. Permeability properties of 
glycol chitosan membrane modified with thiol groups. J Appl 
Polym Sci 1991; 42: 495501. 
12 Li Q, Dunn ET, Grandmaison EW, Goosen MFA. Application and 
properties of chitosan. J Bioact Compat Polym 1992; 7: 370397. 
13 Miyazaki S, Yamaguchi H, Yokouchi C, et al. Sustained release 
and intragastric floating granules of indomethacin using chitosan 
in rabbits. Chem Pharm Bull 1988; 36: 40334038. 
14 Sawayangi Y, Nambu N, Nagai T. Use of chitosan for sustainedrelease 
preparations of water soluble drugs. Chem Pharm Bull 
1982; 30: 42134215. 
15 He P, Davis SS, Illum L. In vitro evaluation of the mucoadhesive 
properties of chitosan microspheres. Int J Pharm 1998; 166: 75 
88. 
16 He P, Davis SS, Illum L. Sustained release chitosan microsphere 
produced by novel spray drying methods. J Microencapsul 1999; 
16: 343355. 
17 Sawayangi Y, Nambu N, Nagai T. Enhancement of dissolution 
properties of griseofulvin from ground mixtures with chitin or 
chitosan. Chem Pharm Bull 1982; 30: 44644467. 
18 Shirashi S, Arahira M, Imai T, Otagiri M. Enhancement of 
dissolution rates of several drugs by low molecular weight chitosan 
and alginate. Chem Pharm Bull 1990; 38: 185187. 
19 Leussen HL, Lehr CM, Rentel CO, et al. Bioadhesive polymers for 
the peroral delivery of drugs. J Control Release 1994; 29: 329 
338. 
20 Leussen HL, Rentel CO, Kotze AF, et al. Mucoadhesive polymers 
in peroral peptide drug delivery, IV: polycarbophil and chitosan are 
potent enhancers of peptide transport across intestinal mucosae in 
vitro. J Control Release 1997; 45: 1523. 
21 Tozaki H, Fujita T, Odoriba T, et al. Validation of a pharmacokinetic 
model of colon-specific drug delivery and the therapeutic 
effects of chitosan capsules containing 5-aminosalicylic acid on 
2,4,6-trinitrobenzene sulphonic acid-induced ulcerative colitis in 
rats. J Pharm Pharmacol 1999; 51: 11071112. 
22 Tozaki H, Fujita T, Odoriba T, et al. Colon specific delivery of R 
68070, a new thromboxane synthase inhibitor using chitosan 
capsules: therapeutic effects against 2,4,6-trinitrobenzene sulphonic 
acid-induced ulcerative colitis in rats. Life Sci 1999; 64: 1155 
1162. 
23 Leong KW, Mao HQ, Truong-Le VL, et al. DNA-polycation 
nanospheres as non-viral gene delivery vehicles. J Control Release 
1998; 53: 183193. 
24 Kristl J, Smid-Korbar J, Struc E, et al. Hydrocolloids and gels of 
chitosan as drug carriers. Int J Pharm 1993; 99: 1319. 
25 Tasker RA, Ross SJ, Dohoo SE, Elson CM. Pharmacokinetics of an 
injectable sustained-release formulation of morphine for use in 
dogs. J Vet Pharmacol Ther 1997; 20: 362367. 
26 Remunan-Lopez C, Portero A, Vila-Jato JL, Alonso MJ. Design 
and evaluation of chitosan/ethylcellulose mucoadhesive bilayered 
devices for buccal drug delivery. J Control Release 1998; 55: 143 
152. 
27 Senel S, Ikinci G, Kas S, et al. Chitosan films and hydrogels of 
chlorhexidine gluconate for oral mucosal delivery. Int J Pharm 
2000; 193: 197203. 
28 Kofuji K, Shibata K, Murata Y, et al. Preparation and drug 
retention of biodegradable chitosan gel beads. Chem Pharm Bull 
1999; 47: 14941496. 
29 Sezer AD, Akbuga J. Release characteristics of chitosan-treated 
alginate beads, 1: sustained release of a macromolecular drug from 
chitosan treated alginate beads. J Microencapsul 1999; 193: 197 
203. 
30 Ganza-Gonzalez A, Anguiano-Igea S, Otero-Espinar FJ, Mendez 
JB. Chitosan and chondroitin microspheres for oral administration 
controlled release of metoclopromide. Eur J Pharm Biopharm 
1999; 48: 149155. 
31 Huang RG, Schwartz JB, Offner CM. Microencapsulation of 
chlorpheniramine maleate-resin particles with crosslinked chitosan 
for sustained release. Pharm Dev Technol 1999; 4: 107115. 
32 Yomota C, Miyazaki T, Okada S. Sustained-release effect of the 
direct compressed tablet based on chitosan and Na alginate. 
Yakugaku Zasshi 1994; 114: 257263. 
33 Sabnis S, Rege P, Block LH. Use of chitosan in compressed tablets 
of diclofenac sodium: inhibition of drug release in an acidic 
environment. Pharm Dev Technol 1997; 2: 243255. 
34 Takeuchi H, Yamamoto H, Niwa T, et al. Enteral absorption of 
insulin in rats from mucoadhesive chitosan-coated liposomes. 
Pharm Res 1996; 13: 896901. 
35 Bayomi MA, al-Suwayeh SA, el-Helw AM, Mesnad AF. Preparation 
of casein-chitosan microspheres containing diltiazem hydrochloride 
by an aqueous coacervation technique. Pharma Acta Helv 
1998; 73: 187192. 
36 Miyazaki S, Nakayama A, Oda M, et al. Drug release from oral 
mucosal adhesive tablets of chitosan and sodium alginate. Int J 
Pharm 1995; 118: 257263. 
37 Sakurai K, Maegawa T, Takahashi T. Glass transition temperature 
of chitosan and miscibility of chitosan/poly(N-vinyl pyrrolidone) 
blends. Polymer 2000; 41: 70517056. 
38 Gocho H, Shimizu H, Tanioka A, et al. Effect of polymer chain end 
on sorption isotherm of water by chitosan. Carbohydr Polym 
2000; 41: 8790. 
39 Errington N, Harding SE, Varum KM, Illum L. Hydrodynamic 
characterization of chitosans varying in degree of acetylation. Int J 
Biol Macromol 1993; 15: 113117. 
40 Skaugrud O. Chitosan  new biopolymer for cosmetics and drugs. 
Drug Cosmet Ind 1991; 148: 2429. 
Chitosan 161

41 Gebelein CG, Dunn RL, eds. Progress in Biomedical Polymers. 
New York: Plenum Press, 1990: 283. 
42 Gooday GW, Jeuniaux C, Muzzarelli RAA, eds. Chitin in Nature 
and Technology. New York: Plenum Press, 1986: 435. 
43 Arai K, Kinumaki T, Fujita T. Toxicity of chitosan. Bull Tokai Reg 
Fish Res Lab 1968; 43: 8994. 
20 General References 
Brine CJ, Sandford PA, Zikakis JP, eds. Advances in Chitin and 
Chitosan. London: Elsevier Applied Science, 1992. 
Skjak-Braek G, Anthonsen T, Sandford P, eds. Chitin and Chitosan: 
Sources, Chemistry, Biochemistry, Physical Properties and Applications. 
Amsterdam: Elsevier, 1992. 
21 Authors 
DS Jones, HJ Mawhinney. 
22 Date of Revision 
28 August 2005. 
162 Chitosan

Chlorhexidine 
1 Nonproprietary Names 
BP: Chlorhexidine acetate 
Chlorhexidine gluconate solution 
Chlorhexidine hydrochloride 
JP: Chlorhexidine gluconate solution 
Chlorhexidine hydrochloride 
PhEur: Chlorhexidini diacetas 
Chlorhexidini digluconatis solutio 
Chlorhexidini dihydrochloridum 
Chlorhexidine gluconate solution 
Chlorhexidine is usually encountered as the acetate, gluconate, 
or hydrochloride salt, and a number of pharmacopeias contain 
monographs for such materials. See Sections 9 and 17. 
2 Synonyms 
1,6-bis[N0-(p-Chlorophenyl)-N5-biguanido]hexane; N,N00-bis 
(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide; 
1,6-di(40-chlorophenyldiguanido)hexane. 
3 Chemical Name and CAS Registry Number 
N,N00-Bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide 
[55-56-1] 
4 Empirical Formula and Molecular Weight 
C22H30Cl2N10 505.48 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chlorhexidine salts are widely used in pharmaceutical formulations 
in Europe and Japan for their antimicrobial properties.(
1,2) Although mainly used as disinfectants, chlorhexidine 
salts are also used as antimicrobial preservatives. 
As excipients, chlorhexidine salts are mainly used for the 
preservation of eye-drops at a concentration of 0.01% w/v; 
generally the acetate or gluconate salt is used for this purpose. 
Solutions containing 0.0020.006% w/v chlorhexidine gluconate 
have also been used for the disinfection of hydrophilic 
contact lenses. 
For skin disinfection, chlorhexidine has been formulated as 
a 0.5% w/v solution in 70% v/v ethanol and, in conjunction 
with detergents, as a 4%w/v surgical scrub. Chlorhexidine salts 
may also be used in topical antiseptic creams, mouthwashes, 
dental gels, and in urology for catheter sterilization and bladder 
irrigation.(14) 
Chlorhexidine salts have additionally been used as constituents 
of medicated dressings, dusting powders, sprays, and 
creams. 
8 Description 
Chlorhexidine occurs as an odorless, bitter tasting, white 
crystalline powder. See Section 17 for information on chlorhexidine 
salts. 
9 Pharmacopeial Specifications 
See Table I. 
See also Section 17. 
10 Typical Properties 
Antimicrobial activity: chlorhexidine and its salts exhibit 
antimicrobial activity against Gram-positive and Gramnegative 
microorganisms.(5) At the low concentrations 
normally used for preservation and antisepsis, chlorhexidine 
salts are rapidly bactericidal. However, species of Proteus 
and Pseudomonas are less susceptible to chlorhexidine, 
which is also inactive against acid-fast bacilli, bacterial 
spores, and some fungi. Chlorhexidine salts are effective 
against some lipophilic viruses such as adenovirus, herpes 
virus, and influenza virus. Optimum antimicrobial activity 
occurs at pH 57. Above pH 8, the chlorhexidine base may 
precipitate from aqueous solutions. 
Bacteria (Gram-positive): chlorhexidine salts are active 
against most species; the minimum inhibitory concentration 
(MIC) is normally in the range 110 mg/mL, although much 
higher concentrations are necessary for Streptococcus 
faecalis. Typical MIC values are shown in Table II. 
Bacteria (Gram-negative): chlorhexidine salts are less active 
against Gram-negative species than against Gram-positive 
species. Typical MICs are 115 mg/mL, but pseudomonads, 
particularly Pseudomonas aeruginosa, may be more resistant. 
Serratia marcescens may also be resistant. Combinations 
of chlorhexidine acetate with the following substances 
have shown enhanced or more than additive activity 
towards Pseudomonas aeruginosa: benzalkonium chloride; 
benzyl alcohol; bronopol; edetic acid; phenylethanol, and 
phenylpropanol.(6,7) Typical MIC values are shown in Table 
III.

Table II: Typical minimum inhibitory concentrations (MIC) of 
chlorhexidine against Gram-positive bacteria. 
Microorganism MIC (mg/mL) 
Bacillus spp. 1.03.0 
Clostridium spp. 1.870.0 
Corynebacterium spp. 5.010.0 
Staphylococcus spp. 0.56.0 
Streptococcus faecalis 20005000 
Streptococcus spp. 0.17.0 
Fungi: chlorhexidine salts are slowly active against molds 
and yeasts, although they are generally less potent in their 
inhibitory activity against fungi than against bacteria. 
Typical MIC values are shown in Table IV. 
Table III: Typical MIC values of chlorhexidine against Gram-negative 
bacteria. 
Microorganism MIC (mg/mL) 
Escherichia coli 2.57.5 
Klebsiella spp. 1.512.5 
Proteus spp. 3100 
Pseudomonas spp. 360 
Serratia marcescens 375 
Salmonella spp. 1.615 
Table IV: Typical MIC values of chlorhexidine against fungi. 
Microorganism MIC (mg/mL) 
Aspergillus spp. 75.0500.0 
Candida albicans 7.015.0 
Microsporum spp. 12.018.0 
Penicillium spp. 150.0200.0 
Saccharomyces spp. 50.0125.0 
Trichophyton spp. 2.514.0 
Spores: chlorhexidine salts are inactive against spores at 
normal room temperature.(8) At 981008C there is some 
activity against mesophilic spores. 
Critical micelle concentration: 0.6% w/v (depends on other 
ions in solution).(9) 
Melting point: 1321348C 
See also Section 17 for additional information. 
SEM: 1 
Excipient: Chlorhexidine 
Manufacturer: SST Corp. 
Magnification: 600 
Table I: Pharmacopeial specifications for chlorhexidine. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
pH 
Chlorhexidine 
gluconate solution 
5.57.0 5.57.0 5.57.0 
Relative density 
Chlorhexidine 
gluconate solution 
1.061.07 1.061.07 1.061.07 
4-Chloroaniline 
Chlorhexidine acetate  40.25%  
Chlorhexidine 
gluconate solution 
. . 4500 mg/mL 
Chlorhexidine 
hydrochloride 
. 4500 ppm  
Related substances  . . 
Loss on drying 
Chlorhexidine acetate  43.5%  
Chlorhexidine 
hydrochloride 
42.0% 41.0%  
Sulfated ash 
Chlorhexidine acetate  40.15%  
Chlorhexidine 
gluconate solution 
40.10%   
Chlorhexidine 
hydrochloride 
40.10% 40.1%  
Heavy metals 410 ppm   
Arsenic 
Chlorhexidine acetate 42 ppm   
Chlorhexidine 
hydrochloride 
42 ppm   
Assay 
Chlorhexidine acetate  98.0101.0%  
Chlorhexidine 
gluconate solution 
19.021.0% 19.021.0% 19.021.0% 
Chlorhexidine 
hydrochloride 
598.0% 98.0101.0%  
164 Chlorhexidine

SEM: 2 
Excipient: Chlorhexidine 
Manufacturer: SST Corp. 
Magnification: 2400 
11 Stability and Storage Conditions 
Chlorhexidine and its salts are stable at normal storage 
temperatures when in the powdered form. However, chlorhexidine 
hydrochloride is hygroscopic, absorbing significant 
amounts of moisture at temperatures up to 378C and relative 
humidities up to 80%. 
Heating to 1508C causes decomposition of chlorhexidine 
and its salts, yielding trace amounts of 4-chloroaniline. 
However, chlorhexidine hydrochloride is more thermostable 
than the acetate and can be heated at 1158C for 1 hour without 
appreciable formation of 4-chloroaniline. 
In aqueous solution, chlorhexidine salts may undergo 
hydrolysis to form 4-chloroaniline. Following autoclaving of 
a 0.02% w/v chlorhexidine gluconate solution at pH 9 for 30 
minutes at 1208C, it was found that 1.56% w/w of the original 
chlorhexidine content had been converted into 4-chloroaniline; 
for solutions at pH 6.3 and 4.7 the 4-chloroaniline content was 
0.27% w/w and 0.13% w/w, respectively, of the original 
gluconate content.(10) In buffered 0.05% w/v chlorhexidine 
acetate solutions, maximum stability occurs at pH 5.6. 
When chlorhexidine solutions were autoclaved at various 
time and temperature combinations, the rate of hydrolysis 
increased markedly above 1008C, and as pH increased or 
decreased from pH 5.6. At a given pH, chlorhexidine gluconate 
produced more 4-chloroaniline than the acetate. 
It was predicted that in an autoclaved solution containing 
0.01% w/v chlorhexidine, the amount of 4-chloroaniline 
formed would be about 0.00003%. At these low concentrations 
there would be little likelihood of any toxic hazard as a 
result of the increase in 4-chloroaniline content in the 
autoclaved solution. 
Chlorhexidine solutions and aqueous-based products may 
be packaged in glass and high-density polyethylene or 
polypropylene bottles provided that they are protected from 
light. If not protected from light, chlorhexidine solutions 
containing 4-chloroaniline discolor owing to polymerization 
of the 4-chloroaniline.(1113) 
Cork-based closures or liners should not be used in 
packaging in contact with chlorhexidine solutions. 
As a precaution against contamination with Pseudomonas 
species resistant to chlorhexidine, stock solutions may be 
protected by the inclusion of 7% w/v ethanol or 4% w/v 
propan-2-ol. 
Chlorhexidine salts, and their solutions, should be stored in 
well-closed containers, protected from light, in a cool, dry 
place. 
12 Incompatibilities 
Chlorhexidine salts are cationic in solution and are therefore 
incompatible with soaps and other anionic materials. Chlorhexidine 
salts are compatible with most cationic and nonionic 
surfactants, but in high concentrations of surfactant chlorhexidine 
activity can be substantially reduced owing to micellar 
binding. 
Chlorhexidine salts of low aqueous solubility are formed 
and may precipitate from chlorhexidine solutions of concentration 
greater than 0.05% w/v, when in the presence of inorganic 
acids, certain organic acids, and salts (e.g. benzoates, bicarbonates, 
borates, carbonates, chlorides, citrates, iodides, nitrates, 
phosphates, and sulfates).(14) At chlorhexidine concentrations 
below 0.01% w/v precipitation is less likely to occur. 
In hard water, insoluble salts may form owing to interaction 
with calcium and magnesium cations. Solubility may be 
enhanced by the inclusion of surfactants such as cetrimide. 
Other substances incompatible with chlorhexidine salts 
include viscous materials such as acacia, sodium alginate, 
sodium carboxymethylcellulose, starch, and tragacanth.(15,16) 
Also incompatible are brilliant green, chloramphenicol, copper 
sulfate, fluorescein sodium, formaldehyde, silver nitrate, and 
zinc sulfate. 
Interaction has been reported between chlorhexidine gluconate 
and the hydrogel poly(2-hydroxyethyl methacrylate), 
which is a component of some hydrophilic contact lenses.(17,18) 
13 Method of Manufacture 
Chlorhexidine may be prepared either by condensation of 
polymethylene bisdicyandiamide with 4-chloroaniline hydrochloride 
or by condensation of 4-chlorophenyl dicyandiamine 
with hexamethylenediamine dihydrochloride. Chlorhexidine 
may also be synthesized from a series of biguanides.(19) 
14 Safety 
Chlorhexidine and its salts are widely used, primarily as topical 
disinfectants. As excipients, chlorhexidine salts are mainly used 
as antimicrobial preservatives in ophthalmic formulations. 
Animal studies suggest that the acute oral toxicity of 
chlorhexidine is low, with little or no absorption from the 
gastrointestinal tract. However, although humans have consumed 
up to 2 g of chlorhexidine daily for 1 week, without 
untoward symptoms, chlorhexidine is not generally used as an 
excipient in orally ingested formulations. 
Reports have suggested that there may be some systemic 
effects in humans following oral consumption of chlorhexidine.(
2022) Similarly, the topical application of chlorhexidine 
or its salts produced evidence of very slight percutaneous 
absorption of chlorhexidine, although the concentrations 
absorbed were insufficient to produce systemic adverse 
effects.(23) 
Chlorhexidine 165

Severe hypersensitivity reactions, including anaphylactic 
shock, have been reported following the topical administration 
of chlorhexidine,(2428) although such instances are rare given 
the extensive use of chlorhexidine and it salts. 
In ophthalmic preparations, irritation of the conjunctiva 
occurs with chlorhexidine solutions of concentration stronger 
than 0.1% w/v. Accidental eye contact with 4% w/v 
chlorhexidine gluconate solution may result in corneal 
damage.(29) 
The aqueous concentration of chlorhexidine normally 
recommended for contact with mucous surfaces is 0.05% 
w/v. At this concentration, there is no irritant effect on soft 
tissues, nor is healing delayed. The gluconate salt (1% w/v) is 
frequently used in creams, lotions, and disinfectant solutions. 
Direct instillation of chlorhexidine into the middle ear can 
result in ototoxicity;(30) when used in dental preparations, 
staining of teeth and oral lesions may occur.(31,32) 
Use of chlorhexidine on the brain or meninges is extremely 
dangerous. 
LD50 (mouse, IP): 0.04 g/kg(33) 
LD50 (mouse, oral): 2.52 g/kg 
LD50 (rat, IP): 0.06 g/kg 
LD50 (rat, IV): 0.02 g/kg 
LD50 (rat, oral): 9.2 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. The dust of chlorhexidine 
and its salts may be irritant to the skin, eyes, and respiratory 
tract. Gloves, eye protection, and a respirator are recommended. 
16 Regulatory Status 
Chlorhexidine salts are included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Chlorhexidine acetate; chlorhexidine gluconate; chlorhexidine 
hydrochloride. 
Chlorhexidine acetate 
Empirical formula: C22H30Cl2N102C2H4O2 
Molecular weight: 625.64 
CAS number: [56-95-1] 
Synonyms: chlorhexidini acetas; chlorhexidine diacetate; 1,10- 
hexamethylenebis[5-(4-chlorophenyl)biguanide] diacetate; 
Hibitane diacetate. 
Appearance: a white or almost white, microcrystalline powder. 
Melting point: 1548C 
Moisture content: chlorhexidine acetate is hygroscopic, absorbing 
significant amounts of moisture at relative humidities up 
to about 80% and temperatures up to 378C. 
Partition coefficients: 
Mineral oil : water = 0.075; 
Peanut oil : water = 0.04. 
Solubility: soluble 1 in 15 of ethanol (95%), 1 in 55 of water; 
slightly soluble in glycerin and propylene glycol. 
Safety:
LD50 (mouse, IP): 0.04 g/kg(33) 
LD50 (mouse, IV): 0.03 g/kg 
LD50 (mouse, oral): 2 g/kg 
LD50 (mouse, SC): 0.33 g/kg 
Comments: aqueous solutions may be sterilized by autoclaving; 
the solutions should not be alkaline or contain other 
ingredients that affect the stability of chlorhexidine. See 
Sections 11 and 12. 
The EINECS number for chlorhexidine acetate is 200- 
302-4. 
Chlorhexidine gluconate 
Empirical formula: C22H30Cl2N102C6H12O7 
Molecular weight: 897.88 
CAS number: [18472-51-0] 
Synonyms: chlorhexidine digluconate; chlorhexidini digluconatis; 
1,10-hexamethylenebis[5-(4-chlorophenyl)biguanide] 
digluconate; Hibiclens; Hibiscrub; Hibitane; Unisept. 
Appearance: chlorhexidine gluconate is usually used as an 
almost colorless or pale yellow-colored aqueous solution. 
Acidity/alkalinity: pH = 5.57.0 for a 5% w/v aqueous 
dilution. 
Solubility: miscible with water; soluble in acetone and ethanol 
(95%). 
Safety:
LD50 (mouse, IV): 0.02 g/kg(33) 
LD50 (mouse, oral): 1.8 g/kg 
LD50 (mouse, SC): 1.14 g/kg 
LD50 (rat, IV): 0.02 g/kg 
LD50 (rat, oral): 2 g/kg 
LD50 (rat, SC): 3.32 g/kg 
Comments: the commercially available 5% w/v chlorhexidine 
gluconate solution contains a nonionic surfactant to prevent 
precipitation and is not suitable for use in body cavities or 
for the disinfection of surgical instruments containing 
cemented glass components. Aqueous dilutions of commercially 
available chlorhexidine gluconate solutions may be 
sterilized by autoclaving. See Sections 11 and 12. 
The EINECS number for chlorhexidine gluconate is 242- 
354-0. 
Chlorhexidine hydrochloride 
Empirical formula: C22H30Cl2N102HCl 
Molecular weight: 578.44 
CAS number: [3697-42-5] 
Synonyms: chlorhexidine dihydrochloride; chlorhexidini 
hydrochloridum; 1,10-hexamethylenebis[5-(4-chlorophenyl)
biguanide]dihydrochloride. 
Appearance: a white or almost white, crystalline powder. 
Melting point: 2618C, with decomposition. 
Solubility: sparingly soluble in water; very slightly soluble in 
ethanol (95%); soluble 1 in 50 of propylene glycol. 
Safety: LD50 (mouse, SC): >5 g/kg(33) 
Comments: chlorhexidine hydrochloride may be sterilized by 
dry heat. See Sections 11 and 12. 
The EINECS number for chlorhexidine hydrochloride is 
223-026-6. 
18 Comments 
The EINECS number for chlorhexidine is 200-238-7. 
19 Specific References 
1 Juliano C, Gavini E, Cossu M, et al. Mucoadhesive alginate 
matrices containing sodium carboxymethyl starch for buccal drug 
delivery in in vitro and in vivo studies. STP Pharma Sci 2004; 
14(2): 159163. 
166 Chlorhexidine

2 Lupuleasa D, Hirajau V, Mititelu M, et al. Bucoadhesive dosage 
form with chlorhexidine dichlorhydrate. Farmacia 2003; 51(5): 
4955. 
3 Leyes Borrajo JL, Garcia VL, Lopez CG, et al. Efficacy of 
chlorhexidine mouthrinses with and without alcohol: a clinical 
study. J Peridontol 2002; 73(3): 317321. 
4 Alaki SM, Loesche WJ, da Fonesca MA, et al. Preventing the 
transfer of Streptococcus mutans from primary molars to 
permanent first molars using chlorhexidine. Pediatr Dent 2002; 
24(2): 103108. 
5 Prince HN, Nonemaker WS, Norgard RC, Prince DL. Drug 
resistance studies with topical antiseptics. J Pharm Sci 1978; 67: 
16291631. 
6 Richards RME, McBride RJ. Enhancement of benzalkonium 
chloride and chlorhexidine activity against Pseudomonas aeruginosa 
by aromatic alcohols. J Pharm Sci 1973; 62: 20352037. 
7 Russell AD, Furr JR. Comparitive sensitivity of smooth, rough and 
deep rough strains of Escherichia coli to chlorhexidine, quaternary 
ammonium compounds and dibromopropamidine isethionate. Int 
J Pharm 1987; 36: 191197. 
8 Shaker LA, Russell AD, Furr JR. Aspects of the action of 
chlorhexidine on bacterial spores. Int J Pharm 1986; 34: 5156. 
9 Heard DD, Ashworth RW. The colloidal properties of chlorhexidine 
and its interaction with some macromolecules. J Pharm 
Pharmacol 1968; 20: 505512. 
10 Jaminet F, Delattre L, Delporte JP, Moes A. Influence of 
sterilization temperature and pH on the stability of chlorhexidine 
solutions [in French]. Pharm Acta Helv 1970; 45: 6063. 
11 Goodall RR, Goldman J, Woods J. Stability of chlorhexidine in 
solutions. Pharm J 1968; 200: 3334. 
12 Dolby J, Gunnarsson B, Kronberg L, Wikner H. Stability of 
chlorhexidine when autoclaving. Pharm Acta Helv 1972; 47: 615 
620. 
13 Myers JA. Hospital infections caused by contaminated fluids 
[letter]. Lancet 1972; ii: 282. 
14 Oelschla. ger H, Canenbley R. Clear indication of chlorhexidine 
dihydrochloride precipitate in isotonic eye-drops: report based on 
experience on the use of chlorhexidine as a preservative. Pharm 
Ztg 1983; 128: 11661168. 
15 Yousef RT, El-Nakeeb MA, Salama S. Effect of some pharmaceutical 
materials on the bactericidal activities of preservatives. Can J 
Pharm Sci 1973; 8: 5456. 
16 McCarthy TJ, Myburgh JA. The effect of tragacanth gel on 
preservative activity. Pharm Weekbl 1974; 109: 265268. 
17 Plaut BS, Davies DJG, Meakin BJ, Richardson NE. The mechanism 
of interaction between chlorhexidine digluconate and poly(2- 
hydroxyethyl methacrylate). J Pharm Pharmacol 1981; 33: 8288. 
18 Stevens LE, Durrwachter JR, Helton DO. Analysis of chlorhexidine 
sorption in soft contact lenses by catalytic oxidation of 
[14C]chlorhexidine and by liquid chromatography. J Pharm Sci 
1986; 75: 8386. 
19 Rose FL, Swain G. Bisguanides having antibacterial activity. J 
Chem Soc 1956; 44224425. 
20 Massano G, Ciocatto E, Rosabianca C, et al. Striking aminotransferase 
rise after chlorhexidine self-poisoning [letter]. Lancet 
1982; i: 289. 
21 Emerson D, Pierce C. A case of a single ingestion of 4% Hibiclens. 
Vet Hum Toxicol 1988; 30: 583. 
22 Quinn MW, Bini RM. Bradycardia associated with chlorhexidine 
spray [letter]. Arch Dis Child 1989; 64: 892893. 
23 Alder VG, Burman D, Simpson RA, et al. Comparison of 
hexachlorophane and chlorhexidine powders in prevention of 
neonatal infection. Arch Dis Child 1980; 55: 277280. 
24 Lockhart AS, Harle CC. Anaphylactic reactions due to chlorhexidine 
allergy [letter]. Br J Anaesth 2001; 87(6): 940941. 
25 Wahlberg JE,Wennersten G. Hypersensitivity and photosensitivity 
to chlorhexidine. Dermatologica 1971; 143: 376379. 
26 Okano M, Nomura M, Hata S, et al. Anaphylactic symptoms due 
to chlorhexidine gluconate. Arch Dermatol 1989; 125: 5052. 
27 Evans RJ. Acute anaphylaxis due to topical chlorhexidine acetate. 
Br Med J 1992; 304: 686. 
28 Chisholm DG, Calder I, Peterson D, Powell M. Intranasal 
chlorhexidine resulting in an anaphylactic circulatory arrest. Br 
Med J 1997; 315: 785. 
29 Tabor E, Bostwick DC, Evans CC. Corneal damage due to eye 
contact with chlorhexidine gluconate [letter]. J Am Med Assoc 
1989; 261: 557558. 
30 Honigman JL. Disinfectant ototoxicity [letter]. Pharm J 1975; 215: 
523. 
31 Addy M, Moran J, Griffiths AA, Wills-Wood NJ. Extrinsic tooth 
discoloration by metals and chlorhexidine I: surface protein 
denaturation or dietary precipitation? Br Dent J 1985; 159: 
281285. 
32 Addy M, Moran J. Extrinsic tooth discoloration by metals and 
chlorhexidine II: clinical staining produced by chlorhexidine, iron 
and tea. Br Dent J 1985; 159: 331334. 
33 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 471. 
20 General References 
Davies GE, Francis J, Martin AR, et al. 1,6-Di-40-chlorophenyldiguanidohexane 
(Hibitane): laboratory investigation of a new antibacterial 
agent of high potency. Br J Pharmacol Chemother 1954; 9: 
192196. 
McCarthy TJ. The influence of insoluble powders on preservatives in 
solution. J Mond Pharm 1969; 12: 321328. 
Senior N. Some observations on the formulation and properties of 
chlorhexidine. J Soc Cosmet Chem 1973; 24: 259278. 
21 Authors 
SC Owen. 
22 Date of Revision 
25 August 2005. 
Chlorhexidine 167

Chlorobutanol 
1 Nonproprietary Names 
BP: Chlorobutanol 
JP: Chlorobutanol 
PhEur: Chlorobutanolum anhydricum 
USPNF: Chlorobutanol 
2 Synonyms 
Acetone chloroform; chlorbutanol; chlorbutol; trichloro-tertbutanol; 
b,b,b-trichloro-tert-butyl alcohol. 
3 Chemical Name and CAS Registry Number 
1,1,1-Trichloro-2-methyl-2-propanol [57-15-8] 
4 Empirical Formula and Molecular Weight 
C4H7Cl3O 177.46 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chlorobutanol is primarily used in ophthalmic or parenteral 
dosage forms as an antimicrobial preservative at concentrations 
up to 0.5% w/v; see Section 10. It is commonly used as an 
antibacterial agent for epinephrine solutions, posterior pituitary 
extract solutions, and ophthalmic preparations intended 
for the treatment of miosis. It is especially useful as an 
antibacterial agent in nonaqueous formulations. Chlorobutanol 
is also used as a preservative in cosmetics (see Section 16); 
as a plasticizer for cellulose esters and ethers; and has been used 
therapeutically as a mild sedative and local analgesic. 
8 Description 
Volatile, colorless or white crystals with a musty, camphoraceous 
odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for chlorobutanol. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters . .  
Melting point 5768C .  
Anhydrous  958C  
Hemihydrate  788C  
Acidity . . . 
Water (anhydrous form) 46.0% 41.0% 41.0% 
Hemihydrate  4.55.5% 46.0% 
Chloride 40.071% . 40.07% 
Anhydrous  4300 ppm  
Hemihydrate  4100 ppm  
Residue on ignition 40.10%   
Sulfated ash  40.1%  
Organic volatile 
impurities 
  . 
Assay (anhydrous 
basis) 
598.0% 98.0101.0% 98.0100.5% 
Note: the JP 2001 and USPNF 23 allow either the anhydrous form or the hemihydrate; the PhEur 
2005 includes them as separate monographs. 
10 Typical Properties 
Antimicrobial activity: chlorobutanol has both antibacterial 
and antifungal properties. It is effective against Grampositive 
and Gram-negative bacteria and some fungi, e.g., 
Candida albicans, Pseudomonas aeruginosa, and Staphylococcus 
albus. Antimicrobial activity is bacteriostatic, rather 
than bactericidal, and is considerably reduced above pH 5.5. 
In addition, activity may also be reduced by increasing heat 
and by incompatibilities between chlorobutanol and other 
excipients or packaging materials; see Sections 11 and 12. 
However, activity may be increased by combination with 
other antimicrobial preservatives; see Section 18. Typical 
minimum inhibitory concentrations (MICs) are: Grampositive 
bacteria 650 mg/mL; Gram-negative bacteria 
1000 mg/mL; yeasts 2500 mg/mL; fungi 5000 mg/mL. 
Boiling point: 1678C 
Melting point: 
76788C for the hemihydrate; 
95978C for the anhydrous form. 
Refractive index: nD
25 = 1.4339 
Solubility: see Table II. 
Table II: Solubility of chlorobutanol. 
Solvent Solubility at 208C 
Chloroform Freely soluble 
Ethanol (95%) 1 in 1 
Ether Freely soluble 
Glycerin 1 in 10 
Methanol Freely soluble 
Volatile oils Freely soluble 
Water 1 in 125

11 Stability and Storage Conditions 
Chlorobutanol is volatile and readily sublimes. In aqueous 
solution degradation is catalyzed by hydroxide ions. Stability is 
good at pH 3 but becomes progressively worse with increasing 
pH.(1) The half-life at pH 7.5 for a chlorobutanol solution 
stored at 258C was determined to be approximately 3 
months.(2) In a 0.5% w/v aqueous chlorobutanol solution at 
room temperature, chlorobutanol is almost saturated and may 
crystallize out of solution if the temperature is reduced. 
Losses of chlorobutanol also occur owing to its volatility, 
with appreciable amounts being lost during autoclaving; at pH 
5 about 30% of chlorobutanol is lost.(3) Porous containers 
result in losses from solutions, and polyethylene containers 
result in rapid loss. Losses of chlorobutanol during autoclaving 
in polyethylene containers may be reduced by pre-autoclaving 
the containers in a solution of chlorobutanol; the containers 
should then be used immediately.(4) There is also appreciable 
loss of chlorobutanol through stoppers in parenteral vials. 
The bulk material should be stored in a well-closed 
container at a temperature of 8158C. 
12 Incompatibilities 
Owing to problems associated with sorption, chlorobutanol is 
incompatible with plastic vials,(48) rubber stoppers, bentonite,(
9) magnesium trisilicate,(9) polyethylene, and polyhydroxyethylmethacrylate, 
which has been used in soft contact 
lenses.(10) To a lesser extent, carboxymethylcellulose and 
polysorbate 80 reduce antimicrobial activity by sorption or 
complex formation. 
13 Method of Manufacture 
Chlorobutanol is prepared by condensing acetone and chloroform 
in the presence of solid potassium hydroxide. 
14 Safety 
Chlorobutanol is widely used as a preservative in a number of 
pharmaceutical formulations, particularly ophthalmic preparations. 
Although animal studies have suggested that chlorobutanol 
may be harmful to the eye, in practice the widespread use 
of chlorobutanol as a preservative in ophthalmic preparations 
has been associated with few reports of adverse reactions. A 
study of the irritation potential of a local anesthetic on the 
murine cornea indicated significant corneal surface damage in 
the presence of 0.5% w/v chlorobutanol, which may be related 
to the preservatives effective concentration.(11) Reported 
adverse reactions to chlorobutanol include: cardiovascular 
effects following intravenous administration of heparin sodium 
injection preserved with chlorobutanol;(12) neurological effects 
following administration of a large dose of morphine infusion 
preserved with chlorobutanol;(13) and hypersensitivity reactions, 
although these are regarded as rare.(1416) 
The lethal human dose of chlorobutanol is estimated to be 
50500 mg/kg.(17) 
LD50 (dog, oral): 0.24 g/kg(18,19) 
LD50 (mouse, oral): 0.99 g/kg 
LD50 (rabbit, oral): 0.21 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Chlorobutanol may be 
irritant to the skin, eyes, and mucous membranes. Eye 
protection and gloves are recommended along with a respirator 
in poorly ventilated environments. There is a slight fire hazard 
on exposure to heat or flame. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM, IV, and SC 
injections, inhalations, nasal, otic, ophthalmic, and topical 
preparations). Labeling must state contains chlorobutanol up 
to 0.5%. Included in nonparenteral and parenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
In the UK, the maximum concentration of chlorobutanol 
permitted for use in cosmetics, other than foams, is 0.5%. It is 
not suitable for use in aerosols. 
17 Related Substances 
Phenoxyethanol; phenylethyl alcohol. 
18 Comments 
It has been reported that a combination of chlorobutanol and 
phenylethanol, both at 0.5% w/v concentration, has shown 
greater antibacterial activity than either compound alone. An 
advantage of the use of this combination is that chlorobutanol 
dissolves in the alcohol; the resulting liquid can then be 
dissolved in an aqueous pharmaceutical preparation without 
the application of heat. 
The EINECS number for chlorobutanol is 200-317-6. 
19 Specific References 
1 Patwa NV, Huyck CL. Stability of chlorobutanol. J Am Pharm 
Assoc 1966; NS6: 372373. 
2 Nair AD, Lach JL. The kinetics of degradation of chlorobutanol. J 
Am Pharm Assoc (Sci) 1959; 48: 390395. 
3 Lang JC, Roehrs RE, Rodeheaver DP, et al. Design and evaluation 
of ophthalmic pharmaceutical products. In: Banker GS, Rhodes 
CT, eds. Modern Pharmaceutics, 4th edn. New York: Marcel 
Dekker, 2002: 415478. 
4 Blackburn HD, Polack AE, Roberts MS. The effect of container 
pre-treatment on the interaction between chlorbutol and polyethylene 
during autoclaving. Aust J Hosp Pharm 1983; 13: 153 
156. 
5 Lachman L,Weinstein S, Hopkins G, et al. Stability of antibacterial 
preservatives in parenteral solutions I: factors influencing the loss 
of antimicrobial agents from solutions in rubber-stoppered 
containers. J Pharm Sci 1962; 51: 224232. 
6 Friesen WT, Plein EM. The antibacterial stability of chlorobutanol 
stored in polyethylene bottles. Am J Hosp Pharm 1971; 28: 507 
512. 
7 Blackburn HD, Polack AE, Roberts MS. Preservation of ophthalmic 
solutions: some observations on the use of chlorbutol in plastic 
containers [letter]. J Pharm Pharmacol 1978; 30: 666. 
8 Holdsworth DG, Roberts MS, Polack AE. Fate of chlorbutol 
during storage in polyethylene dropper containers and simulated 
patient use. J Clin Hosp Pharm 1984; 9: 2939. 
9 Yousef RT, El-Nakeeb MA, Salama S. Effect of some pharmaceutical 
materials on the bactericidal activities of preservatives. Can J 
Pharm Sci 1973; 8: 5456. 
10 Richardson NE, Davies DJG, Meakin BJ, Norton DA. The 
interaction of preservatives with polyhydroxyethylmethacrylate 
(polyHEMA). J Pharm Pharmacol 1978; 30: 469475. 
11 Kalin P, Mayer JM, Etter JC. Influence of preservatives on the 
irritation potential of a local anaesthetic on murine cornea. Eur J 
Pharm Biopharm 1996; 42: 402. 
Chlorobutanol 169

12 Bowler GMR, Galloway DW, Meiklejohn BH, Macintyre CCA. 
Sharp fall in blood pressure after injection of heparin containing 
chlorbutol [letter]. Lancet 1986; i: 848849. 
13 DeChristoforo R, Corden BJ, Hood JC, et al. High-dose morphine 
infusion complicated by chlorobutanol-induced somnolence. Ann 
Intern Med 1983; 98: 335336. 
14 Dux S, Pitlik S, Perry G, Rosenfeld JB. Hypersensitivity reaction to 
chlorobutanol-preserved heparin [letter]. Lancet 1981; i: 149. 
15 Itabashi A, Katayama S, Yamaji T. Hypersensitivity to chlorobutanol 
in DDAVP solution [letter]. Lancet 1982; i: 108. 
16 Hofmann H, Goerz G, Plewig G. Anaphylactic shock from 
chlorobutanol-preserved oxytocin. Contact Dermatitis 1986; 15: 
241. 
17 Gosselin RE, Hodge HC, Smith RP, Gleason MN. Clinical 
Toxicology of Commercial Products, 4th edn. Baltimore: Williams 
& Wilkins, 1976: II-119. 
18 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 3838. 
19 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 784. 
20 General References 
Summers QA, Nesbit MR, Levin R, Holgate ST. A non-bronchoconstrictor, 
bacteriostatic preservative for nebuliser solutions. Br J Clin 
Pharmacol 1991; 31: 204206. 
21 Authors 
RA Nash. 
22 Date of Revision 
22 August 2005. 
170 Chlorobutanol

Chlorocresol 
1 Nonproprietary Names 
BP: Chlorocresol 
PhEur: Chlorocresolum 
USPNF: Chlorocresol 
2 Synonyms 
Aptal; Baktol; 4-chloro-m-cresol; p-chloro-m-cresol; 1-chloro- 
4-hydroxy-2-methylbenzene; 2-chloro-5-hydroxytoluene; 6- 
chloro-3-hydroxytoluene; 4-chloro-3-methylphenol; 3-methyl- 
4-chlorophenol; Nipacide PC; parachlorometacresol; PCMC. 
3 Chemical Name and CAS Registry Number 
4-Chloro-3-methylphenol [59-50-7] 
4 Empirical Formula and Molecular Weight 
C7H7ClO 142.58 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chlorocresol is used as an antimicrobial preservative in 
cosmetics and pharmaceutical formulations. It is generally 
used in concentrations up to 0.2% in a variety of preparations 
except those intended for oral administration or that contact 
mucous membrane. Chlorocresol is effective against bacteria, 
spores, molds, and yeasts; it is most active in acidic media. 
Preservative efficacy may be reduced in the presence of some 
other excipients, particularly nonionic surfactants, see Sections 
10 and 12. 
In higher concentrations, chlorocresol is an effective 
disinfectant. See Table I. 
Table I: Uses of chlorocresol. 
Use Concentration (%) 
Eye drops 0.05 
Injections 0.1 
Shampoos and other cosmetics 0.10.2 
Topical creams and emulsions 0.0750.12 
8 Description 
Colorless or almost colorless, dimorphous crystals or crystalline 
powder with a characteristic phenolic odor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for chlorocresol. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Appearance of solution . . 
Melting range 64678C 63668C 
Nonvolatile matter 40.1% 40.1% 
Acidity or alkalinity .  
Related substances .  
Assay 98.0101.0% 99.0101.0% 
10 Typical Properties 
Antimicrobial activity: chlorocresol has bactericidal activity 
against both Gram-positive and Gram-negative organisms 
(including Pseudomonas aeruginosa), spores, molds, and 
yeasts. It is most active in acidic solutions, with antimicrobial 
effectiveness decreasing with increasing pH; it is inactive 
above pH 9. Antimicrobial activity may also be reduced by 
loss of chlorocresol from a formulation due to incompatibilities 
with packaging materials or other excipients, such as 
nonionic surfactants, see Section 12. Synergistic antimicrobial 
effects between chlorocresol and other antimicrobial preservatives, 
such as 2-phenylethanol, have been reported.(1,2) 
Reported minimum inhibitory concentrations (MICs) for 
chlorocresol are shown in Table III.(3) Like most antimicrobials, 
chlorocresol has a non-linear dose response.(4,5) 
Bacteria: concentrations of approximately 0.08%, with a 
contact time of 10 minutes, are bactericidal. A typical MIC 
is 0.02%. 
Fungi: chlorocresol is active against molds and yeasts. 
Fungicidal concentrations (after 24 hours of contact) are in 
the range 0.010.04%.

Table III: Minimum inhibitory concentrations (MICs) for 
chlorocresol.(3) 
Microorganism MIC (mg/mL) 
Aspergillus niger 2500 
Candida albicans 2500 
Escherichia coli 1250 
Klebsiella pneumoniae 625 
Pseudomonas aeruginosa 1250 
Pseudomonas fluorescens 1250 
Staphylococcus aureus 625 
Spores: at temperatures of 808C or above and in concentrations 
greater than 0.012%, chlorocresol is active against 
spores. It is much less active at room temperature. Heating 
at 981008C for 30 minutes in the presence of 0.2% 
chlorocresol has previously been used as a compendial 
method for the sterilization of solutions of substances that 
would not withstand autoclaving. 
Boiling point: 2358C 
Dissociation constant: pKa = 9.2 
Flash point: 1188C 
Melting point: dimorphous crystals with a melting point of 
55.58C and 658C. 
Partition coefficients: at 258C 
Liquid paraffin : water = 1.53; 
Octanol : water = 3; 
Peanut oil : water = 117. 
Solubility: see Table IV. 
Table IV: Solubility of chlorocresol. 
Solvent Solubility at 208C unless otherwise stated 
Acetone Soluble 
Alkali hydroxide solutions Soluble 
Chloroform Soluble 
Ethanol 1 in 0.4 
Ether Soluble 
Fixed oils Soluble 
Glycerin Soluble 
Terpenes Soluble 
Water 1 in 260(a) 
1 in 50 at 1008C(a) 
(a) Aqueous solubility is decreased in the presence of electrolytes, particularly sodium chloride, 
potassium chloride, and potassium sulfonate.(6) 
Vapor pressure: 0.008 kPa at 208C; 
0.67 kPa at 1008C. 
11 Stability and Storage Conditions 
Chlorocresol is stable at room temperature but is volatile in 
steam. Aqueous solutions may be sterilized by autoclaving. On 
exposure to air and light, aqueous solutions may become 
yellow colored. Solutions in oil or glycerin may be sterilized by 
heating at 1608C for 1 hour. The bulk material should be stored 
in a well-closed container, protected from light, in a cool, dry 
place. 
12 Incompatibilities 
Chlorocresol can decompose on contact with strong alkalis, 
evolving heat and fumes that ignite explosively. It is also 
incompatible with oxidizing agents, copper, and with solutions 
of calcium chloride, codeine phosphate, diamorphine hydrochloride, 
papaveretum, and quinine hydrochloride.(7) Discoloration 
also occurs with iron salts. Chlorocresol additionally 
exhibits strong sorption or binding tendencies to organic 
materials such as rubber, certain plastics, and nonionic 
surfactants.(811) 
Chlorocresol may be lost from solutions to rubber closures, 
and in contact with polyethylene may initially be rapidly 
removed by sorption and then by permeation, the uptake being 
temperature dependent. Presoaking of components may reduce 
losses due to sorption, but not those by permeation.(12,13) 
Chlorocresol may also be taken up by polymethylmethacrylate 
and by cellulose acetate. Losses to polypropylene or rigid 
polyvinyl chloride are usually small.(14) 
At a concentration of 0.1%, chlorocresol may be completely 
inactivated in the presence of nonionic surfactants, such as 
polysorbate 80.(9) However, other studies have suggested an 
enhancement of antimicrobial properties in the presence of 
surfactants.(15)(16) Bactericidal activity is also reduced, due to 
binding, by cetomacrogol, methylcellulose, pectin, or cellulose 
derivatives.(9,11) In emulsified or solubilized systems, chlorocresol 
readily partitions into the oil phase, particularly into 
vegetable oils and higher concentrations will be required for 
efficient preservation.(10,17) 
13 Method of Manufacture 
Chlorocresol is prepared by the chlorination of m-cresol. 
14 Safety 
Chlorocresol is used primarily as a preservative in topical 
pharmaceutical formulations but has also been used in 
nebulized solutions(18) and ophthalmic and parenteral preparations. 
It should not, however, be used in formulations for 
intrathecal, intracisternal, or peridural injection. 
Chlorocresol is metabolized by conjugation with glucuronic 
acid and sulfate and is excreted in the urine, mainly as the 
conjugate, with little chlorocresol being excreted unchanged. 
Although less toxic than phenol, chlorocresol may be 
irritant to the skin, eyes, and mucous membranes and has 
been reported to cause some adverse reactions when used as an 
excipient.(19,20) 
Sensitization reactions may follow the prolonged application 
of strong solutions to the skin, although patch tests have 
shown that chlorocresol is not a primary irritant at concentrations 
up to 0.2%. Cross sensitization with the related 
preservative chloroxylenol has also been reported.(21)(22) At 
concentrations of 0.005% w/v, chlorocresol has been shown to 
produce a reversible reduction in the ciliary movement of 
human nasal epithelial cells in vitro; and at concentrations of 
0.1% chlorocresol produces irreversible ciliostasis; therefore it 
should be used with caution in nasal preparations.(23) However, 
a clinical study in asthma patients challenged with chlorocresol 
or saline concluded that preservative might be used safely in 
nebulizer solution.(18) 
Chlorocresol at a concentration as low as 0.05% produces 
ocular irritation in rabbits.(20) Despite such reports, chlorocresol 
has been tested in ophthalmic preparations.(24,25) 
When used systemically, notably in a heparin injection 
preserved with chlorocresol 0.15%, delayed irritant and 
hypersensitivity reactions attributed to chlorocresol have been 
reported.(26,27) See also Section 19. 
LD50 (mouse, IV): 0.07 g/kg(28) 
LD50 (mouse, oral): 0.6 g/kg 
172 Chlorocresol

LD50 (mouse, SC): 0.36 g/kg 
LD50 (rabbit, dermal): >5 g/kg 
LD50 (rat, dermal): >2 g/kg 
LD50 (rat, oral): 1.83 g/kg 
LD50 (rat, SC): 0.4 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Chlorocresol can be irritant 
to the skin, eyes, and mucous membranes. Eye protection, 
gloves, and protective clothing are recommended. Chlorocresol 
presents a slight fire hazard when exposed to heat or flame. It 
burns to produce highly toxic fumes containing phosgene and 
hydrogen chloride. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical creams 
and emulsions). Included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Cresol; chloroxylenol. 
18 Comments 
Chlorocresol has a characteristic odor which is difficult to mask 
in formulations, even at concentrations of 0.050.1%. 
Although used in Europe, chlorocresol is not used in the 
USA in parenteral formulations. Chlorocresol has also been 
used as an experimental in vitro diagnostic agent for the 
diagnosis of hyperthermia.(29) 
The EINECS number for chlorocresol is 200-431-6. 
19 Specific References 
1 Denyer SP, Hugo WB, Harding VD. The biochemical basis of 
synergy between the antibacterial agents, chlorocresol and 2- 
phenylethanol. Int J Pharm 1986; 29: 2936. 
2 Abdelaziz AA, El-Nakeeb MA. Sporicidal activity of local 
anaesthetics and their binary combinations with preservatives. J 
Clin Pharm Ther 1988; 13: 249256. 
3 Wallha. usser KH. p-Chloro-m-cresol. In: Kabara JJ, ed. Cosmetic 
and Drug Preservation Principles and Practice. New York: Marcel 
Dekker, 1984: 683684. 
4 Lambert RJW, Johnston MD, Hanlon GW, Denyer SP. Membrane 
damage to bacteria caused by single and combined biocides. J Appl 
Microbiol 2003; 94: 10151023. 
5 Lambert RJW, Johnston MD, Hanlon GW, Denyer SP. Theory of 
antimicrobial combinations: biocide mixturessynergy or additions? 
J Appl Microbiol 2003; 94: 747759. 
6 Gadalla MAF, Saleh AM, Motawi MM. Effect of electrolytes on 
the solubility and solubilization of chlorocresol. Pharmazie 1974; 
29: 105107. 
7 McEwan JS, Macmorran GH. The compatibility of some 
bactericides. Pharm J 1947; 158: 260262. 
8 Yousef RT, El-Nakeeb MA, Salama S. Effect of some pharmaceutical 
materials on the bactericidal activities of preservatives. Can J 
Pharm Sci 1973; 8: 5456. 
9 McCarthy TJ. Dissolution of chlorocresol from various pharmaceutical 
formulations. Pharm Weekbl 1975; 110: 101106. 
10 Kazmi SJA, Mitchell AG. Preservation of solubilized and 
emulsified systems I: correlation of mathematically predicted 
preservative availability with antimicrobial activity. J Pharm Sci 
1978; 67: 12601266. 
11 Kazmi SJA, Mitchell AG. Preservation of solubilized and 
emulsified systems II: theoretical development of capacity and its 
role in antimicrobial activity of chlorocresol in cetomacrogolstabilized 
systems. J Pharm Sci 1978; 67: 12661271. 
12 McCarthy TJ. Interaction between aqueous preservative solutions 
and their plastic containers III. Pharm Weekbl 1972; 107: 17. 
13 Roberts MS, Polack AE, Martin G, Blackburn HD. The storage of 
selected substances in aqueous solution in polyethylene containers: 
the effect of some physicochemical factors on the disappearance 
kinetics of the substances. Int J Pharm 1979; 2: 295306. 
14 McCarthy TJ. Interaction between aqueous preservative solutions 
and their plastic containers. Pharm Weekbl 1970; 105: 557563. 
15 Kurup TRR, Wan LSC, Chan LW. Preservative requirements in 
emulsions. Pharma Acta Helv 1992; 67: 204208. 
16 Kurup TRR, Wan LSC, Chan LW. Effect of surfactants on the 
antimicrobial activity of preservatives. Pharma Acta Helv 1991; 
66: 274280. 
17 Sznitowska M, Janicki S, Dabrowska EA, Gajewksa M. Physicochemical 
screening of antimicrobial agents as potential preservatives 
for submicron emulsions. Eur J Pharm Sci 2002; 15: 489 
495. 
18 Summers QA, Nesbit MR, Levin R, Holgate ST. A nonbronchoconstrictor, 
bacteriostatic preservative for nebuliser solutions. 
Br J Clin Pharmacol 1991; 31: 204206. 
19 Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992: 8790. 
20 Zondlo M. Final report on the safety assessment of p-chloro-mcresol. 
J Toxicol 1997; 16: 235268. 
21 Burry JN, Kirk J, Reid JG, Turner T. Chlorocresol sensitivity. 
Contact Dermatitis 1975; 1: 4142. 
22 Andersen KE, Hamann K. How sensitizing is chlorocresol? Allergy 
tests in guinea pigs vs. the clinical experience. Contact Dermatitis 
1984; 11: 1120. 
23 Agu RU, Jorissen M, Willems T, et al. Effects of pharmaceutical 
compounds on ciliary beating in human nasal epithelial cells: a 
comparative study of cell culture models. Pharm Res 1999; 16: 
13801385. 
24 Palanichamy S, Ramakrishnan PN, Balasubramanian S, et al. 
Preservation of sodium chloride eye lotion BPC against contamination 
with Pseudomonas aeruginosa. Indian Drugs 1982; 19: 
153155. 
25 Palanichamy S, Ramakrishnan PN, Murugesh N, et al. Preservation 
of compound zinc sulfate eye lotion BPC 1963 against 
contamination with Pseudomonas aeruginosa. Indian J Hosp 
Pharm 1982; 19: 6465. 
26 Hancock BW, Naysmith A. Hypersensitivity to chlorocresolpreserved 
heparin. Br Med J 1975; 3: 746747. 
27 Ainley EJ, Mackie IG, Macarthur D. Adverse reaction to 
chlorocresol-preserved heparin [letter]. Lancet 1977; i: 705. 
28 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 790. 
29 Wappler F, Anetseder M, Baur CP, et al. Multicenter evaluation of 
in vitro contracture testing with bolus administration of 4-chlorom-
cresol for diagnosis of malignant hyperthermia susceptibility. 
Eur J Anaesth 2003; 20: 528536. 
20 General References 
Denyer SP, Wallha. usser KH. Antimicrobial preservatives and their 
properties. In: Denyer SP, Baird R, eds. Guide to Microbiological 
Control in Pharmaceuticals. Chichester: Ellis Horwood, 1990: 251 
273. 
Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 171. 
21 Authors 
S Nema. 
22 Date of Revision 
27 August 2005. 
Chlorocresol 173

Chlorodifluoroethane (HCFC) 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
1,1-Difluoro-1-chloroethane; Dymel 142b; Genetron 142b; 
HCFC 142b; P-142b; propellant 142b; refrigerant 142b; 
Solkane 142b. 
3 Chemical Name and CAS Registry Number 
1-Chloro-1,1-difluoroethane [75-68-3] 
4 Empirical Formula and Molecular Weight 
C2H3ClF2 100.50 
5 Structural Formula 
6 Functional Category 
Aerosol propellant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chlorodifluoroethane is a hydrochlorofluorocarbon (HCFC) 
aerosol propellant previously used in topical pharmaceutical 
formulations. However, it is no longer permitted for use in 
pharmaceutical formulations because its harmful effects on the 
environment. It was also generally used in conjunction with 
difluoroethane to form a propellant blend with a specific 
gravity of 1. Chlorodifluoroethane was also used in combination 
with chlorodifluoromethane and hydrocarbon propellants. 
Chlorodifluoroethane may be used as a vehicle for dispersions 
and emulsions. 
8 Description 
Chlorodifluoroethane is a liquefied gas and exists as a liquid at 
room temperature when contained under its own vapor 
pressure, or as a gas when exposed to room temperature and 
atmospheric pressure. The liquid is practically odorless and 
colorless. Chlorodifluoroethane is noncorrosive and nonirritating. 
9 Pharmacopeial Specifications 
 
10 Typical Properties 
Autoignition temperature: 6328C 
Boiling point: 9.88C 
Critical temperature: 137.18C 
Density: 
1.11 g/cm3 for liquid at 258C; 
1.03 g/cm3 for liquid at 54.58C. 
Flammability: flammable. Limits of flammability 6.217.9% 
v/v in air. 
Melting point: 1318C 
Solubility: soluble 1 in 715 parts of water at 208C. 
Vapor density (absolute): 4.487 g/m3 at standard temperature 
and pressure. 
Vapor density (relative): 3.48 (air = 1) 
Vapor pressure: 
339 kPa (49.2 psia) at 258C (29.1 psig at 21.18C); 
772 kPa (112.0 psia) at 54.58C. 
Viscosity (dynamic): 0.33 mPa s (0.33 cP) for liquid at 218C. 
11 Stability and Storage Conditions 
Chlorodifluoroethane is a nonreactive and stable material. The 
liquefied gas is stable when used as a propellant and should be 
stored in a metal cylinder in a cool, dry place. 
12 Incompatibilities 
Compatible with the usual ingredients used in the formulation 
of pharmaceutical aerosols. Chlorodifluoroethane can react 
vigorously with oxidizing materials. 
13 Method of Manufacture 
Chlorodifluoroethane is prepared by the chlorination of 
difluoroethane in the presence of a suitable catalyst; hydrochloric 
acid is also formed. The chlorodifluoroethane is purified 
to remove all traces of water and hydrochloric acid, as well as 
traces of the starting and intermediate materials. 
14 Safety 
Chlorodifluoroethane is no longer permitted for use as an 
aerosol propellant in topical pharmaceutical formulations. It is 
generally regarded as an essentially nontoxic and nonirritant 
material. 
Deliberate inhalation of excessive quantities of chlorofluorocarbon 
propellant may result in death, and the following 
warning statements must appear on the label of all aerosols: 
WARNING: Avoid inhalation. Keep away from eyes or 
other mucous membranes. 
(Aerosols designed specifically for oral and nasal inhalation 
need not contain this statement.) 
WARNING: Do not inhale directly; deliberate inhalation of 
contents can cause death.

or 
WARNING: Use only as directed; intentional misuse by 
deliberately concentrating and inhaling the contents can be 
harmful or fatal. 
Additionally, the label should contain the following information: 
WARNING: Contents under pressure. Do not puncture or 
incinerate container. Do not expose to heat or store at room 
temperature above 1208F (498C). Keep out of the reach of 
children. 
In the USA, the Environmental Protection Agency (EPA) 
additionally requires the following information on all aerosols 
containing chlorofluorocarbons as the propellant: 
WARNING: Contains a chlorofluorocarbon that may harm 
the public health and environment by reducing ozone in the 
upper atmosphere. 
15 Handling Precautions 
Chlorodifluoroethane is usually encountered as a liquefied gas 
and appropriate precautions for handling such materials should 
be taken. Eye protection, gloves, and protective clothing are 
recommended. Chlorodifluoroethane should be handled in a 
well-ventilated environment. Chlorofluorocarbon vapors are 
heavier than air and do not support life; therefore, when 
cleaning large tanks that have contained chlorofluorocarbons, 
adequate provisions for oxygen supply in the tanks must be 
made in order to protect workers cleaning the tanks. 
Chlorodifluoroethane is flammable; see Section 10. When 
heated to decomposition, chlorodifluoroethane emits toxic 
fumes. 
16 Regulatory Status 

17 Related Substances 
Chlorodifluoromethane. 
Chlorodifluoromethane 
Empirical formula: CHClF2 
Molecular weight: 86.47 
CAS number: [75-45-6] 
Synonyms: Arcton 22; difluorochloromethane; Dyriel 22; 
Frigen 22; HCFC 22; Isceon 22; P-22; propellant 22; 
refrigerant 22. 
Boiling point: 40.88C 
Critical temperature: 968C 
Density: 1.19 g/cm3 for liquid at 258C. 
Melting point: 1468C 
Solubility: freely soluble in acetone, chloroform, and ether; 
soluble 1 in 330 parts of water at 258C. 
Vapor density (absolute): 3.860 g/cm3 at standard temperature 
and pressure. 
Vapor density (relative): 2.98 (air = 1) 
Vapor pressure: 
1041 kPa (151 psia) at 258C; 
2137 kPa (310 psia) at 54.58C. 
Handling precautions: the long-term exposure limit (8-hour 
TWA) for chlorodifluoromethane is 3590 mg/m3 
(1000 ppm).(1) 
Comments: chlorodifluoromethane is a hydrochlorofluorocarbon 
(HCFC) aerosol propellant used in topical pharmaceutical 
formulations. 
18 Comments 
For a discussion of the numerical nomenclature applied to this 
aerosol propellant, see Chlorofluorocarbons. 
19 Specific References 
1 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. Caldwell: WE 
Dorland, 1982: 305335. 
Johnson MA. Flammability aspects of dimethy ether, p22, p-142b, p- 
1152a. Aerosol Age 1988; 33(8): 32, 34, 36, 3839. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 1935. 
Sciarra JJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and 
Practice of Pharmacy, 19th edn. Easton, PA: Mack Publishing Co., 
1995: 16761692. 
Sciarra JJ. Aerosol suspensions and emulsions. In: Lieberman H, Rieger 
J, Banker G, eds. Pharmaceutical Dosage Forms: Disperse Systems, 
vol. 2, 2nd edn. New York: Marcel Dekker, 1996: 319356. 
Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. 
Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 
547574. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 137145. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005.
Chlorodifluoroethane (HCFC) 175

Chlorofluorocarbons (CFC) 
(a) Dichlorodifluoromethane (Propellant 12) 
(b) Dichlorotetrafluoroethane (Propellant 114) 
(c) Trichloromonofluoromethane (Propellant 11) 
1 Nonproprietary Names 
(a) USPNF: Dichlorodifluoromethane 
(b) USPNF: Dichlorotetrafluoroethane 
(c) USPNF: Trichloromonofluoromethane 
2 Synonyms 
Arcton; Dymel; Freon; Frigen; Genetron; Halon; Isceon; 
Isotron. 
Commonly also known as propellant-x or refrigerant-x 
(where x is 12, 114, or 11, for (a), (b), or (c), respectively). 
3 Chemical Name and CAS Registry Number 
(a) Dichlorodifluoromethane [75-71-8] 
(b) 1,2-Dichloro-1,1,2,2-tetrafluoroethane [76-14-2] 
(c) Trichlorofluoromethane [75-69-4] 
4 Empirical Formula and Molecular Weight 
(a) CCl2F2 120.91 
(b) C2Cl2F4 170.92 
(c) CCl3F 137.37 
5 Structural Formula 
6 Functional Category 
Aerosol propellants. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane 
are chlorofluorocarbon (CFC) 
aerosol propellants used in pharmaceutical formulations. 
Dichlorodifluoromethane is used as an aerosol propellant in 
metered-dose inhaler (MDI) formulations, either as the sole 
propellant or in combination with dichlorotetrafluoroethane, 
trichloromonofluoromethane, or mixtures of these chlorofluorocarbons. 
Dichlorodifluoromethane may also be used as 
a propellant in an aerosolized sterile talc used for intrapleural 
administration and is also used alone in some MDIs containing 
a steroid. 
Dichlorotetrafluoroethane is used in combination with 
dichlorodifluoromethane, and in several cases with dichlorodifluoromethane 
and trichloromonofluoromethane, as the 
propellant in metered-dose oral and nasal aerosols. 
Trichloromonofluoromethane is used in combination with 
dichlorodifluoromethane as the propellant in metered-dose 
inhaler aerosols. It is also used in combination with dichlorotetrafluoroethane 
and dichlorodifluoromethane. 
These three propellants may be blended to obtain suitable 
solubility characteristics for MDIs when formulated as solutions. 
They will produce suitable vapor pressures so that 
optimum particle-size distribution as well as suitable respiratory 
fractions may be achieved. 
Blends of trichloromonofluoromethane and dichlorodifluoromethane 
(propellant 11/12) or propellant 11/114/12 
produce vapor pressures of 103484 kPa (1570 psig) at 218C, 
which adequately cover the range of pressures required to 
produce the proper particle-size distribution for satisfactory 
aerosol products. Trichloromonofluoromethane is unique 
among the chlorofluorocarbon propellants in that it is a liquid 
at room temperature and atmospheric pressure and can be used 
to prepare a slurry with insoluble medicinal agents. 
8 Description 
Dichlorodifluoromethane is a liquefied gas and exists as a 
liquid at room temperature when contained under its own 
vapor pressure, or as a gas when exposed to room temperature 
and atmospheric pressure. The liquid is practically odorless and 
colorless. The gas in high concentrations has a faint etherlike 
odor. Dichlorodifluoromethane is noncorrosive, nonirritating, 
and nonflammable. 
Dichlorotetrafluoroethane is a colorless, nonflammable 
liquefied gas with a faint, ethereal odor. 
Trichloromonofluoromethane is a clear, volatile liquid at 
room temperature and atmospheric pressure. It has a characteristic 
carbon tetrachloride-like odor and is nonirritating 
and nonflammable. 
9 Pharmacopeial Specifications 
See Table I.

Table I: Pharmacopeial specifications from USPNF 23. 
Test Propellant 12 Propellant 114 Propellant 11 
Identification . . . 
Boiling temperature 308C 48C 248C 
Water 40.001% 40.001% 40.001% 
High-boiling 
residues 
40.01% 40.01% 40.01% 
Inorganic chlorides . . . 
Chromatographic 
purity 
. . . 
Assay 99.6100.0% 99.6100.0% 99.6100.0% 
10 Typical Properties 
See Table II for selected typical properties. 
11 Stability and Storage Conditions 
Chlorofluorocarbon propellants are nonreactive and stable at 
temperatures up to 5508C. The liquefied gas is stable when used 
as a propellant and should be stored in a metal cylinder in a 
cool, dry place. 
12 Incompatibilities 
The presence of greater than 5% water in solutions that contain 
trichloromonofluoromethane may lead to hydrolysis of the 
propellant and the formation of traces of hydrochloric acid, 
which may be irritant to the skin or cause corrosion of metallic 
canisters. Trichloromonofluoromethane may also react with 
aluminum, in the presence of ethanol, to cause corrosion within 
a cylinder with the formation of hydrogen gas. Similarly, 
alcohols in the presence of trace amounts of oxygen, peroxides, 
or other free-radical catalysts may react with trichloromonofluoromethane 
to form trace quantities of hydrochloric acid. 
Both dichlorodifluoromethane and dichlorotetrafluoroethane 
are compatible with most ingredients used in pharmaceutical 
aerosols. Because of their poor miscibility with water, 
most MDIs are formulated as suspensions. However, solution 
MDIs can be prepared through the use of ethanol as a cosolvent 
for water and propellant, resulting in a clear solution (provided 
the water content is less than 5%). 
13 Method of Manufacture 
Dichlorodifluoromethane is prepared by the reaction of 
hydrogen fluoride with carbon tetrachloride in the presence 
of a suitable catalyst, such as polyvalent antimony. The 
dichlorodifluoromethane formed is further purified to remove 
all traces of water and hydrochloric acid as well as traces of the 
starting and intermediate materials. 
Trichloromonofluoromethane is also obtained by this 
process. 
Dichlorotetrafluoroethane is prepared by the reaction of 
hydrogen fluoride with chlorine and perchloroethylene in the 
presence of a suitable catalyst such as polyvalent antimony. 
14 Safety 
Dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane 
have been used for over 40 years as 
propellants in topical, oral, and nasal aerosol formulations and 
are generally regarded as nontoxic and nonirritant materials 
when used as directed. 
The propellants used for metered-dose inhalant aerosol 
products generally vaporize quickly and most of the vapors 
escape and are not inhaled. However, a small amount of the 
propellant may be inhaled with the active ingredient and be 
carried to the respiratory system. These amounts of propellant 
Table II: Selected typical properties for chlorofluorocarbon propellants. 
Test Propellant 12 Propellant 114 Propellant 11 
Boiling point 29.88C 4.18C 23.78C 
Critical pressure 4.01MPa (39.6 atm) 3268 kPa (474 psia) 4.38MPa (43.2 atm) 
Critical temperature 111.58C 145.78C 1988C 
Density 
Liquid at 218C 1.325 g/cm3 1.468 g/cm3 1.485 g/cm3 
Liquid at 54.58C 1.191 g/cm3 1.360 g/cm3 1.403 g/cm3 
Flammability Nonflammable Nonflammable Nonflammable 
Freezing point 1588C 948C 1118C 
Kauri-butanol value 18 12 60 
Solubility at 208C (unless otherwise stated) 
Ethanol (95%) Soluble Soluble Soluble 
Ether Soluble Soluble Soluble 
Water 1 in 3570 at 258C 1 in 7690 at 258C 1 in 909 at 258C 
Surface tension at 258C 9mN/m (9 dynes/cm) 13mN/m (13 dynes/cm) 19mN/m (19 dynes/cm) 
Vapor density 
Absolute 5.398 g/m3 7.63 g/m3 6.133 g/m3 
Relative 4.19 (air = 1) 5.92 (air = 1) 5.04 (air = 1) 
Vapor pressure 
At 218C 585.4 kPa (84.9 psia) 190.3 kPa (27.6 psia) 92.4 kPa (13.4 psia) 
At 54.58C 1351.4 kPa (196.0 psia) 506.8 kPa (73.5 psia) 268.9 kPa (39.0 psia) 
Viscosity (dynamic) 
Liquid at 218C 0.262 mPa s (0.262 cP) 0.386 mPa s (0.386 cP) 0.439 mPa s (0.439 cP) 
Liquid at 54.58C 0.227 mPa s (0.227 cP) 0.296 mPa s (0.296 cP) 0.336 mPa s (0.336 cP) 
Chlorofluorocarbons (CFC) 177

do not present a toxicological problem and are quickly cleared 
from the lungs. Deliberate inhalation of excessive quantities of 
fluorocarbon propellant may result in death, and the following 
warning statements must appear on the label of all aerosols: 
WARNING: Avoid inhalation. Keep away from eyes or 
other mucous membranes. 
(Aerosols designed specifically for oral inhalation need not 
contain this statement). 
WARNING: Do not inhale directly; deliberate inhalation of 
contents can cause death. 
or 
WARNING: Use only as directed; intentional misuse by 
deliberately concentrating and inhaling the contents can be 
harmful or fatal. 
Additionally, the label should contain the following information: 
WARNING: Contents under pressure. Do not puncture or 
incinerate container. Do not expose to heat or store at room 
temperature above 1208F (498C). Keep out of the reach of 
children. 
In the USA, the Environmental Protection Agency (EPA) 
additionally requires the following information on all aerosols 
containing chlorofluorocarbons as the propellant: 
WARNING: Contains a chlorofluorocarbon that may harm 
the public health and environment by reducing ozone in the 
upper atmosphere. 
(Metered-dose inhalers are exempt from this regulation.) 
15 Handling Precautions 
Dichlorodifluoromethane and dichlorotetrafluoroethane are 
usually encountered as a liquefied gas and appropriate 
precautions for handling such materials should be taken. Eye 
protection, gloves, and protective clothing are recommended. 
These propellants should be handled in a well-ventilated 
environment. Chlorofluorocarbon vapors are heavier than air 
and do not support life; therefore, when cleaning large tanks 
that have contained chlorofluorocarbons, adequate provisions 
for supply of oxygen in the tanks must be made in order to 
protect workers cleaning the tanks. 
Although nonflammable, when heated to decomposition 
chlorofluorocarbons emit toxic fumes containing phosgene and 
fluorides. Although not as volatile as dichlorodifluoroethane 
or dichlorotetrafluoroethane, trichloromonofluoromethane 
should be handled as indicated above. Since it is a liquid at 
room temperature, caution should be exercised in handling this 
material to prevent spillage onto the skin. It is an irritant to the 
eyes. 
The long-term exposure limit (8-hour TWA) for dichlorodifluoromethane 
is 5030 mg/m3 (1000 ppm). The short-term 
exposure limit (15-minute) is 6280 mg/m3 (1250 ppm).(1) 
The long-term exposure limit (8-hour TWA) for dichlorotetrafluoroathane 
is 7110 mg/m3 (1000 ppm). The short-term 
exposure limit (15-minute) is 8890 mg/m3 (1250 ppm).(1) 
The long-term exposure limit (8-hour TWA) for trichlorofluoromethane 
is 5710 mg/m3 (1000 ppm). The short-term 
exposure limit (15-minute) is 7140 mg/m3 (1250 ppm).(1) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (aerosol 
formulations for inhalation, nasal, oral, and topical applications). 
Included in nonparenteral medicines licensed in the UK. 
17 Related Substances 

18 Comments 
Fluorocarbon (FC) aerosol propellants may be identified by a 
standardized numbering nomenclature; for example, dichlorodifluoromethane 
is known as propellant 12, while dichlorotetrafluoroethane 
is known as propellant 114. 
Usually, three digits are used to describe the propellant, 
except when the first digit would be zero, in which case only 
two digits are used. The first digit is one less than the number of 
carbon atoms in the molecule. Thus, if the molecule is a 
methane derivative the first digit would be zero (1  1) and is 
ignored, so that only two digits are used in the propellant 
description; e.g. propellant 12. For an ethane derivative, the 
first digit would be a one (2  1); e.g. propellant 114. 
The second digit is one more than the number of hydrogen 
atoms in the molecule, while the third digit represents the 
number of fluorine atoms in the molecule. The difference 
between the sum of the fluorine and hydrogen atoms and the 
number of atoms required to saturate the carbon chain is the 
number of chlorine atoms in the molecule. Isomers of a 
compound have the same identifying number and an additional 
letter; a, b, c, and so on. Cyclic derivatives are indicated by the 
letter C before the identifying number. With unsaturated 
propellants, the number 1 is used as the fourth digit from the 
right to indicate an unsaturated double bond. 
Thus for dichlorodifluoromethane (propellant 12): 
First digit = 0 signifies number of C atoms = 1 
Second digit = 1 signifies number of H atoms = 0 
Third digit = 2 signifies number of F atoms = 2 
Number of Cl atoms = 4  (2  0) = 2 
Under the terms of the Montreal Protocol, aimed at reducing 
damage to the ozone layer, the use of chlorofluorocarbons, 
including dichlorodifluoromethane, dichlorotetrafluoroethane, 
and trichloromonofluoromethane, has been prohibited from 
January 1996.(26) However, this prohibition does not apply to 
essential uses such as existing pharmaceutical formulations for 
which no alternative chlorofluorocarbon-free product is available. 
New pharmaceutical formulations containing chlorofluorocarbons 
may also be exempted provided they 
demonstrate that there is no technically feasible alternative to 
their use, that the product is of a substantial health benefit, and 
that its use would not involve release of significant quantities of 
chlorofluorocarbon into the atmosphere. The EPA and FDA 
approved essential-use status for dichlorodifluoromethane for a 
sterile aerosol talc used in the treatment of malignant pleural 
effusion in patients with lung cancer. Regulatory bodies in 
individual countries should be consulted for advice on 
chlorofluorocarbon use in MDI formulations. 
Essential-use allowances are allocated in the USA by the 
Environmental Protection Agency following approval of the 
Parties to the Montreal Protocol on Substances that Deplete 
178 Chlorofluorocarbons (CFC)

the Ozone Layer. These allocations are made for a specified 
essential use and cannot be used for other essential uses, traded, 
or sold. This allows for the continued sale of existing exempted 
MDIs and other products designated as an essential use. These 
allocations are granted on an annual basis. Both the EPA and 
the FDA have proposed rules for the eventual elimination of 
CFC-containing MDIs. The development of CFC-free MDIs 
has been slow and time-consuming. Albuterol-containing CFCfree 
MDIs are available in the USA, the UK, and Germany, as 
well as most other countries of the world. A CFC-free MDI 
containing beclomethasone dipropionate has also been 
approved for sale in the UK and USA. In June 2004 the FDA 
proposed the near-term elimination of the essential use 
designation for albuterol MDI. The eventual elimination of 
the essential use exemption is required as part of the United 
States general obligations under the Montreal Protocol. 
Additionally, there is a more immediate requirement for an 
action plan that includes a specific end-date for essential use 
exemptions for CFCs for albuterol MDIs. A phase-out date has 
been proposed for 2010.(7) See Tetrafluoroethane and Heptafluoropropane 
for further details. 
19 Specific References 
1 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
2 Fischer FX, Hess H, Sucker H, Byron PR. CFC propellant 
substitution: international perspectives. Pharm Technol 1989; 
13(9): 44, 48, 50, 52. 
3 Kempner N. Metered dose inhaler CFCs under pressure. Pharm J 
1990; 245: 428429. 
4 Dalby RN. Possible replacements for CFC-propelled metered-dose 
inhalers. Med Device Technol 1991; 2(4): 2125. 
5 CFC-free aerosols; the final hurdle. Manuf Chem 1992; 63(7): 22 
23. 
6 Mackenzie D. Large hole in the ozone agreement. New Scientist 
1992; Nov 28: 5. 
7 Spray Technology and Marketing (June 2003). Sciarra C, Sciarra J. 
CFC-free MDIs. http://www.spraytechnology.com/ 
prev2003.htm#June (accessed 4 January 2005). 
20 General References 
Amin YM, Thompson EB, Shiou WL. Fluorocarbon aerosol propellants 
XII: correlation of blood levels of trichloromonofluormethane to 
cardiovascular and respiratory responses in anesthetized dogs. J 
Pharm Sci 1979; 68: 160163. 
Byron PR, ed. Respiratory Drug Delivery. Boca Raton, FL: CRC Press, 
1990. 
Johnson MA. The Aerosol Handbook, 2nd edn. Caldwell: WE 
Dorland, 1982: 305335. 
Niazi S, Chiou WL. Fluorocarbon aerosol propellants XI: pharmacokinetics 
of dichlorodifluoromethane in dogs following single dose 
and multiple dosing. J Pharm Sci 1977; 66: 4953. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 1935. 
Sawyer E, Green B, Colton HM. Microorganism survival in non-CFC 
propellant P134a and a combination of CFC propellants P11 and 
P12. Pharm Technol 2001; 25(3): 9096. 
Sciarra JJ. Pharmaceutical aerosols. In: Lachman L, Lieberman HA, 
Kanig JL, eds. The Theory and Practice of Industrial Pharmacy, 3rd 
edn. Philadelphia: Lea and Febiger, 1986: 589618. 
Sciarra JJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and 
Practice of Pharmacy, 19th edn. Easton, PA: Mack Publishing Co., 
1995: 16761692. 
Sciarra JJ. In: Banker GS, Rhodes C, eds. Modern Pharmaceutics, 3rd 
edn. New York: Marcel Dekker, 1996: 547574. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 97130. 
Strobach DR. Alternatives to CFCs. Aerosol Age 1988; 3233, 4243. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Chlorofluorocarbons (CFC) 179

Chloroxylenol 
1 Nonproprietary Names 
BP: Chloroxylenol 
USP: Chloroxylenol 
2 Synonyms 
4-Chloro-3,5-dimethylphenol; Nipacide PX; parachlorometaxylenol; 
p-chloro-m-xylenol; PCMX. 
3 Chemical Name and CAS Registry Number 
4-Chloro-3,5-xylenol [88-04-0] 
4 Empirical Formula and Molecular Weight 
C8H9ClO 156.61 
5 Structural Formula 
6 Functional Category 
Antimicrobial preservative; antiseptic; disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Chloroxylenol is a common constituent of many proprietary 
disinfectants used for skin and wound disinfection; see Table I. 
As a pharmaceutical excipient, chloroxylenol is commonly 
used in low concentrations as an antimicrobial preservative in 
topical formulations such as creams and ointments. Chloroxylenol 
is also used in a number of cosmetic formulations. 
Therapeutically, chloroxylenol has been investigated as a 
treatment for acne vulgaris,(1) and also for treating infected root 
canals.(2) 
Table I: Uses of chloroxylenol. 
Use Concentration (%) 
Antiseptic powder 0.5 
Antimicrobial preservative for otic and topical 
preparations 
0.10.8 
Disinfectant 2.55.0 
8 Description 
White or cream-colored crystals or crystalline powder with a 
characteristic phenolic odor. Volatile in steam. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for chloroxylenol. 
Test BP 2004 USP 28 
Identification . . 
Characters .  
Residue on ignition  40.1% 
Water  40.5% 
Iron  40.01% 
Melting range 1141168C 1141168C 
Related substances . . 
Assay 98.0103.0% 598.5% 
10 Typical Properties 
Antimicrobial activity: chloroxylenol is effective against Grampositive 
bacteria but less active against Gram-negative 
bacteria. The activity of chloroxylenol against Gramnegative 
bacilli can be increased by the addition of a 
chelating agent such as edetic acid.(3) Chloroxylenol is 
inactive against bacterial spores. Antimicrobial activity may 
be reduced by loss of chloroxylenol from a formulation due 
to incompatibilities with packaging materials or other 
excipients, such as nonionic surfactants.(4) Solution pH 
does not have a marked effect on the activity of chloroxylenol.(
5) 
Boiling point: 2468C 
Melting point: 115.58C 
Solubility: freely soluble in ethanol (95%); soluble in ether, 
terpenes, and fixed oils; very slightly soluble in water. 
Dissolves in solutions of alkali hydroxides. 
11 Stability and Storage Conditions 
Chloroxylenol is stable at normal room temperature, but is 
volatile in steam. Contact with natural rubber should be 
avoided. Aqueous solutions of chloroxylenol are susceptible to 
microbial contamination and appropriate measures should be 
taken to prevent contamination during storage or dilution. 
Chloroxylenol should be stored in polyethylene, mild steel or 
stainless steel containers, which should be well-closed and kept 
in a cool, dry place. 
12 Incompatibilities 
Chloroxylenol has been reported to be incompatible with 
nonionic surfactants and methylcellulose.

13 Method of Manufacture 
Chloroxylenol is prepared by treating 3,5-dimethylphenol with 
chlorine or sulfuryl chloride (SO2Cl2). 
14 Safety 
Chloroxylenol is generally regarded as a relatively nontoxic 
and nonirritant material when used as an excipient. However, 
allergic skin reactions have been reported.(6,7) Taken orally, 
chloroxylenol is mildly toxic and has been associated with 
isolated reports of fatal(8) or severe instances of self-poisoning.(
9,10) 
LD50 (mouse, IP): 0.115 g/kg(11) 
LD50 (rat, oral): 3.83 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Chloroxylenol is an eye 
irritant and eye protection is recommended. When heated to 
decomposition, chloroxylenol emits toxic fumes. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (otic preparations; 
topical creams and emulsions). Included in nonparenteral 
medicines licensed in the UK. 
17 Related Substances 
Chlorocresol. 
18 Comments 
The EINECS number for chloroxylenol is 201-793-8. 
19 Specific References 
1 Papageorgiou PP, Chu AC. Chloroxylenol and zinc oxide containing 
cream (Nels cream) vs. 5% benzoyl peroxide cream in the 
treatment of acne vulgaris. A double-blind, randomized, controlled 
trial. Clin Exp Dermatol 2000; 25(1): 1620. 
2 Schafer E, Bossmann K. Antimicrobial efficacy of chloroxylenol 
and chlorhexidine in the treatment of infected root canals. Am J 
Dent 2001; 14(4): 233237. 
3 Ayliffe GAJ, Fraise AP, Geddes AM, Mitchell K, eds. Control of 
Hospital Infection, 4th edn. London: Arnold, 2000: 78. 
4 Kazmi SJA, Mitchell AG. Interaction of preservatives with 
cetomacrogol. J Pharm Pharmacol 1971; 23: 482489. 
5 Judis J. Studies on the mechanism of action of phenolic 
disinfectants I. J Pharm Sci 1962; 51: 261265. 
6 Mowad C. Chloroxylenol causing hand dermatitis in a plumber. 
Am J Contact Dermatitis 1998; 9(2): 128129. 
7 Malakar S, Panda S. Post-inflammatory depigmentation following 
allergic contact dermatitis to chloroxylenol [letter]. Br J Dermatol 
2001; 144(6): 12751276. 
8 Meek D, Gabriel R, Piercy DM. Fatal self-poisoning with Dettol. 
Postgrad Med J 1977; 53: 229231. 
9 Joubert P, Hundt H, Du Toit P. Severe Dettol (chloroxylenol and 
terpineol) poisoning. Br Med J 1978; 1: 890. 
10 Chan TYK, Sung JJY, Critchley JAJH. Chemical gastro-oesophagitis, 
upper gastrointestinal haemorrhage and gastroscopic findings 
following Dettol poisoning. Hum Exp Toxicol 1995; 14: 18 
19. 
11 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 906907. 
20 General References 
Chapman DG. Preservatives available for use. In: Board RG, Allwood 
MC, Banks JG, eds. Preservatives in the Food, Pharmaceutical and 
Environmental Industries. Oxford: Blackwell Scientific, 1987. 
Gatti R, Roveri P, Bonazzi D, Cavrini V. HPLC-fluorescence 
determination of chlorocresol and chloroxylenol in pharmaceuticals. 
J Pharm Biomed Anal 1997; 16: 405412. 
21 Authors 
LME McIndoe. 
22 Date of Revision 
24 August 2005. 
Chloroxylenol 181

Cholesterol 
1 Nonproprietary Names 
BP: Cholesterol 
JP: Cholesterol 
PhEur: Cholesterolum 
USPNF: Cholesterol 
2 Synonyms 
Cholesterin; cholesterolum. 
3 Chemical Name and CAS Registry Number 
Cholest-5-en-3b-ol [57-88-5] 
4 Empirical Formula and Molecular Weight 
C27H46O 386.67 
5 Structural Formula 
6 Functional Category 
Emollient; emulsifying agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cholesterol is used in cosmetics and topical pharmaceutical 
formulations at concentrations of 0.35.0% w/w as an 
emulsifying agent. It imparts water-absorbing power to an 
ointment and has emollient activity. 
Cholesterol also has a physiological role. It is the major 
sterol of the higher animals, and it is found in all body tissues, 
especially in the brain and spinal cord. It is also the main 
constituent of gallstones. 
8 Description 
Cholesterol occurs as white or faintly yellow, almost odorless, 
pearly leaflets, needles, powder, or granules. On prolonged 
exposure to light and air, cholesterol acquires a yellow to tan 
color. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cholesterol. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Acidity . . . 
Characters  .  
Clarity of solution .   
Loss on drying 40.3% 40.3% 40.3% 
Melting range 1471508C 1471508C 1471508C 
Organic volatile 
impurities 
  . 
Residue on ignition 40.10%  40.1% 
Solubility in alcohol  . . 
Specific rotation 348 to 388  348 to 388 
Sulfated ash  40.1%  
Assay  95.097.0%  
10 Typical Properties 
Boiling point: 3608C 
Density: 1.052 g/cm3 for anhydrous form. 
Dielectric constant D20: 5.41 
Melting point: 1471508C 
Solubility: see Table II.(13) 
Specific rotation [a]D
20: 
39.58 (2% w/v solution in chloroform); 
31.58 (2% w/v solution in ether). 
Table II: Solubility of cholesterol. 
Solvent Solubility at 208C(13) 
unless otherwise stated 
Acetone Soluble 
Benzene 1 in 7 
Chloroform 1 in 4.5 
Ethanol 1 in 147 at 08C 
1 in 78 at 208C 
1 in 29 at 408C 
1 in 19 at 508C 
1 in 13 at 608C 
Ethanol (95%) 1 in 78 (slowly) 
1 in 3.6 at 808C 
Ether 1 in 2.8 
Hexane 1 in 52 
Isopropyl myristate 1 in 19 
Methanol 1 in 294 at 08C 
1 in 153 at 208C 
1 in 53 at 408C 
1 in 34 at 508C 
1 in 23 at 608C 
Vegetable oils Soluble 
Water Practically insoluble

SEM: 1 
Excipient: Cholesterol 
Manufacturer: Pflatz & Bauer, Inc. 
Magnification: 240 
SEM: 2 
Excipient: Cholesterol 
Manufacturer: Pfaltz & Bauer, Inc. 
Magnification: 2400 
11 Stability and Storage Conditions 
Cholesterol is stable and should be stored in a well-closed 
container, protected from light. 
12 Incompatibilities 
Cholesterol is precipitated by digitonin. 
13 Method of Manufacture 
The commercial material is normally obtained from the spinal 
cord of cattle by extraction with petroleum ethers, but it may 
also be obtained from wool fat. Purification is normally 
accomplished by repeated bromination. Cholesterol may also 
be produced by entirely synthetic means.(4) 
Cholesterol produced from animal organs will always 
contain cholestanol and other saturated sterols. 
See also Section 14. 
14 Safety 
Cholesterol is generally regarded as an essentially nontoxic and 
nonirritant material at the levels employed as an excipient.(3) It 
has, however, exhibited experimental teratogenic and reproductive 
effects, and mutation data have been reported.(5) 
Cholesterol is often derived from animal sources and this 
must be done in accordance with the regulations for human 
consumption. The risk of bovine spongiform encephalopathy 
(BSE) contamination has caused some concern over the use of 
animal-derived cholesterol in pharmaceutical products.(6) 
However, synthetic methods of cholesterol manufacture have 
been developed.(4) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Rubber or plastic gloves, eye 
protection, and a respirator are recommended. 
May be harmful following inhalation or ingestion of large 
quantities, or over prolonged periods of time, owing to the 
possible involvement of cholesterol in atherosclerosis and 
gallstones. May be irritant to the eyes. When heated to 
decomposition, cholesterol emits acrid smoke and irritating 
fumes. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (injections, 
ophthalmic, topical, and vaginal preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Lanolin; lanolin alcohols; lanolin hydrous. 
18 Comments 
A novel cholesterol-based cationic lipid has been developed that 
promotes DNA transfer in cells.(7,8) Cholesterol monohydrate 
becomes anhydrous at 70808C. 
The EINECS number for cholesterol is 200-353-2. 
19 Specific References 
1 Harwood RJ, Cohen EM. Solubility of cholesterol in isopropyl 
myristate. J Soc Cosmet Chem 1977; 28: 7982. 
2 Flynn GL, Shah Y, Prakongpan S, et al. Cholesterol solubility in 
organic solvents. J Pharm Sci 1979; 68: 10901097. 
3 Cosmetic, Toiletry and Fragrance Association. Final report on the 
safety assessment of cholesterol. J Am Coll Toxicol 1986; 5(5): 
491516. 
4 Carmichael H. Safer by synthesis? Chem Br 2001; 37(2): 4042. 
Cholesterol 183

5 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 912. 
6 Anonymous. Beefing about contamination. Pharm Dev Technol 
Eur 1997; 9(11): 12, 14. 
7 Percot A, Briane D, Coudert R, et al. Hydroxyethylated 
cholesterol-based cationic lipid for DNA delivery: effect of 
conditioning. Int J Pharm 2004; 278(1): 143163. 
8 Reynier P, Briane D, Coudert R, et al. Modifications in the head 
group and in the spacer of cholesterol-based cationic lipids 
promote transfection in melanoma B16-F10 cells and tumours. J 
Drug Target 2004; 12(1): 2538. 
20 General References 
Bogardus JB. Unusual cholesterol solubility in water/glyceryl-1-monooctanoate 
solutions. J Pharm Sci 1982; 71: 370372. 
Cadwallader DE, Madan DK. Effect of macromolecules on aqueous 
solubility of cholesterol and hormone drugs. J Pharm Sci 1981; 70: 
442446. 
Feld KM, Higuchi WI, Su C-C. Influence of benzalkonium chloride on 
the dissolution behavior of several solid-phase preparations of 
cholesterol in bile acid solutions. J Pharm Sci 1982; 71: 182188. 
Singh VS, Gaur RC. Dispersion of cholesterol in aqueous surfactant 
solutions: interpretation of viscosity data. J Disper Sci Technol 
1983; 4: 347359. 
Udupa N, Chandraprakash KS, Umadevi P, Pillai GK. Formulation and 
evaluation of methotrexate niosomes. Drug Dev Ind Pharm 1993; 
19: 13311342. 
21 Authors 
SC Owen. 
22 Date of Revision 
12 August 2005. 
184 Cholesterol

Citric Acid Monohydrate 
1 Nonproprietary Names 
BP: Citric acid monohydrate 
JP: Citric acid 
PhEur: Acidum citricum monohydricum 
USP: Citric acid 
2 Synonyms 
E330; 2-hydroxypropane-1,2,3-tricarboxylic acid monohydrate. 
3 Chemical Name and CAS Registry Number 
2-Hydroxy-1,2,3-propanetricarboxylic acid monohydrate 
[5949-29-1] 
4 Empirical Formula and Molecular Weight 
C6H8O7H2O 210.14 
5 Structural Formula 
6 Functional Category 
Acidifying agent; antioxidant; buffering agent; chelating agent; 
flavor enhancer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Citric acid (as either the monohydrate or anhydrous material) is 
widely used in pharmaceutical formulations and food products, 
primarily to adjust the pH of solutions. It has also been used 
experimentally to adjust the pH of tablet matrices in entericcoated 
formulations for colon-specific drug delivery.(1) Citric 
acid monohydrate is used in the preparation of effervescent 
granules, while anhydrous citric acid is widely used in the 
preparation of effervescent tablets.(24) Citric acid has also been 
shown to improve the stability of spray-dried insulin powder in 
inhalation formulations.(5) 
In food products, citric acid is used as a flavor enhancer for 
its tart, acidic taste. Citric acid monohydrate is used as a 
sequestering agent and antioxidant synergist; see Table I. It is 
also a component of anticoagulant citrate solutions. Therapeutically, 
preparations containing citric acid have been used to 
dissolve renal calculi. 
Table I: Uses of citric acid monohydrate. 
Use Concentration (%) 
Buffer solutions 0.12.0 
Flavor enhancer for liquid formulations 0.32.0 
Sequestering agent 0.32.0 
8 Description 
Citric acid monohydrate occurs as colorless or translucent 
crystals, or as a white crystalline, efflorescent powder. It is 
odorless and has a strong acidic taste. The crystal structure is 
orthorhombic. 
SEM: 1 
Excipient: Citric acid monohydrate 
Manufacturer: Pfizer Ltd. 
Magnification: 60

SEM: 2 
Excipient: Citric acid monohydrate 
Manufacturer: Pfizer Ltd. 
Magnification: 600 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for citric acid monohydrate 
(and anhydrous). 
Test JP 2001 PhEur 2005 USP 28(a) 
Identification . . . 
Characters  .  
Appearance of solution  .  
Water 
(hydrous form)  7.59.0% 48.8% 
(anhydrous form) 40.5% 41.0% 40.5% 
Bacterial endotoxins  .  
Residue on ignition 40.1%  40.05% 
Sulfated ash  40.1%  
Calcium .   
Aluminum  40.2 ppm  
Oxalate .  . 
Oxalic acid  4350 ppm  
Sulfate 40.048% 4150 ppm . 
Arsenic 41 ppm  43 ppm 
Heavy metals 410 ppm 410 ppm 40.001% 
Related substances .   
Readily carbonizable 
substances 
. . . 
Polycyclic aromatic 
hydrocarbon 
.   
Organic volatile 
impurities 
  . 
Assay (anhydrous 
basis) 
599.5% 99.5101.0% 99.5100.5% 
(a) Note that the JP 2001 and PhEur 2005 have separate monographs for the monohydrate and 
anhydrous material; the USP 28 has a single monograph for both materials. 
10 Typical Properties 
Acidity/alkalinity: pH = 2.2 (1% w/v aqueous solution) 
Dissociation constant: 
pKa1: 3.128 at 258C; 
pKa2: 4.761 at 258C; 
pKa3: 6.396 at 258C. 
Density: 1.542 g/cm3 
Heat of combustion: 1972 kJ/mol (471.4 kcal/mol) 
Heat of solution: 16.3 kJ/mol (3.9 kcal/mol) at 258C 
Hygroscopicity: at relative humidities less than about 65%, 
citric acid monohydrate effloresces at 258C, the anhydrous 
acid being formed at relative humidities less than about 
40%. At relative humidities between about 65% and 75%, 
citric acid monohydrate absorbs insignificant amounts of 
moisture, but under more humid conditions substantial 
amounts of water are absorbed. 
Melting point: 1008C (softens at 758C) 
Particle size distribution: various grades of citric acid monohydrate 
with different particle sizes are commercially 
available. 
Solubility: soluble 1 in 1.5 parts of ethanol (95%) and 1 in less 
than 1 part of water; sparingly soluble in ether. 
Viscosity (dynamic): 6.5 mPa s (6.5 cP) for a 50% w/v aqueous 
solution at 258C. 
See also Section 17. 
11 Stability and Storage Conditions 
Citric acid monohydrate loses water of crystallization in dry air 
or when heated to about 408C. It is slightly deliquescent in 
moist air. Dilute aqueous solutions of citric acid may ferment on 
standing. 
The bulk monohydrate or anhydrous material should be 
stored in airtight containers in a cool, dry place. 
12 Incompatibilities 
Citric acid is incompatible with potassium tartrate, alkali and 
alkaline earth carbonates and bicarbonates, acetates, and 
sulfides. Incompatibilities also include oxidizing agents, bases, 
reducing agents, and nitrates. It is potentially explosive in 
combination with metal nitrates. On storage, sucrose may 
crystallize from syrups in the presence of citric acid. 
13 Method of Manufacture 
Citric acid occurs naturally in a number of plant species and 
may be extracted from lemon juice, which contains 58% citric 
acid, or pineapple waste. Anhydrous citric acid may also be 
produced industrially by mycological fermentation of crude 
sugar solutions such as molasses, using strains of Aspergillus 
niger. Citric acid is purified by recrystallization; the anhydrous 
form is obtained from a hot concentrated aqueous solution and 
the monohydrate from a cold concentrated aqueous solution. 
14 Safety 
Citric acid is found naturally in the body, mainly in the bones, 
and is commonly consumed as part of a normal diet. Orally 
ingested citric acid is absorbed and is generally regarded as a 
nontoxic material when used as an excipient. However, 
excessive or frequent consumption of citric acid has been 
associated with erosion of the teeth.(6) 
Citric acid and citrates also enhance intestinal aluminum 
absorption in renal patients, which may lead to increased, 
186 Citric Acid Monohydrate

harmful serum aluminum levels. It has therefore been suggested 
that patients with renal failure taking aluminum compounds to 
control phosphate absorption should not be prescribed citric 
acid or citrate-containing products.(7) 
See Section 17 for anhydrous citric acid animal toxicity data. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Direct contact with eyes can cause serious 
damage. Citric acid should be handled in a well-ventilated 
environment or a dust mask should be worn. 
16 Regulatory Status 
GRAS listed. The anhydrous form is accepted for use as a food 
additive in Europe. Included in the FDA Inactive Ingredients 
Guide (inhalations; IM, IV, and other injections; ophthalmic 
preparations; oral capsules, solutions, suspensions and tablets; 
topical and vaginal preparations). Included in nonparenteral 
and parenteral medicines licensed in Japan and the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Anhydrous citric acid; fumaric acid; malic acid; sodium citrate 
dihydrate; tartaric acid. 
Anhydrous citric acid 
Empirical formula: C6H8O7 
Molecular weight: 192.12 
CAS number: [77-92-9] 
Synonyms: acidum citricum anhydricum; citric acid; E330; 2- 
hydroxy-b-1,2,3-propanetricarboxylic acid; 2-hydroxypropane 
1,2,3-tricarboxylic acid. 
Appearance: odorless or almost odorless, colorless crystals or a 
white crystalline powder. Crystal structure is monoclinic 
holohedral. 
Dissociation constants: 
pKa1: 3.128 at 258C; 
pKa2: 4.761 at 258C; 
pKa3: 6.396 at 258C. 
Density: 1.665 g/cm3 
Heat of combustion: 1985 kJ/mol (474.5 kcal/mol) 
Hygroscopicity: at relative humidities between about 2550%, 
anhydrous citric acid absorbs insignificant amounts of water 
at 258C. However, at relative humidities between 50% and 
75%, it absorbs significant amounts, with the monohydrate 
being formed at relative humidities approaching 75%. At 
relative humidities greater than 75% substantial amounts of 
water are absorbed by the monohydrate. 
Melting point: 1538C 
Solubility: soluble 1 in 1 part of ethanol (95%) and 1 in 1 of 
water; sparingly soluble in ether. 
Safety:
LD50 (mouse, IP): 0.9 g/kg(8) 
LD50 (mouse, IV): 0.04 g/kg 
LD50 (mouse, oral): 5.04 g/kg 
LD50 (mouse, SC): 2.7 g/kg 
LD50 (rabbit, IV): 0.33 g/kg 
LD50 (rat, IP): 0.88 g/kg 
LD50 (rat, oral): 3.0 g/kg 
LD50 (rat, SC): 5.5 g/kg 
Comments: the EINECS number for anhydrous citric acid is 
201-069-1. 
18 Comments 
A specification for citric acid monohydrate is contained in the 
Food Chemicals Codex (FCC). 
The EINECS number for citric acid monohydrate is 201- 
069-1. 
19 Specific References 
1 Nykaenen P, Sten T, Juerjenson H, Veski P, Marvola M. Citric acid 
as a pH-regulating additive in granules and the tablet matrix in 
enteric-coated formulations for colon-specific drug delivery. 
Pharmazie 2004; 59(4): 268273. 
2 Anderson NR, Banker GS, Peck GE. Quantitative evaluation of 
pharmaceutical effervescent systems II: stability monitoring by 
reactivity and porosity measurements. J Pharm Sci 1982; 71(1): 7 
13. 
3 Yanze FM, Duru C, Jacob M. A process to produce effervescent 
tablets: fluidized bed dryer melt granulation. Drug Dev Ind Pharm 
2000; 26(11): 11671176. 
4 Nyka.nen P, Lempa.a. S, Aaltonen M-L, et al. Citric acid as excipient 
in multiple-unit enteric-coated tablets for targeting drugs on the 
colon. Int J Pharm 2001; 229(12): 155162. 
5 Todo H, Okamoto H, Iida K, Danjo K. Improvement of stability 
and absorbability of dry insulin powder for inhalation by powdercombination 
technique. Int J Pharm 2004; 271(12): 4152. 
6 Anonymous. Citric acid: tooth enamel destruction. Clin Alert 
1971; No. 151. 
7 Main I, Ward MK. Potentiation of aluminium absorption by 
effervescent analgesic tablets in a haemodialysis patient. Br Med J 
1992; 304: 1686. 
8 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 955. 
20 General References 
Cho MJ, Scieszka JF, Burton PS. Citric acid as an adjuvant for 
transepithelial transport. Int J Pharm 1989; 52: 7981. 
Timko RJ, Lordi NG. Thermal characterization of citric acid solid 
dispersions with benzoic acid and phenobarbital. J Pharm Sci 1979; 
68: 601605. 
21 Authors 
GE Amidon. 
22 Date of Revision 
8 August 2005. 
Citric Acid Monohydrate 187

Colloidal Silicon Dioxide 
1 Nonproprietary Names 
BP: Colloidal anhydrous silica 
PhEur: Silica colloidalis anhydrica 
USPNF: Colloidal silicon dioxide 
2 Synonyms 
Aerosil; Cab-O-Sil; Cab-O-Sil M-5P; colloidal silica; fumed 
silica; light anhydrous silicic acid; silicic anhydride; silicon 
dioxide fumed; Wacker HDK. 
3 Chemical Name and CAS Registry Number 
Silica [7631-86-9] 
4 Empirical Formula and Molecular Weight 
SiO2 60.08 
5 Structural Formula 
SiO2 
6 Functional Category 
Adsorbent; anticaking agent; emulsion stabilizer; glidant; 
suspending agent; tablet disintegrant; thermal stabilizer; 
viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Colloidal silicon dioxide is widely used in pharmaceuticals, 
cosmetics, and food products; see Table I. Its small particle size 
and large specific surface area give it desirable flow characteristics 
that are exploited to improve the flow properties of dry 
powders in a number of processes such as tableting.(13) 
Colloidal silicon dioxide is also used to stabilize emulsions 
and as a thixotropic thickening and suspending agent in gels 
and semisolid preparations.(4)With other ingredients of similar 
refractive index, transparent gels may be formed. The degree of 
viscosity increase depends on the polarity of the liquid (polar 
liquids generally require a greater concentration of colloidal 
silicon dioxide than nonpolar liquids). Viscosity is largely 
independent of temperature. However, changes to the pH of a 
system may affect the viscosity; see Section 11. 
In aerosols, other than those for inhalation, colloidal silicon 
dioxide is used to promote particulate suspension, eliminate 
hard settling, and minimize the clogging of spray nozzles. 
Colloidal silicon dioxide is also used as a tablet disintegrant and 
as an adsorbent dispersing agent for liquids in powders.(5) 
Colloidal silicon dioxide is frequently added to suppository 
formulations containing lipophilic excipients to increase 
viscosity, prevent sedimentation during molding, and decrease 
the release rate.(6,7) Colloidal silicone dioxide is also used as an 
adsorbent during the preparation of wax microspheres;(8) as a 
thickening agent for topical preparations;(9) and has been used 
to aid the freeze-drying of nanocapsules and nanosphere 
suspensions.(10) 
Table I: Uses of colloidal silicon dioxide. 
Use Concentration (%) 
Aerosols 0.52.0 
Emulsion stabilizer 1.05.0 
Glidant 0.10.5 
Suspending and thickening agent 2.010.0 
8 Description 
Colloidal silicon dioxide is a submicroscopic fumed silica with 
a particle size of about 15 nm. It is a light, loose, bluish-whitecolored, 
odorless, tasteless, nongritty amorphous powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for colloidal silicon dioxide. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
pH (4% w/v dispersion) 3.55.5 3.55.5 
Arsenic  48 mg/g 
Chloride 4250 ppm  
Heavy metals 425 ppm  
Loss on drying  42.5% 
Loss on ignition 45.0% 42.0% 
Organic volatile impurities  . 
Assay (on ignited sample) 99.0100.5% 99.0100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 3.54.4 (4% w/v aqueous dispersion) 
Density (bulk): 0.0290.042 g/cm3 
Density (tapped): See Tables III, IV and V. 
Flowability: 35.52% (Carr compressibility index) 
Moisture content: See Figure 1.(11,12) 
Particle size distribution: 716 nm. See also Figure 2. 
Refractive index: 1.46 
Solubility: practically insoluble in organic solvents, water, and 
acids, except hydrofluoric acid; soluble in hot solutions of 
alkali hydroxide. Forms a colloidal dispersion with water. 
Specific gravity: 2.2

Specific surface area: 200400m2/g (Stroehlein apparatus, 
single point); 50380m2/g (BET method). See also Tables 
III, IV and V. 
Several grades of colloidal silicon dioxide are commercially 
available, which are produced by modifying the manufacturing 
process. The modifications do not affect the silica content, 
specific gravity, refractive index, color, or amorphous form. 
However, particle size, surface areas, and densities are affected. 
The physical properties of three commercially available 
colloidal silicon dioxides, Aerosil (Degussa), Cab-O-Sil (Cabot 
Corporation), and Wacker HDK (Wacker-Chemie GmbH) are 
shown in Tables III, IV and V, respectively. 
Table III: Physical properties of Aerosil. 
Grade Specific surface area(a) 
(m2/g) 
Density (tapped) 
(g/cm3) 
130 130  25 0.05 
130vs 130  25 0.12 
200 200  25 0.05 
200vs 200  25 0.12 
300 300  30 0.05 
380 380  30 0.05 
(a) BET method. 
Table IV: Physical properties of Cab-O-Sil.(13) 
Grade Specific surface area(a) 
(m2/g) 
Density (tapped) 
(g/cm3) 
LM-5 130  25 0.04 
LM-50 150  25 0.04 
M-5 200  25 0.04 
H-5 325  25 0.04 
EH-5 390  40 0.04 
M-7D 200  25 0.10 
(a) BET method. 
Table V: Physical properties of Wacker HDK.(14) 
Grade Specific surface area(a) 
(m2/g) 
Density (tapped) 
(g/cm3) 
S13 125  15 0.05 
V15 150  20 0.05 
N20 200  30 0.04 
T30 300  30 0.04 
T40 400  40 0.04 
H15 120  20 0.04 
H20 170  30 0.04 
H30 250  30 0.04 
H2000 140  30 0.22 
H3004 210  30 0.08 
H2015 110  30 0.20 
H2050 110  30 0.20 
(a) BET method. 
SEM: 1 
Excipient: Colloidal silicon dioxide (Aerosil A-200) 
Manufacturer: Degussa 
Lot No.: 87A-1 (04169C) 
Magnification: 600 Voltage: 20 kV 
SEM: 2 
Excipient: Colloidal silicon dioxide (Aerosil A-200) 
Manufacturer: Degussa 
Lot No.: 87A-1 (04169C) 
Magnification: 2400 Voltage: 20 kV 
11 Stability and Storage Conditions 
Colloidal silicon dioxide is hygroscopic but adsorbs large 
quantities of water without liquefying. When used in aqueous 
systems at a pH 07.5, colloidal silicon dioxide is effective in 
Colloidal Silicon Dioxide 189

increasing the viscosity of a system. However, at a pH greater 
than 7.5 the viscosity-increasing properties of colloidal silicon 
dioxide are reduced; and at a pH greater than 10.7 this ability is 
lost entirely since the silicon dioxide dissolves to form 
silicates.(13) Colloidal silicon dioxide powder should be stored 
in a well-closed container. 
Some grades of colloidal silicon dioxide have hydrophobic 
surface treatments that greatly minimize their hygroscopicity. 
Figure 1: Sorptiondesorption isotherm for colloidal silicon dioxide. 
*: Sorption 
&: Desorption 
Figure 2: Particle size distribution of colloidal silicon dioxide (Aerosil 
A-200). 
12 Incompatibilities 
Incompatible with diethylstilbestrol preparations.(15) 
13 Method of Manufacture 
Colloidal silicon dioxide is prepared by the vapor hydrolysis of 
chlorosilanes, such as silicon tetrachloride, at 18008C using a 
hydrogenoxygen flame. 
14 Safety 
Colloidal silicon dioxide is widely used in oral and topical 
pharmaceutical products and is generally regarded as an 
essentially nontoxic and nonirritant excipient. However, 
intraperitoneal and subcutaneous injection may produce local 
tissue reactions and/or granulomas. Colloidal silicon dioxide 
should therefore not be administered parenterally. 
LD50 (rat, IV): 15 mg/kg(16) 
LD50 (rat, oral): 3.16 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Precautions should be taken to avoid inhalation 
of colloidal silicon dioxide. In the absence of suitable containment 
facilities, a dust mask should be worn when handling 
small quantities of material. For larger quantities, a dust 
respirator is recommended. 
Inhalation of colloidal silicon dioxide dust may cause 
irritation to the respiratory tract but it is not associated with 
fibrosis of the lungs (silicosis), which can occur upon exposure 
to crystalline silica. 
16 Regulatory Acceptance 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules, suspensions, and tablets; transdermal and 
vaginal preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 

18 Comments 
The PhEur 2005 also contains a specification for hydrated 
colloidal silicone dioxide. The incidence of microbial contamination 
of colloidal silicon dioxide is low. 
The EINECS number for colloidal silicon dioxide is 231- 
545-4. 
19 Specific References 
1 Lerk CF, Bolhuis GK, Smedema SS. Interaction of lubricants and 
colloidal silica during mixing with excipients I: its effect on 
tabletting. Pharm Acta Helv 1977; 52: 3339. 
2 Lerk CF, Bolhuis GK. Interaction of lubricants and colloidal silica 
during mixing with excipients II: its effect on wettability and 
dissolution velocity. Pharm Acta Helv 1977; 52: 3944. 
3 Gore AY, Banker GS. Surface chemistry of colloidal silica and a 
possible application to stabilize aspirin in solid matrixes. J Pharm 
Sci 1979; 68: 197202. 
190 Colloidal Silicon Dioxide

4 Daniels R, Kerstiens B, Tishinger-Wagner H, Rupprecht H. The 
stability of drug absorbates on silica. Drug Dev Ind Pharm 1986; 
12: 21272156. 
5 Sherriff M, Enever RP. Rheological and drug release properties of 
oil gels containing colloidal silicon dioxide. J Pharm Sci 1979; 68: 
842845. 
6 Tukker JJ, De Blaey CJ. The addition of colloidal silicon dioxide to 
suspension suppositories II. The impact on in vitro release and 
bioavailability. Acta Pharm Technol 1984; 30: 155160. 
7 Realdon N, Ragazzi E, Zotto MD, Fini GD. Effects of silicium 
dioxide on drug release from suppositories. Drug Dev Ind Pharm 
1997; 23: 10251041. 
8 Mani N, Suh HR, Jun HW. Microencapsulation of a hydrophilic 
drug into a hydrophobic matrix using a salting-out procedure. II. 
Effects of adsorbents on microsphere properties. Drug Dev Ind 
Pharm 2004; 30(1): 8393. 
9 Gallagher SJ, Trollet L, Carter TP, Heard CM. Effects of membrane 
type and liquid/liquid phase boundary on in vitro release of 
ketoprofen from gel formulations. J Drug Target 2003; 11(6): 
373379. 
10 Schaffazick SR, Pohlman AR, Dalla-Costa T, Guterres SS. Freezedrying 
polymeric colloidal suspensions: nanocapsules, nanospheres 
and nanodispersion. A comparative study. Eur J Pharm 
Biopharm 2003; 56(3): 501505. 
11 Ettlinger M, Ferch H, Mathias J. Adsorption at the surface of 
fumed silica [in German]. Arch Pharm 1987; 320: 115. 
12 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8: 355369. 
13 Cabot Corporation. Technical literature: Cab-O-Sil fumed silicas, 
the performance additives, 1995. 
14 Wacker-Chemie GmbH. Technical literature: Wacker HDK fumed 
silica, 1998. 
15 Johansen H, Moller N. Solvent deposition of drugs on excipients 
II: interpretation of dissolution, adsorption and absorption 
characteristics of drugs. Arch Pharm Chem (Sci) 1977; 5: 3342. 
16 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 3205. 
20 General References 
Yang KY, Glemza R, Jarowski CI. Effects of amorphous silicon dioxides 
on drug dissolution. J Pharm Sci 1979; 68: 560565. 
21 Authors 
SC Owen. 
22 Date of Revision 
22 August 2005. 
Colloidal Silicon Dioxide 191

Coloring Agents 
1 Nonproprietary Names 
See Section 17 and Tables I, II, III, and IV. 
2 Synonyms 
See Section 17 for specific, selected coloring agents. 
3 Chemical Name and CAS Registry Number 
See Tables I, II, III, and IV. 
4 Empirical Formula and Molecular Weight 
See Section 17 for specific selected coloring agents. 
Table I: European Union list of coloring materials authorized for coloring medicinal products up to January 2002. See also Section 16. 
E number Common name CAS number Alternate name 
E100 Curcumin [458-37-7] Turmeric 
E101 Riboflavin [83-88-5] Lactoflavin 
E102 Tartrazine [1934-21-0] 
E104 Quinoline yellow [8004-92-0] 
E110 Sunset yellow FCF [2783-94-0] 
E120 Carmine [1260-17-9] Cochineal, carminic acid 
E122 Carmoisine [3567-69-9] 
E123 Amaranth [915-67-3] 
E124 Ponceau 4R [2611-82-7] 
E127 Erythrosine [16423-68-0] 
E129 Allura red AC [25956-17-6] 
E131 Patent blue V [3536-49-0] 
E132 Indigo carmine [860-22-0] Indigotine 
E133 Brilliant blue FCF [2650-18-2] 
E140 Chlorophylls [479-61-8] for (i) Magnesium chlorophyll 
[519-62-0] for (ii) 
E141 Copper complexes of chlorophylls and chlorophyllins  
E142 Green S [3087-16-9] Brilliant green BS 
E150 Caramel [8028-89-5] 
E151 Brilliant black BN [2519-30-4] Black PN 
E153 Vegetable carbon [7440-44-0] Carbo medicinalis vegetabilis 
E160 Carotenoids 
(a) Alpha-, beta-, gamma-carotene [7235-40-7] 
(b) Capsanthin [465-42-9] Paprika oleoresin 
(c) Capsorubin [470-38-2] Paprika oleoresin 
(d) Lycopene [502-65-8] 
(e) Beta-apo-80 carotenal [1107-26-2] 
(f) Ethyl ester of beta-apo-80 carotenoic acid  
E161 Xanthophylls 
(b) Lutein [127-40-2] 
(g) Canthaxanthin [514-78-3] 
E162 Beetroot red [7659-95-2] Betanin 
E163 Anthocyanins 
Cyanidin [528-58-5] 
Delphidin [528-53-0] 
Malvidin [643-84-5] 
Pelargonidin [134-04-3] 
Peonidin [134-01-0] 
Petunidin [1429-30-7] 
E170(a) Calcium carbonate [471-34-1] 
E171 Titanium dioxide [13463-67-7] 
E172 Iron oxides and hydroxides [977053-38-5] 
E173 Aluminum [7429-90-5] 
(a) For surface coloring only. 
Note: List of colors taken from Directive 94/34/EC, Annex I and IV. (Official Journal EC 1994; L237/13).

5 Structural Formula 
See Section 17 for specific selected coloring agents. 
6 Functional Category 
Colorants; opacifiers. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Coloring agents are used mainly to impart a distinctive 
appearance to a pharmaceutical dosage form. The main 
categories of dosage form that are colored are: 
. Tablets: either the core itself or the coating. 
. Hard or soft gelatin capsules: the capsule shell or coated 
beads. 
. Oral liquids. 
. Topical creams and ointments. 
Color is a useful tool to help identify a product in its 
manufacturing and distribution stages. Patients, especially 
those using multiple products, often rely on color to be able 
to recognize the prescribed medication.(1) The use of different 
colors for different strengths of the same drug can also help 
eliminate errors. 
Many drug products look similar; hence color in combination 
with shape and/or an embossed or printed logo can help 
with identification. Also, this combination can assist in the 
prevention of counterfeiting. 
Unattractive medication can be made more acceptable to 
the patient by the use of color, and color can also be used to 
make a preparation more uniform when an ingredient in the 
formulation has itself a variable appearance from batch to 
batch.(2) 
Some of the insoluble colors or pigments have the additional 
benefit when used in tablet coatings or gelatin shells of 
providing useful opacity, which can contribute to the stability 
of light-sensitive active materials in the tablet or capsule 
formulation. Pigments such as the iron oxides, titanium 
Table II: Permanently listed color additives subject to US certification in 2002, excluding those approved exclusively for use in medical devices. 
Color Common name CAS number 21 CFR references to drug use 
FD&C blue #1 Brilliant blue FCF [2650-18-2] 74.1101 
FD&C blue #2 Indigotine [860-22-0] 74.1102 
D&C blue #4 Alphazurine FG [6371-85-3] 74.1104 
D&C blue #9 Indanthrene blue [130-20-1] 74.1109 
FD&C green #3 Fast green FCF [2353-45-9] 74.1203 
D&C green #5 Alizarin cyanine green F [4403-90-1] 74.1205 
D&C green #6 Quinizarine green SS [128-80-3] 74.1206 
D&C green #8 Pyranine concentrated [6358-69-6] 74.1208 
D&C orange #4 Orange II [633-96-5] 74.1254 
D&C orange #5 Dibromofluorescein [596-03-2] 74.1255 
D&C orange #10 Diiodofluorescein [38577-97-8] 74.1260 
D&C orange #11 Erythrosine yellowish Na [38577-97-8] 74.1261 
FD&C red #3(a) Erythrosine [16423-68-0] 74.1303 
FD&C red #4 Ponceau SX [4548-53-2] 74.1304 
D&C red #6 Lithol rubin B [5858-81-1] 74.1306 
D&C red #7 Lithol rubin B Ca [5281-04-9] 74.1307 
D&C red #17 Toney red [85-86-9] 74.1317 
D&C red #21 Tetrabromofluorescein [15086-94-9] 74.1321 
D&C red #22 Eosine [17372-87-1] 74.1322 
D&C red #27 Tetrachlorotetrabromofluorescein [13473-26-2] 74.1327 
D&C red #28 Phloxine B [18472-87-2] 74.1328 
D&C red #30 Helindone pink CN [2379-74-0] 74.1330 
D&C red #31 Brilliant lake red R [6371-76-2] 74.1331 
D&C red #33 Acid fuchsine [3567-66-6] 74.1333 
D&C red #34 Lake bordeaux B [6417-83-0] 74.1334 
D&C red #36 Flaming red [2814-77-9] 74.1336 
D&C red #39 Alba red [6371-55-7] 74.1339 
FD&C red #40 Allura red AC [25956-17-6] 74.1340 
FD&C red #40 lake Allura Red AC [68583-95-9] 74.1340 
D&C violet #2 Alizurol purple SS [81-48-1] 74.1602 
FD&C yellow #5 Tartrazine [1934-21-0] 74.1705 
FD&C yellow #6 Sunset yellow FCF [2783-94-0] 74.1706 
D&C yellow #7 Fluorescein [2321-07-5] 74.1707 
Ext. D&C yellow #7 Naphthol yellow S [846-70-8] 74.1707(a) 
D&C yellow #8 Uranine [518-47-8] 74.1708 
D&C yellow #10 Quinoline yellow WS [8004-92-0] 74.1710 
D&C yellow #11 Quinoline yellow SS [8003-22-3] 74.1711 
(a) Dye is permanently listed. The lake is not permitted in medicinal products (see Table III). 
Coloring Agents 193

dioxide, and some of the aluminum lakes are especially useful 
for this purpose.(3) 
Of the many classifications possible for pharmaceutical 
coloring agents, one of the most useful is to simply divide the 
colors into those that are soluble in water (dyes) and those that 
are insoluble in water (pigments). 
Colors for clear liquid preparations are limited to the dyes;(4) 
e.g. see Section 17. 
For surface coloration, which includes coated tablets, the 
choice of color is usually restricted to insoluble pigments. The 
reasons for this include their lack of color migration, greater 
opacity, and enhanced color stability over water-soluble 
colors.(5) 
Lakes are largely water-insoluble forms of the common 
synthetic water-soluble dyes. They are prepared by adsorbing a 
sodium or potassium salt of a dye onto a very fine substrate of 
hydrated alumina, followed by treatment with a further soluble 
aluminum salt. The lake is then purified and dried.(6) 
Lakes are frequently used in coloring tablet coatings since, 
for this purpose, they have the general advantages of pigments 
over water-soluble colors. See Table V. 
8 Description 
The physical appearances of coloring agents vary widely. See 
Section 17 for specific selected coloring agents. 
9 Pharmacopeial Specifications 
Some materials used as pharmaceutical coloring agents are 
included in various pharmacopeias; for example, titanium 
dioxide is included in the PhEur 2005. However, if titanium 
dioxide is being used exclusively as a colorant, then the specific 
purity criteria from Directive 95/45/EC apply.(7) 
10 Typical Properties 
Typical properties of specific selected coloring agents are shown 
in Section 17. Selected properties are shown in Tables V, VI, and 
VII. 
11 Stability and Storage Conditions 
Pharmaceutical coloring agents form a chemically diverse 
group of materials that have widely varying stability properties. 
Specific information for selected colors is shown in Table VII 
and can be found inWoznicki and Schoneker.(4) See also Section 
17.
While some colors, notably the inorganic pigments, show 
excellent stability, other coloring agents, such as some organic 
colors, have poor stability properties but are used in formulations 
because of their low toxicity.(8) 
Table III: Provisionally listed color additives subject to US certification in 2002. 
Color Common name CAS number 21 CFR references to drug use 
FD&C lakes General See individual color 82.51 
D&C lakes General See individual color 82.1051 
Ext. D&C lakes General See individual color 82.2051 
FD&C blue #1 lake Brilliant blue FCF [53026-57-6] 82.101 
FD&C blue #2 lake Indigotine [16521-38-3] 82.102 
D&C blue #4 lake Alphazurine FG [6371-85-3] 82.1104 
FD&C green #3 lake Fast green FCF [2353-45-9] 82.1203 
D&C green #5 lake Alizarin cyanine green F [4403-90-1] 82.1205 
D&C green #6 lake Quinizarine green SS [128-80-3] 82.1206 
D&C orange #4 lake Orange II [633-56-5] 82.1254 
D&C orange #5 lake Dibromofluorescein [596-03-2] 74.1255 
D&C orange #10 lake Diiodofluorescein [38577-97-8] 82.1260 
D&C orange #11 lake Erythosine yellowish Na [38577-97-8] 82.1261 
FD&C red #4 lake Ponceau SX [4548-53-2] 82.1304 
D&C red #6 lake Lithol rubin B [17852-98-1] 82.1306 
D&C red #7 lake Lithol rubin B Ca [5281-04-9] 82.1307 
D&C red #17 lake Toney red [85-86-9] 82.1317 
D&C red #21 lake Tetrabromofluorescein [15086-94-9] 82.1321 
D&C red #22 lake Eosine [17372-87-1] 82.1322 
D&C red #27 lake Tetrachlorotetrabromo 
fluorescein 
[13473-26-2] 82.1327 
D&C red #28 lake Phloxine B [18472-87-2] 82.1328 
D&C red #30 lake Helindone pink CN [2379-74-0] 82.1330 
D&C red #31 lake Brilliant lake red R [6371-76-2] 82.1331 
D&C red #33 lake Acid fuchsine [3567-66-6] 82.1333 
D&C red #34 lake Lake bordeaux B [6417-83-0] 82.1334 
D&C red #36 lake Flaming red [2814-77-9] 82.1336 
D&C violet #2 lake Alizurol purple SS [81-48-1] 82.1602 
FD&C yellow #5 lake Tartrazine [12225-21-7] 82.1705 
FD&C yellow #6 lake Sunset yellow FCF [15790-07-5] 82.1706 
D&C yellow #7 lake Fluorescein [2321-07-5] 82.1707 
Ext. D&C yellow #7 lake Naphthol yellow S [846-70-8] 82.2707 
D&C yellow #8 lake Uranine [518-47-8] 82.1708 
D&C yellow #10 lake Quinoline yellow WS [68814-04-0] 82.1710 
194 Coloring Agents

Table V: Typical characteristic properties of aluminum lakes. 
Average particle size 510 mm 
Moisture content 1215% 
Oil absorption 4045(a) 
Specific gravity 1.72.0 g/cm3 
pH stability range 4.08.0 
(a) ASTM D281-31, expressed as grams of oil per 100 g of color. 
Some natural and synthetic organic colors are particularly 
unstable in light. However, with appropriate manufacturing 
procedures, combined with effective product packaging, these 
colors may be used successfully in formulations, thus making a 
wide choice of colors practically available. 
Lakes, inorganic dyes, and synthetic dyes should be stored in 
well-closed, light-resistant containers at a temperature below 
308C. 
For most natural and nature-identical colors, the storage 
conditions are more stringent and a manufacturers recommendations 
for a particular coloring agent should be followed. 
To extend their shelf-life, some natural colors are supplied as 
gelatin-encapsulated or similarly encapsulated powders and 
may be sealed in containers under nitrogen. 
Table VI: Approximate solubilities for selected colors at 258C (g/ 
100 mL)(a) 
Color Water Glycerin Propylene 
glycol 
Ethanol 
(95%) 
Ethanol 
(50%) 
Brilliant blue FCF 18 20 20 1.5 20 
Indigo carmine 1.5 1 0.1 Trace 0.2 
FD&C green #3 17 15 15 0.2 7 
Erythrosine 12 22 22 2 4 
Allura red AC 20 3 1.5 Trace 1 
Tartrazine 15 18 8 Trace 4 
Sunset yellow 18 15 2 Trace 2 
(a) The solubility of individual batches of commercial product will differ widely depending on the 
amounts of salt, pure dye, moisture and subsidiary dyes present. 
12 Incompatibilities 
See Section 17 for incompatibilities of specific selected coloring 
agents; see also Woznicki and Schoneker,(4) and Walford.(9,10) 
13 Method of Manufacture 
See Section 17 and Walford(9,10) for information on specific 
selected coloring agents. 
14 Safety 
Coloring agents are used in a variety of oral and topical 
pharmaceutical formulations, in addition to their extensive use 
in foodstuffs and cosmetic products. 
Toxicology studies are routinely conducted on an ongoing 
basis by organizations such as the World Health Organization 
(WHO), the US Food and Drug Administration (FDA), and the 
European Commission (EC). The outcome of this continuous 
review is that the various regulatory bodies around the world 
have developed lists of permitted colors that are generally 
regarded as being free from serious adverse toxicological 
effects. However, owing to the widespread and relatively large 
use of colors in food, a number of coloring agents in current use 
have been associated with adverse effects, although in a 
relatively small number of people.(11,12) Restrictions or bans 
on the use of some coloring agents have been imposed in some 
countries, while the same colors may be permitted for use in a 
different country. As a result the same color may have a 
different regulatory status in different territories of the world. 
The lake of erythrosine (FD&C red #3), for example, has 
been delisted (see Section 16) in the USA since 1990, following 
studies in rats that suggested that it was carcinogenic. This 
delisting was as a result of the Delaney Clause, which restricts 
the use of any color shown to induce cancer in humans or 
animals in any amount. However, erythrosine was not regarded 
as being an immediate hazard to health and products containing 
it were permitted to be used until supplies were 
exhausted.(13) 
Tartrazine (FD&C yellow #5) has also been the subject of 
controversy over its safety, and restrictions are imposed on its 
use in some countries; see Section 17. 
In general, concerns over the safety of coloring agents in 
pharmaceuticals and foods are associated with reports of 
hypersensitivity(1416) and hyperkinetic activity, especially 
among children.(17) 
In the USA, specific labeling requirements are in place for 
prescription drugs that contain tartrazine (see Section 18) as 
this color was found to be the potential cause of hives in fewer 
Table IV: List of color additives exempt from certification permitted for 
drug use in the USA in 2002. 
Color CAS number 21 CFR references 
to drug use 
Alumina [1332-73-6] 73.1010 
Aluminum powder [7429-90-5] 73.1645 
Annatto extract [8015-67-6] 73.1030 
Beta-carotene [7235-40-7] 73.1095 
Bismuth oxychloride [7787-59-9] 73.1162 
Bronze powder [7440-66-6] 73.1646 
Calcium carbonate [471-34-1] 73.1070 
Canthaxanthin [514-78-3] 73.1075 
Caramel [8028-89-5] 73.1085 
Chromiumcobaltaluminum 
oxide 
[68187-11-1] 73.1015 
Chromium hydroxide green [12182-82-0] 73.1326 
Chromium oxide green [1308-38-9] 73.1327 
Cochineal extract; carmine [1260-17-9] 73.1100 
[1390-65-4] 
Copper powder [7440-50-6] 73.1647 
Dihydroxyacetone [62147-49-3] 73.1150 
Ferric ammonium citrate [1185-57-5] 73.1025 
Ferric ammonium ferrocyanide [25869-00-5] 73.1298 
Ferric ferrocyanide [14038-43-8] 73.1299 
Guanine [68-94-0] 73.1329 
[73-40-5] 
Iron oxides synthetic [977053-38-5] 73.1200 
Logwood extract [8005-33-2] 73.1410 
Mica [12001-26-2] 73.1496 
Potassium sodium copper 
chlorophyllin 
 73.1125 
Pyrogallol [87-66-1] 73.1375 
Pyrophyllite [8047-76-5] 73.1400 
Talc [14807-96-6] 73.1550 
Titanium dioxide [13463-67-7] 73.1575 
Zinc oxide [1314-13-2] 73.1991 
Coloring Agents 195

than one in 10 000 people. In the EU, medicinal products 
containing tartrazine, sunset yellow, carmoisine, amaranth, 
ponceau 4R or brilliant black BN must carry a warning on the 
label concerning possible allergic reactions. 
15 Handling Precautions 
Pharmaceutical coloring agents form a diverse group of 
materials and manufacturers data sheets should be consulted 
for safety and handling data for specific colors. 
In general, inorganic pigments and lakes are of low hazard 
and standard chemical handling precautions should be 
observed depending upon the circumstances and quantity of 
material handled. Special care should be taken to prevent 
excessive dust generation and inhalation of dust. 
The organic dyes, natural colors, and nature-identical colors 
present a greater hazard and appropriate precautions should 
accordingly be taken. 
16 Regulatory Status 
Coloring agents have an almost unique status as pharmaceutical 
excipients in that most regulatory agencies of the world 
hold positive lists of colors that may be used in medicinal 
products. Only colors on these lists may be used and some 
colors may be restricted quantitatively. The legislation also 
defines purity criteria for the individual coloring agents. In 
many regions around the world there is a distinction between 
colors that may be used in drugs and those for food use. 
European Union legislation: 
The primary legislation that governs coloring matters that 
may be added to medicinal products is Council Directive 78/ 
25/EEC of 12 December 1977.(18) This Directive links the 
pharmaceutical requirements with those for foods in the EU. 
Unfortunately, the Directive makes some specific references 
to food legislation from 1962 that has subsequently been 
repealed. However the European Commission has provided 
guidance on cross references to the current food color 
legislation as contained in Council Directive 94/36/EC.(19) 
In addition, the Scientific Committee on Medicinal Products 
and Medical Devices has delivered opinions on the 
suitability and safety of amaranth,(20) erythrosine,(21) 
canthaxanthin,(22) aluminum,(23) and silver(24) as colors 
for medicines. Silver was considered unsuitable. Table I gives 
the current position taking the above information into 
account. Directive 95/45/EC(7) lays down specific purity 
criteria for food colors and essentially replaces the provisions 
of the 1962 Directive. 
United States legislation: 
The 1960 Color Additive Amendment to the Food Drug and 
Cosmetic Act defines the responsibility of the Food and 
Drug Administration in the area of pharmaceutical colorants. 
Tables II, III, and IV provide lists of permitted 
colors.(25) The list is superficially long, but many of the 
coloring agents have restricted use. For the so-called 
certified colors, the FDA operates a scheme whereby each 
batch of color produced is certified as analytically correct by 
the FDA prior to the issuing of a certification number and 
document that will permit sale of the batch in question. 
Colors requiring certification are described as FD&C (Food 
Drug and Cosmetic); D&C (Drug and Cosmetic) or 
External D&C. The remaining colors are described as 
uncertified colors and are mainly of natural origin. The 
USA also operates a system of division of certified colors 
into permanently and provisionally listed colors. Provisionally 
listed colors require the regular intervention of the FDA 
Commissioner to provide continued listing of these colors. 
Should the need arise, the legislative process for removal of 
these colors from use is comparatively easy. 
Licensing authority approval: 
In addition to national approvals and lists, a pharmaceutical 
licensing authority can impose additional restrictions at the 
time of application review. Within the EU this generally 
takes the form of restricting colors, such as tartrazine and 
other azo colors, in medicinal products for chronic 
administration, and especially in medicines for allergic 
conditions. 
17 Related Substances 
Beta-carotene; indigo carmine; iron oxides; sunset yellow FCF; 
tartrazine; titanium dioxide. 
Beta-carotene 
Empirical formula: C40H56 
Molecular weight: 536.85 
CAS number: [7235-40-7] 
Synonyms: betacarotene; b-carotene; b,b-carotene; E160a. 
Structure: 
Appearance: occurs in the pure state as red crystals when 
recrystallized from light petroleum. 
Table VII: Stability properties of selected colors. 
Color Heat Light Acid Base Oxidizing agents Reducing agents 
Brilliant blue FCF Good Moderate Very good Moderate Moderate Poor 
Indigo carmine Good Very poor Moderate Poor Poor Good 
FD&C green #3 Good Fair Good Poor Poor Very poor 
Erythrosine Good Poor Insoluble Good Fair Very poor 
Allura red AC Good Moderate Good Moderate Fair Fair 
Tartrazine Good Good Good Moderate Fair Fair 
Sunset yellow Good Moderate Good Moderate Fair Fair 
D&C yellow #10 Good Fair Good Moderate Poor Good 
196 Coloring Agents

Color Index No.: 
CI 75130 (natural) 
CI 40800 (synthetic) 
Melting point: 1838C 
Purity (EU): 
Arsenic: 43 ppm 
Lead: 410 ppm 
Mercury: 41 ppm 
Cadmium: 41 ppm 
Heavy metals: 440 ppm 
Assay: 596% total coloring matters expressed as betacarotene 
Identification: maximum in cyclohexane at 453456nm 
Sulfated ash: 40.2% 
Subsidiary coloring matters: carotenoids other than betacarotene, 
43.0% of total coloring matters. 
Purity (US): 
Arsenic: 43 ppm 
Assay: 96101% 
Lead: 410 ppm 
Residue on ignition: 40.2% 
Loss on drying: 40.2% 
Solubility: soluble 1 in 30 parts of chloroform; practically 
insoluble in ethanol, glycerin, and water. 
Incompatibilities: generally incompatible with oxidizing agents; 
decolorization will take place. 
Stability: beta-carotene is very susceptible to oxidation and 
antioxidants such as ascorbic acid, sodium ascorbate, or 
tocopherols should be added. Store protected from light at a 
low temperature (208C) in containers sealed under nitrogen. 
Method of manufacture: all industrial processes for preparing 
carotenoids are based on b-ionone. This material can be 
obtained by total synthesis from acetone and acetylene via 
dehydrolinalol. The commercially available material is 
usually extended on a matrix such as acacia or maltodextrin. 
These extended forms of beta-carotene are dispersible 
in aqueous systems. Beta-carotene is also available as 
micronized crystals suspended in an edible oil such as 
peanut oil. 
Comments: beta-carotene is capable of producing colors 
varying from pale yellow to dark orange. It can be used as 
a color for sugar-coated tablets prepared by the ladle 
process. However, beta-carotene is very unstable to light and 
air, and products containing this material should be securely 
packaged to minimize degradation. Beta-carotene is particularly 
unstable when used in spray-coating processes, 
probably owing to atmospheric oxygen attacking the finely 
dispersed spray droplets. 
Because of its poor water solubility, beta-carotene cannot 
be used to color clear aqueous systems, and cosolvents such 
as ethanol must be used. 
Suppositories have been successfully colored with betacarotene 
in approximately 0.1% concentration. 
The EINECS number for beta-carotene is 230-636-6. 
Indigo carmine 
Empirical formula: C16H8N2Na2O8S2 
Molecular weight: 466.37 
CAS number: [860-22-0] 
Synonyms: 2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)- 
2,3-dihydro-3-oxo-1H-indole-5-sulfonic acid disodium salt; 
disodium 5,50-indigotin disulfonate; E132; FD&C blue #2; 
indigotine; sodium indigotin disulfonate; soluble indigo 
blue. 
Structure: 
Appearance: dark blue powder. Aqueous solutions are blue 
or bluish-purple. 
Absorption maximum: 604nm 
Color Index No.: CI 73015 
Purity (EU): 
Arsenic: 43 ppm 
Lead: 410 ppm 
Mercury: 41 ppm 
Cadmium: 41 ppm 
Heavy metals: 440 ppm 
Ether-extractable matter: 40.2% under neutral conditions 
Accessory colorings: 41.0% 
Isatin-5-sulfonic acid: 41.0% 
Water-insoluble matter: 40.2% 
Assay: 585% total coloring matters, calculated as the 
sodium salt 
Disodium 3,30-dioxo-2,20-biindoylidene-5,70-disulfonate: 
418%. 
Water-insoluble matter: 40.2%. 
Subsidiary coloring matters: excluding provision above, 
41.0% 
Organic compounds other than coloring matters: 40.5% 
Unsulfonated primary aromatic amines:40.01%, as aniline 
Purity (US): 
Arsenic: 43 ppm 
2-(1,3-Dihydro-3-oxo-2H-indol-2-ylidene)-2,3-dihydro-3- 
oxo-1H-indole-5-sulfonic acid sodium salt: 42% 
2-(1,3-Dihydro-3-oxo-7-sulfo-2H-indol-2-ylidene)-2,3- 
dihydro-3-oxo-1H-indole-5-sulfonic acid disodium salt: 
418% 
Isatin-5-sulfonic acid: 40.4% 
Lead: 410 ppm 
Mercury: 41 ppm 
5-Sulfoanthranilic acid: 40.2% 
Total color: 585% 
Volatile matter, chlorides and sulfates (calculated as the 
sodium salts): 415.0% at 1358C 
Water-insoluble matter: 40.4% 
Solubility: see Table VIII. 
Table VIII: Solubility of indigo carmine. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone Practically insoluble 
Ethanol (75%) 1 in 1430 
Glycerin 1 in 100 
Propylene glycol 1 in 1000 
Propylene glycol (50%) 1 in 167 
Water 1 in 125 at 28C 
1 in 63 at 258C 
1 in 45 at 608C 
Coloring Agents 197

Incompatibilities: poorly compatible with citric acid and 
saccharose solutions. Incompatible with ascorbic acid, 
gelatin, glucose, lactose, oxidizing agents, and saturated 
sodium bicarbonate solution. 
Stability: sensitive to light. 
Method of manufacture: indigo is sulfonated with concentrated 
or fuming sulfuric acid. 
Safety: LD50 (rat, IV): 93 mg/kg 
Comments: Indigo carmine is an indigoid dye used to color oral 
and topical pharmaceutical preparations. It is used with 
yellow colors to produce green colors. Indigo carmine is also 
used to color nylon surgical sutures and is used diagnostically 
as a 0.8% w/v injection. 
Sunset yellow FCF 
Empirical formula: C16H10N2Na2O7S2 
Molecular weight: 452.37 
CAS number: [2783-94-0] 
Synonyms: E110; FD&C yellow #6; 6-hydroxy-5-[(4-sulfophenyl)
azo]-2-naphthalenesulfonic acid disodium salt; 1-psulfophenylazo-
2-naphthol-6-sulfonic acid disodium salt; 
yellow orange S. 
Structure: 
Appearance: reddish yellow powder. Aqueous solutions are 
bright orange colored. 
Absorption maximum: 482nm 
Color Index No.: CI 15985 
Purity (EU): 
Arsenic: 43 ppm 
Lead: 410 ppm 
Mercury: 41 ppm 
Cadmium: 41 ppm 
Heavy metals: 440 ppm 
Ether-extractable matter: 40.2% under neutral conditions 
Assay: 585% total coloring matters as the sodium salt 
Subsidiary colors: 45% 
Water-insoluble matter: 40.2% 
Organic compounds other than coloring matters: 40.5% 
Unsulfonated primary aromatic amines: 40.01% as aniline 
Ether-extractable matter: 40.2% under neutral conditions 
Purity (US): 
Arsenic: 43 ppm 
Lead: 410 ppm 
Mercury: 41 ppm 
4-Aminobenzenesulfonic acid: 40.2% as the sodium salt 
6-Hydroxy-2-naphthalenesulfonic acid: 40.3% as the 
sodium salt 
6,60-Oxybis[2-naphthalenesulfonic acid]: 41% as the disodium 
salt 
4,40-(1-Triazene-1,3-diyl)bis[benzenesulfonic acid]: 40.1% 
as the disodium salt 
4-Aminobenzene: 450 ppb 
4-Aminobiphenyl: 415 ppb 
Aniline: 4250 ppb 
Azobenzene: 4200 ppb 
Benzidine: 41 ppb 
1,3-Diphenyltriazene: 440 ppb 
1-(Phenylazo)-2-naphthalenol: 410 ppm 
Total color: 587% 
Sum of volatile matter at 1358C, chlorides and sulfates: 
413.0% 
Water-insoluble matter: 40.2% 
Solubility: see Table IX. 
Incompatibilities: poorly compatible with citric acid, saccharose 
solutions, and saturated sodium bicarbonate solutions. 
Incompatible with ascorbic acid, gelatin, and glucose. 
Method of manufacture: diazotized sulfanilic acid is coupled 
with Schaeffers salt (sodium salt of b-naphthol-6-sulfonic 
acid). 
Safety:
LD50 (mouse, IP): 4.6 g/kg 
LD50 (mouse, oral): >6 g/kg 
LD50 (rat, IP): 3.8 g/kg 
LD50 (rat, oral): >10 g/kg 
Comments: sunset yellow FCF is a monoazo dye. 
The EINECS number for sunset yellow FCF is 220-491-7. 
Table IX: Solubility of Sunset yellow FCF. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone 1 in 38.5 
Ethanol (75%) 1 in 333 
Glycerin 1 in 5 
Propylene glycol 1 in 45.5 
Propylene glycol (50%) 1 in 5 
Water 1 in 5.3 at 28C 
1 in 5.3 at 258C 
1 in 5 at 608C 
Tartrazine 
Empirical formula: C16H9N4Na3O9S2 
Molecular weight: 534.39 
CAS number: [1934-21-0] 
Synonyms: 4,5-dihydro-5-oxo-1-(4-sulfophenyl)-4-[(4-sulfophenyl)
azo]-1H-pyrazole-3-carboxylic acid trisodium salt; 
E102; FD&C yellow #5; hydrazine yellow. 
Structure: 
Appearance: yellow or orange-yellow powder. Aqueous 
solutions are yellow-colored; the color is retained upon 
addition of hydrochloric acid solution, but with sodium 
hydroxide solution a reddish color is formed. 
Absorption maximum: 425nm 
Color Index No.: CI 19140 
Purity (EU): 
Arsenic: 43 ppm 
Lead: 410 ppm 
198 Coloring Agents

Mercury: 41 ppm 
Cadmium: 41 ppm 
Heavy metals: 440 ppm 
Assay: 585% total coloring matters as the sodium salt 
Organic compounds other than coloring matters: 40.5% 
Unsulfonated primary aromatic amines: 40.01% as aniline 
Ether-extractable matter: 40.2% under neutral conditions 
Accessory colorings: 41.0% 
Water-insoluble matter: 40.2% 
Purity (US): 
Arsenic: 43 ppm 
Lead: 410 ppm 
Mercury: 41 ppm 
Total color: 587.0% 
Volatile matter, chlorides and sulfates (calculated as the 
sodium salts): 413.0% at 1358C 
Water-insoluble matter: 40.2% 
4,40-[4,5-Dihydro-5-oxo-4-[(4-sulfophenyl)hydrazono]-1Hpyrazol-
1,3-diyl]bis[benzenesulfonic acid]: 40.1% as the 
trisodium salt 
4-Aminobenzenesulfonic acid: 40.2% as the sodium salt 
4,5-Dihydro-5-oxo-1-(4-sulfophenyl)-1H-pyrazole-3-carboxylic 
acid: 40.2% as the disodium salt 
Ethyl or methyl 4,5-dihydro-5-oxo-1-(4-sulfophenyl)-1Hpyrazole-
3-carboxylate: 40.1% as the sodium salt 
4,40-(1-Triazene-1,3-diyl)bis[benzenesulfonic acid]: 
40.05% as the disodium salt 
4-Aminobenzene: 475 ppb 
4-Aminobiphenyl: 45 ppb 
Aniline: 4100 ppb 
Azobenzene: 440 ppb 
Benzidine: 41 ppb 
1,3-Diphenyltriazene: 440 ppb 
Solubility: see Table X. 
Table X: Solubility of tartrazine. 
Solvent Solubility at 208C unless otherwise stated 
Acetone Practically insoluble 
Ethanol (75%) 1 in 91 
Glycerin 1 in 5.6 
Propylene glycol 1 in 14.3 
Propylene glycol (50%) 1 in 5 
Water 1 in 26 at 28C 
1 in 5 at 258C 
1 in 5 at 608C 
Incompatibilities: poorly compatible with citric acid solutions. 
Incompatible with ascorbic acid, lactose, 10% glucose 
solution, and saturated aqueous sodium bicarbonate solution. 
Gelatin accelerates the fading of the color. 
Method of manufacture: phenylhydrazine p-sulfonic acid is 
condensed with sodium ethyl oxalacetate; the product 
obtained from this reaction is then coupled with diazotized 
sulfanilic acid. 
Safety:
LD50 (mouse, oral): >6 g/kg 
LD50 (mouse, IP): 4.6 g/kg 
LD50 (rat, oral): 10 g/kg 
LD50 (rat, IP): 3.8 g/kg 
Comments: tartrazine is a monoazo, or pyrazolone, dye. It is 
used to improve the appearance of a product and to impart a 
distinctive coloring for identification purposes. 
US regulations require that prescription drugs for human 
use containing tartrazine bear the warning statement: 
This product contains FD&C yellow #5 (tartrazine) 
which may cause allergic-type reactions (including 
bronchial asthma) in certain susceptible persons. 
Although the overall incidence of sensitivity to FD&C 
yellow #5 (tartrazine) in the general population is low, it is 
frequently seen in patients who are also hypersensitive to 
aspirin. 
18 Comments 
Titanium dioxide is used extensively to impart a white color to 
film-coated tablets, sugar-coated tablets, and gelatin capsules. It 
is also used in lakes as an opacifier, to extend the color. See 
Titanium dioxide for further information. 
In the EU, colors used in pharmaceutical formulations and 
colors used in cosmetics are controlled by separate regulations. 
Cosmetic colors are also classified according to their use, e.g. 
those that may be used in external products that are washed off 
after use. 
19 Specific References 
1 Hess H, Schrank J. Coloration of pharmaceuticals: possibilities 
and technical problems. Acta Pharm Technol 1979; 25 (Suppl. 8): 
7787. 
2 Aulton ME, Abdul-Razzak MH, Hogan JE. The mechanical 
properties of hydroxypropylmethylcellulose films derived from 
aqueous systems part 1: the influence of solid inclusions. Drug Dev 
Ind Pharm 1984; 10: 541561. 
3 Rowe RC. The opacity of tablet film coatings. J Pharm Pharmacol 
1984; 36: 569572. 
4 Woznicki EJ, Schoneker DR. Coloring agents for use in 
pharmaceuticals. In: Swarbrick J, Boylan JC, eds. Encyclopedia 
of Pharmaceutical Technology, vol. 3. New York: Marcel Dekker, 
1990: 65100. 
5 Porter SC. Tablet coating. Drug Cosmet Ind 1981; 128(5): 46, 48, 
50, 53, 8693. 
6 Marmion DM. Handbook of US Colorants for Foods, Drugs and 
Cosmetics, 3rd edn. New York: Wiley-Interscience, 1991. 
7 European Commission. Official Journal EC. 1995; L226/1. 
8 Delonca H, Laget J-P, Saunal H, Ahmed K. Stability of principal 
tablet coating colors II: effect of adjuvants on color stability [in 
French]. Pharm Acta Helv 1983; 58: 332337. 
9 Walford J, ed. Developments in Food Colors, vol. 1. New York: 
Elsevier, 1980. 
10 Walford J, ed. Developments in Food Colors, vol. 2. New York: 
Elsevier, 1980. 
11 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation 
Agents: a Handbook of Excipients. New York: Marcel Dekker, 
1989: 159165. 
12 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. 
Boca Raton, FL: CRC Press, 1992. 
13 Blumenthal D. Red No. 3 and other colorful controversies. FDA 
Consumer 1990; 21: 18. 
14 Bell T. Colourants and drug reactions [letter]. Lancet 1991; 338: 
5556. 
15 Le.vesque H, Moore N, Courtois H. Reporting adverse drug 
reactions by proprietary name [letter]. Lancet 1991; 338: 393. 
16 Dietemann-Molard A, Braun JJ, Sohier B, Pauli G. Extrinsic 
allergic alveolitis secondary to carmine [letter]. Lancet 1991; 338: 
460. 
17 Pollock I, Young E, Stoneham M, et al. Survey of colourings and 
preservatives in drugs. Br Med J 1989; 299: 649651. 
18 European Commission. Official Journal EC. 1978; L11/18. 
19 European Commission. Official Journal EC. 1994; L237/13. 
Coloring Agents 199

20 European Commission (1998). Opinion on toxicological data on 
colouring agents for medicinal products: amaranth, adopted by the 
Scientific Committee on Medicinal Products and Medical Devices 
on 21 October 1998. http://europa.eu.int/comm/health/ph_risk/ 
committees/scmp/scmp_en.htm (accessed 30 June 2005). 
21 European Commission (1998). Opinion on toxicological data on 
colouring agents for medicinal products: erythrosin, adopted by 
the Scientific Committee on Medicinal Products and Medical 
Devices on 21 October 1998. http://europa.eu.int/comm/health/ 
ph_risk/committees/scmp/docshtml/scmp_out08_en.htm (accessed 
24 January 2005). 
22 European Commission (1998). Opinion on toxicological data 
colouring agents for medicinal products: canthaxanthine, adopted 
by the Scientific Committee on Medicinal Products and Medical 
Devices on 21 October 1998. http://europa.eu.int/comm/health/ 
ph_risk/committees/scmp/docshtml/scmp_out10_en.htm (accessed 
24 January 2005). 
23 European Commission (1999). Opinion on toxicological data on 
colouring agents for medicinal products: aluminum, adopted by 
the Scientific Committee on Medicinal Products and Medical 
Devices on 14 April 1999. http://europa.eu.int/comm/health/ 
ph_risk/committees/scmp/docshtml/scmp_out21_en.htm (accessed 
24 January 2005). 
24 European Commission (2000). Opinion on toxicological data on 
colouring agents for medicinal products: E174 silver, adopted by 
the Scientific Committee on Medicinal Products and Medical 
Devices on 27 June 2000. http://europa.eu.int/comm/health/ 
ph_risk/committees/scmp/documents/out30_en.pdf (accessed 24 
January 2005). 
25 Code of Federal Regulations. Title 21 Parts 74, 81, 82. 
20 General References 
Jones BE. Colours for pharmaceutical products. Pharm Technol Int 
1993; 5(4): 1416, 1820. 
21 Authors 
C Mroz. 
22 Date of Revision 
27 August 2005. 
200 Coloring Agents

Copovidone 
1 Nonproprietary Names 
BP: Copovidone 
PhEur: Copovidonum 
USPNF: Copovidone 
2 Synonyms 
Acetic acid vinyl ester, polymer with 1-vinyl-2-pyrrolidinone; 
copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio 
of 3 : 2 by mass; copolyvidone; Kollidon VA 64; Luviskol VA; 
Plasdone S-630; poly(1-vinylpyrrolidoneco-vinyl acetate); 
polyvinylpyrrolidonevinyl acetate copolymer; PVP/VA; PVP/ 
VA copolymer. 
3 Chemical Name and CAS Registry Number 
Acetic acid ethenyl ester, polymer with 1-ethenyl-2-pyrrolidinone 
[25086-89-9] 
4 Empirical Formula and Molecular Weight 
(C6H9NO)n(C4H6O2)m (111.1)n . (86.1)m 
The ratio of n to m is approximately n = 1.2m. Molecular 
weights of 45 00070 000 have been determined for Kollidon 
VA 64. The average molecular weight of copovidone is usually 
expressed as a K-value. 
The K-value of Kollidon VA 64 is nominally 28, with a range 
of 25.230.8. The K-value of Plasdone S 630 is specified 
between 25.4 and 34.2. K-values are calculated from the 
kinematic viscosity of a 1% aqueous solution. Molecular 
weight can be calculated with the formula: 
M = 22.22 (K . 0.075K2)1.65 
The PhEur 2005 and USPNF 23 (Suppl. 1) describe 
copovidone as a copolymer of 1-ethenylpyrrolidin-2-one and 
ethenyl acetate in the mass proportion of 3 : 2. 
5 Structural Formula 
6 Functional Category 
Film-former; granulating agent; tablet binder. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Copovidone is used as a tablet binder, a film-former, and as part 
of the matrix material used in controlled-release formulations. 
In tableting, copovidone can be used as a binder for direct 
compression(13) and as a binder in wet granulation.(4,5) 
Copovidone is often added to coating solutions as a filmforming 
agent. It provides good adhesion, elasticity, and 
hardness, and can be used as a moisture barrier. 
See Table I. 
Table I: Uses of copovidone. 
Use Concentration (%) 
Film-forming agent 0.55.0(a) 
Tablet binder, direct 
compression 
2.05.0 
Tablet binder, wet 
granulation 
2.05.0 
(a) This corresponds to the % w/w copovidone in the film-forming solution formulation, before 
spraying. 
8 Description 
Copovidone is a white to yellowish-white amorphous powder. 
It is typically spray-dried with a relatively fine particle size. It 
has a slight odor and a faint taste. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for copovidone. 
Test PhEur 2005 USPNF 23 (Suppl. 1) 
Aldehydes 4500 ppm 40.05% 
Appearance of solution . . 
Characters .  
Ethenyl acetate 35.342.0% 35.341.4% 
Heavy metals 420 ppm  
Hydrazine 41 ppm 41 ppm 
Identification . . 
K-value 90110% 90.0110.0% 
Loss on drying 45.0% 45.0% 
Monomers 40.1% 40.1% 
Nitrogen content 7.08.0% 7.08.0% 
Peroxides 4400 ppm 40.04% 
2-Pyrrolidone 40.5%  
Sulfated ash 40.1% 40.1% 
Viscosity, expressed as 
K-value 
.  
10 Typical Properties 
Density(bulk): 0.240.28 g/cm3 
Density (tapped): 0.350.45 g/cm3 
Flash point: 2158C 
Flowability: relatively free-flowing powder. 
Glass transition temperature: 1068C for Plasdone S-630.(6) 
Hygroscopicity: at 50% relative humidity, copovidone gains 
less than 10% weight. 
K-value: 25.434.2 for Plasdone S-630.(6)

SEM: 1 
Excipient: Copovidone (Kollidon VA 64) 
Manufacturer: BASF 
Magnification: 400 Voltage: 10 kV 
Melting point: 1408C 
Solubility: greater than 10% solubility in 1,4-butanediol, 
glycerol, butanol, chloroform, dichloromethane, ethanol 
(95%), glycerol, methanol, polyethylene glycol 400, propan-
2-ol, propanol, propylene glycol, and water. Less than 
1% solubility in cyclohexane, diethyl ether, liquid paraffin, 
and pentane. 
Viscosity (dynamic): the viscosity of aqueous solutions depends 
on the molecular weight and the concentration. At 
concentrations less than 10%, the viscosity is less than 
10 mPa s (258C). 
11 Stability and Storage Conditions 
Copovidone is stable and should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Copovidone is compatible with most organic and inorganic 
pharmaceutical ingredients. When exposed to high water levels, 
copovidone may form molecular adducts with some materials; 
see Crospovidone and Povidone. 
13 Method of Manufacture 
Copovidone is manufactured by free-radical polymerization of 
vinylpyrrolidone and vinyl acetate in a ratio of 6 : 4. The 
synthesis is conducted in an organic solvent owing to the 
insolubility of vinyl acetate in water. 
14 Safety 
Copovidone is used widely in pharmaceutical formulations and 
is generally regarded as nontoxic. However, it is moderately 
toxic by ingestion, producing gastric disturbances. It has no 
irritating or sensitizing effects on the skin. 
LD50 (rat, oral): >0.63 g/kg(7) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition, 
copovidone emits toxic vapors of NOx. Eye protection, 
gloves, and a dust mask are recommended. 
16 Regulatory Status 
Copovidone is included in the FDA Inactive Ingredients Guide 
(oral tablets, oral film-coated tablets, sustained action). 
17 Related Substances 
Crospovidone; povidone. 
18 Comments 
Kollidon VA 64, has a spherical structure, with a high 
proportion of damaged spheres. The shell-like structure reduces 
flowability, but the damaged spheres cover a greater surface 
area of the filler particles, increasing the efficacy of its use as a 
dry binder.(8) Furthermore, when used in transdermal drug 
delivery systems, copovidone has been shown to significantly 
alter the melting behavior, by reducing the heat of fusion and 
the melting point of estradiol and various other sex steroids.(9) 
Plasdone S-630 has been used in direct compression 
experiments with active substances that are difficult to 
compress, such as acetaminophen (paracetamol); and has 
been shown to produce harder tablets than those containing 
the same actives but made with microcrystalline cellulose.(10) 
In general, copovidone has better plasticity than povidone as 
a tablet binder, and is less hygroscopic, more elastic, and less 
tacky in film-forming applications than povidone. 
Up to about 1975, copovidone was marketed by BASF 
under the name Luviskol VA 64. Luviskol is currently used only 
for the technical/cosmetic grade of copovidone. 
19 Specific References 
1 Moroni A. A novel copovidone binder for dry granulation and 
direct-compression tableting. Pharm Tech 2001; 25 (Suppl.): 824. 
2 Selmeczi B. The influence of the compressional force on the 
physical properties of tablets made by different technological 
processes. Arch Pharm (Weinheim) 1974; 307(10): 755760. 
3 Stamm A, Mathis C. The liberation of propyromazine from tablets 
prepared by direct compression. J Pharm Belg 1990; 29(4): 375 
389. 
4 Vojnovic D, Rubessa F, Bogataj M, Mrhar A. Formulation and 
evaluation of vinylpyrrolidone/vinylacetate copolymer microspheres 
with griseofulvin. J Microencapsul 1993; 10(1): 8999. 
5 Kristensen HG, Holm P, Jaegerskou A, Schaefer T. Granulation in 
high speed mixers. Part 4: Effect of liquid saturation on the 
agglomeration. Pharm Ind 1984; 46(7): 763767. 
6 International Specialty Products. Technical Literature: Plasdone S- 
630, 2002. 
7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 17. 
8 Kolter K, Flick D. Structure and dry binding activity of different 
polymers, including Kollidon VA 64. Drug Dev Ind Pharm 2000; 
26(11): 11591165. 
9 Lipp R. Selection and use of crystallization inhibitors for matrixtype 
transdermal drug-delivery systems containing sex steroids. J 
Pharm Pharmacol 1998; 50: 13431349. 
202 Copovidone

10 International Specialty Products. Technical literature: Plasdone 
S0630: A binder for direct compression and wet/dry granulation, 
2002. 
20 General References 
BASF. Technical literature: Kollidon VA 64, March 2000. 
21 Authors 
OA AbuBaker, D Pipkorn. 
22 Date of Revision 
1 August 2005. 
Copovidone 203

Corn Oil 
1 Nonproprietary Names 
BP: Refined maize oil 
JP: Corn oil 
PhEur: Maydis oleum raffinatum 
USPNF: Corn oil 
2 Synonyms 
Maize oil; Majsao CT. 
3 Chemical Name and CAS Registry Number 
Corn oil [8001-30-7] 
4 Empirical Formula and Molecular Weight 
Corn oil is composed of fatty acid esters with glycerol, known 
commonly as triglycerides. Typical corn oil produced in the 
USA contains five major fatty acids: linoleic 58.9%; oleic 
25.8%; palmitic 11.0%; stearic 1.7%; and linolenic 1.1%. 
Corn grown outside the USA yields corn oil with lower linoleic, 
higher oleic, and higher saturated fatty acid levels. Corn oil also 
contains small quantities of plant sterols. 
The USPNF 23 describes corn oil as the refined fixed oil 
obtained from the embryo of Zea mays Linne. (Fam. 
Gramineae). 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Corn oil is used primarily in pharmaceutical formulations as a 
solvent for intramuscular injections or as a vehicle for topical 
preparations. Emulsions containing up to 67% corn oil are also 
used as oral nutritional supplements; see also Section 18. When 
combined with surfactants and gel-forming polymers, it is used 
to formulate veterinary vaccines. 
Corn oil has a long history of use as an edible oil and may be 
used in tablets or capsules for oral administration. 
8 Description 
Clear, light yellow-colored, oily liquid with a faint characteristic 
odor and slightly nutty, sweet taste resembling cooked 
sweet corn. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for corn oil. 
Test JP 2001 PhEur 2005 USPNF 23 
Acid value 40.2 40.5  
Alkaline impurities  .  
Characters . .  
Cottonseed oil   . 
Composition of fatty 
acids 
 . . 
Fatty acids less than 
C16 
 40.6%  
Arachidic acid  40.8%  
Behenic acid  40.5%  
Oleic acid  20.042.2%  
Eicosaenoic acid  40.5%  
Linoleic acid  39.465.6%  
Linolenic acid  0.51.5%  
Palmitic acid  8.616.5%  
Stearic acid  43.3%  
Other fatty acids  40.5%  
Sterols  40.3%  
Water  40.1%  
Free fatty acids   . 
Heavy metals   40.001% 
Iodine value 103130  102130 
Organic volatile 
impurities 
  . 
Peroxide value  410.0  
Refractive index  1.474  
Saponification value 187195  187193 
Specific gravity 0.9150.921 0.920 0.9140.921 
Unsaponifiable matter 41.5% 42.8% 41.5% 
10 Typical Properties 
Acid value: 26 
Autoignition temperature: 3938C 
Density: 0.9150.918 g/cm3 
Flash point: 3218C 
Hydroxyl value: 812 
Melting point: 18 to 108C 
Refractive index: 
nD
25 = 1.4701.474; 
nD
40 = 1.4641.468. 
Solubility: miscible with benzene, chloroform, dichloromethane, 
ether, and hexane; practically insoluble in ethanol 
(95%) and water. 
Viscosity (dynamic): 3739 mPa s (3739 cP) 
11 Stability and Storage Conditions 
Corn oil is stable when protected with nitrogen in tightly sealed 
bottles. Prolonged exposure to air leads to thickening and 
rancidity. Corn oil may be sterilized by dry heat, maintaining it 
at 1508C for 1 hour.(1)

Corn oil should be stored in an airtight, light-resistant 
container in a cool, dry place. Exposure to excessive heat 
should be avoided. 
12 Incompatibilities 
The photooxidation of corn oil is sensitized by cosmetic and 
drug-grade samples of coated titanium oxide and zinc oxide.(2) 
13 Method of Manufacture 
Refined corn oil is obtained from the germ or embryo of Zea 
mays Linne. (Fam. Gramineae), which contains nearly 50% of 
the fixed oil compared with 3.06.5% in the whole kernel. The 
oil is obtained from the embryo by expression and/or solvent 
extraction. Refining involves the removal of free fatty acids, 
phospholipids, and impurities; decolorizing with solid adsorbents; 
dewaxing by chilling; and deodorization at high 
temperature and under vacuum. 
14 Safety 
Corn oil is generally regarded as a relatively nontoxic and 
nonirritant material with an extensive history of usage in food 
preparation. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Spillages of this material are 
very slippery and should be covered with an inert absorbent 
material prior to disposal. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM injections, 
oral capsules and tablets). Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Almond oil; canola oil; cottonseed oil; peanut oil; sesame oil; 
soybean oil; sunflower oil. 
18 Comments 
Owing to its high content of unsaturated acids, corn oil has 
been used as a replacement for fats and oils containing a high 
content of saturated acids in the diets of patients with 
hypercholesterolemia. 
A specification for corn oil is contained in the Food 
Chemicals Codex (FCC). The EINECS number for corn oil is 
232-281-2. 
19 Specific References 
1 Pasquale D, Jaconia D, Eisman P, Lachman L. A study of sterilizing 
conditions for injectable oils. Bull Parenter Drug Assoc 1964; 
18(3): 111. 
2 Sayre RM, Dowdy JC. Titanium dioxide and zinc oxide induce 
photooxidation of unsaturated lipids. Cosmet Toilet 2000; 115: 
7580, 82. 
20 General References 
Halbaut L, Barbe. C, Aro. ztegui M, de la Torre C. Oxidative stability of 
semi-solid excipient mixtures with corn oil and its implication in the 
degradation of vitamin A. Int J Pharm 1997; 147: 3140. 
Mann JI, Carter R, Eaton P. Re-heating corn oil does not saturate its 
double bonds [letter]. Lancet 1977; ii: 401. 
Watson SA, Ramstead PE, eds. Corn Chemistry and Technology. St. 
Paul, MN: American Association of Cereal Chemists Inc., 1987: 53 
78. 
21 Authors 
KS Alexander 
22 Date of Revision 
22 August 2005. 
Corn Oil 205

Cottonseed Oil 
1 Nonproprietary Names 
USPNF: Cottonseed oil 
2 Synonyms 
Cotton oil; refined cottonseed oil. 
3 Chemical Name and CAS Registry Number 
Cottonseed oil [8001-29-4] 
4 Empirical Formula and Molecular Weight 
A typical analysis of refined cottonseed oil indicates the 
composition of the acids present as glycerides to be as follows: 
linoleic acid 39.3%; oleic acid 33.1%; palmitic acid 19.1%; 
stearic acid 1.9%; arachidic acid 0.6%, and myristic acid 0.3%. 
Also present are small quantities of phospholipid, phytosterols, 
and pigments. The toxic polyphenolic pigment gossypol is 
present in raw cottonseed and in the oil cake remaining after 
expression of oil; it is not found in the refined oil. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cottonseed oil is used in pharmaceutical formulations primarily 
as a solvent for intramuscular injections. It has been used in 
intravenous emulsions as a fat source in parenteral nutrition 
regimens, although its use for this purpose has been superseded 
by soybean oil emulsions; see Section 14. It has also been used 
as an adjuvant in cholecystography and as a pediculicide and 
acaricide. It has the nutritive and emollient properties of fixed 
vegetable oils. By virtue of its high content of unsaturated acid 
glycerides (especially linoleic acid), it is used for dietary control 
of blood cholesterol levels in the prophylaxis and treatment of 
atherosclerosis. It is used as a solvent and vehicle for injections; 
as an emollient vehicle for other medications; and orally as a 
mild cathartic (in a dose of 30mL or more). It can also retard 
gastric secretion and motility, and increase caloric intake. It has 
been used in the manufacture of soaps, oleomargarine, lard 
substitutes, glycerin, lubricants, and cosmetics. 
Cottonseed oil has been used as a tablet binder for 
acetaminophen; for characterization of the hot-melt fluid bed 
coating process;(1) in the manufacturing of stable oral 
pharmaceutical powders; in encapsulation of enzymes; and as 
an aqueous dispersion in pharmaceutical coating. 
8 Description 
Pale yellow or bright golden yellow-colored, clear oily liquid. It 
is odorless, or nearly so, with a bland, nutty taste. At 
temperatures below 108C particles of solid fat may separate 
from the oil, and at about 5 to 08C the oil becomes solid or 
nearly so. If it solidifies, the oil should be remelted and 
thoroughly mixed before use. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cottonseed oil. 
Test USPNF 23 
Identification . 
Free fatty acids . 
Heavy metals 40.001% 
Iodine value 109120 
Organic volatile impurities . 
Specific gravity 0.9150.921 
10 Typical Properties 
Autoignition temperature: 3448C 
Density: 0.916 g/cm3 
Flash point: 3218C 
Freezing point: 5 to 08C 
Heat of combustion: 37.1 kJ/g 
Refractive index: nD
40 = 1.46451.4655 
Solubility: slightly soluble in ethanol (95%); miscible with 
carbon disulfide, chloroform, ether, hexane, and petroleum 
ether. 
Surface tension: 
35.4mN/m (35.4 dynes/cm) at 208C; 
31.3mN/m (31.3 dynes/cm) at 808C. 
Viscosity (dynamic): up to 70.4 mPa s (70.4 cP) at 208C 
11 Stability and Storage Conditions 
Cottonseed oil is stable if stored in a well-filled, airtight, lightresistant 
container in a cool, dry place. 
12 Incompatibilities 

13 Method of Manufacture 
Cottonseed oil is the refined fixed oil obtained from the seed of 
cultivated varieties of Gossypium hirsutum Linne. or of other 
species of Gossypium (Fam. Malvaceae). The seeds contain 
about 15% oil. The testae of the seeds are first separated and 
the kernels are then exposed to powerful expression in a 
hydraulic press. The crude oil thus obtained has a bright red or 
blackish-red color and requires purification before it is suitable 
for food or pharmaceutical purposes.

Cottonseed oil is refined by treatment with diluted alkali to 
neutralize acids, decolorized with fullers earth or activated 
carbon, deodorized with steam under reduced pressure, and 
chilled to separate glycerides and resinous substances of higher 
melting point. 
14 Safety 
Cottonseed oil emulsions have in the past been used in longterm 
intravenous nutrition regimens.(2,3) A complex of adverse 
reactions, called the overloading syndrome(4) has been seen 
with chronic administration of cottonseed oil emulsion. This 
consisted of anorexia, nausea, abdominal pain, headache, fever, 
and sore throat. Signs of impaired liver function, anemia, 
hepatosplenomegaly, thrombocytopenia, and spontaneous 
hemorrhage due to delayed blood clotting have been reported. 
For parenteral nutrition purposes, cottonseed oil has been 
replaced by soybean oil,(2,5,6) especially in pregnant women, 
where the use of cottonseed lipid emulsion has been associated 
with adverse effects.(7) 
A notable difference between the cottonseed oil emulsion 
and the soybean oil emulsion is the particle size. The cottonseed 
oil emulsion has much larger particles than the soybean oil 
emulsion. These larger particles may have been handled 
differently by the body, thus perhaps accounting for some of 
the toxic reactions. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Spillages of this material are 
very slippery and should be covered with an inert absorbent 
material prior to disposal. 
Cottonseed oil is a combustible liquid when exposed to heat 
or flame. If it is allowed to impregnate rags or oily waste, there 
is a risk due to spontaneous heating. Dry chemicals such as 
carbon dioxide should be used to fight any fires. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM injections, 
oral, capsule, tablet and sublingual preparations). Included in 
the Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Almond oil; canola oil; corn oil; hydrogenated vegetable oil; 
peanut oil; sesame oil; soybean oil; sunflower oil. 
18 Comments 
A specification for unhydrogenated cottonseed oil is contained 
in the Food Chemicals Codex (FCC). The EINECS number for 
cottonseed oil is 232-280-7. 
19 Specific References 
1 Jozwiakowski MJ, Jones DM, Franz RM. Characterization of a 
hot-melt fluid bed coating process for fine granules. Pharm Res 
1990; 7: 11191126. 
2 McNiff BL. Clinical use of 10% soybean oil emulsion. Am J Hosp 
Pharm 1977; 34: 10801086. 
3 Cole WH. Fat emulsion for intravenous use. J Am Med Assoc 
1958; 166: 10421043. 
4 Goulon M, Barois A, Grosbuis S, Schortgen G. Fat embolism after 
repeated perfusion of lipid emulsion. Nouv Presse Med 1974; 3: 
1318. 
5 Davis SS. Pharmaceutical aspects of intravenous fat emulsions. J 
Hosp Pharm 1974; 32: 149160, 165171. 
6 Singh M, Ravin LJ. Parenteral emulsions as drug carrier systems. J 
Parenter Sci Technol 1986; 41: 3441. 
7 Amato P, Quercia RA. Historical perspective and review of the 
safety of lipid emulsion in pregnancy. Nutr Clin Prac 1991; 6(5): 
189192. 
20 General References 

21 Authors 
KS Alexander. 
22 Date of Revision 
22 August 2005. 
Cottonseed Oil 207

Cresol 
1 Nonproprietary Names 
BP: Cresol 
JP: Cresol 
USPNF: Cresol 
2 Synonyms 
Cresylic acid; cresylol; hydroxytoluene; tricresol. 
3 Chemical Name and CAS Registry Number 
Methylphenol [1319-77-3] 
4 Empirical Formula and Molecular Weight 
C7H8O 108.14 
5 Structural Formula 
m-Cresol 
6 Functional Category 
Antimicrobial preservative; disinfectant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cresol is used at 0.150.3% concentration as an antimicrobial 
preservative in intramuscular, intradermal, and subcutaneous 
injectable pharmaceutical formulations. It is also used as a 
preservative in some topical formulations and as a disinfectant. 
Cresol is not suitable as a preservative for preparations that are 
to be freeze-dried.(1) 
8 Description 
Cresol consists of a mixture of cresol isomers, predominantly 
m-cresol, and other phenols obtained from coal tar or 
petroleum. It is a colorless, yellowish to pale brownish-yellow, 
or pink-colored liquid, with a characteristic odor similar to 
phenol but more tarlike. An aqueous solution has a pungent 
taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cresol. 
Test BP 2004 JP 2001 USPNF 23 
Identification . . . 
Characters .   
Specific gravity 1.0291.044 1.0321.041 1.0301.038 
Distilling range . . 1952058C 
Acidity .   
Hydrocarbons 40.15% . . 
Volatile bases 40.15%   
Hydrocarbons and 
volatile bases 
combined 
40.25%   
Phenol   45.0% 
Sulfur compounds . .  
Nonvolatile matter 40.1%   
10 Typical Properties 
Acidity/alkalinity: a saturated aqueous solution is neutral or 
slightly acidic to litmus. 
Antimicrobial activity: cresol is similar to phenol but has 
slightly more antimicrobial activity. It is moderately active 
against Gram-positive bacteria, less active against Gramnegative 
bacteria, yeasts, and molds. Cresol is active below 
pH 9; optimum activity is obtained in acidic conditions. 
Synergistic effects between cresol and other preservatives 
have been reported.(2,3) When used as a disinfectant most 
common pathogens are killed within 10 minutes by 
0.30.6% solutions. Cresol has no significant activity 
against bacterial spores. 
Solubility: see Table II. 
Table II: Solubility of cresol. 
Solvent Solubility at 208C 
Benzene Miscible 
Chloroform Freely soluble 
Ethanol (95%) Freely soluble 
Ether Freely soluble 
Fixed alkali hydroxides Freely soluble 
Fixed and volatile oils Freely soluble 
Glycerin Miscible 
Water 1 in 50 
11 Stability and Storage Conditions 
Cresol and aqueous cresol solutions darken in color with age 
and on exposure to air and light. 
Cresol should be stored in a well-closed container, protected 
from light, in a cool, dry place. 
12 Incompatibilities 
Cresol has been reported to be incompatible with chlorpromazine.(
4) Antimicrobial activity is reduced in the presence of 
nonionic surfactants.

13 Method of Manufacture 
Cresol may be obtained from coal tar or prepared synthetically 
by either sulfonation or oxidation of toluene. 
14 Safety 
Reports of adverse reactions to cresol are generally associated 
with the use of either the bulk material or cresol-based 
disinfectants, which may contain up to 50% cresol, rather 
than for its use as a preservative. 
Cresol is similar to phenol although it is less caustic and 
toxic. However, cresol is sufficiently caustic to be unsuitable for 
skin and wound disinfection. In studies in rabbits, cresol was 
found to be metabolized and excreted primarily as the 
glucuronide.(5) 
A patient has survived ingestion of 12 g of cresol though 
with severe adverse effects.(6) 
LD50 (mouse, oral): 0.76 g/kg(7) 
LD50 (rabbit, skin): 2 g/kg 
LD50 (rat, oral): 1.45 g/kg 
See also Sections 17 and 18. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Cresol may be irritant to the 
skin, eyes, and mucous membranes. Eye protection, gloves, and 
a respirator are recommended. In the UK, the occupational 
exposure limit for cresol is 22 mg/m3 (5 ppm) long-term (8-hour 
TWA).(8) In the USA, the permissible and recommended 
exposure limits are 22 mg/m3 long-term and 10 mg/m3 longterm 
respectively.(9) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM, IV, 
intradermal, and SC injections). Included in parenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Chlorocresol; m-cresol; o-cresol; p-cresol; phenol. 
m-Cresol 
Empirical formula: C7H8O 
Molecular weight: 108.14 
CAS number: [108-39-4] 
Synonyms: m-cresylic acid; 3-hydroxytoluene; meta-cresol; 3- 
methylphenol. 
Appearance: colorless or yellowish liquid with a characteristic 
phenolic odor. 
Boiling point: 2028C 
Density: 1.034 g/cm3 at 208C 
Flash point: 868C (closed cup) 
Melting point: 11128C 
Refractive index: nD
20 = 1.5398 
Solubility: soluble in organic solvents; soluble 1 in 40 parts of 
water. 
Safety:
LD50 (cat, SC): 0.15 g/kg(7,10) 
LD50 (mouse, IP): 0.17 g/kg 
LD50 (mouse, oral): 0.83 g/kg 
LD50 (mouse, SC): 0.45 g/kg 
LD50 (rabbit, IV): 0.28 g/kg 
LD50 (rabbit, oral): 1.1 g/kg 
LD50 (rabbit, SC): 0.5 g/kg 
LD50 (rabbit, skin): 2.05 g/kg 
LD50 (rat, oral): 2.02 g/kg 
LD50 (rat, skin): 1.1 g/kg 
o-Cresol 
Empirical formula: C7H8O 
Molecular weight: 108.14 
CAS number: [95-48-7] 
Synonyms: o-cresylic acid; 2-hydroxytoluene; 2-methylphenol; 
ortho-cresol. 
Appearance: colorless deliquescent solid with a characteristic 
odor; it becomes yellow on storage. 
Boiling point: 1911928C 
Density: 1.047 g/cm3 at 208C 
Flash point: 81838C (closed cup) 
Melting point: 308C 
Refractive index: nD
20 = 1.553 
Safety:
LD50 (cat, SC): 0.6 g/kg(7,10) 
LD50 (mouse, oral): 0.34 g/kg 
LD50 (mouse, SC): 0.35 g/kg 
LD50 (mouse, skin): 0.62 g/kg 
LD50 (rabbit, IV): 0.2 g/kg 
LD50 (rabbit, oral): 0.8 g/kg 
LD50 (rabbit, SC): 0.45 g/kg 
LD50 (rat, oral): 1.35 g/kg 
LD50 (rat, skin): 0.62 g/kg 
p-Cresol 
Empirical formula: C7H8O 
Molecular weight: 108.14 
CAS number: [106-44-5] 
Synonyms: p-cresylic acid; 4-hydroxytoluene; 4-methylphenol; 
para-cresol. 
Appearance: crystalline solid. 
Boiling point: 201.88C 
Density: 1.0341 g/cm3 at 208C 
Flash point: 868C (closed cup) 
Melting point: 35.58C 
Refractive index: nD
20 = 1.5395 
Solubility: soluble in ethanol (95%) and ether; very slightly 
soluble in water. 
Safety:
LD50 (cat, SC): 0.08 g/kg(7,10) 
LD50 (mouse, IP): 0.03 g/kg 
LD50 (mouse, oral): 0.34 g/kg 
LD50 (mouse, SC): 0.15 g/kg 
LD50 (rabbit, IV): 0.16 g/kg 
LD50 (rabbit, oral): 1.1 g/kg 
LD50 (rabbit, SC): 0.3 g/kg 
LD50 (rabbit, skin): 0.3 g/kg 
LD50 (rat, oral): 1.80 g/kg 
LD50 (rat, skin): 0.75 g/kg 
18 Comments 
m-Cresol is generally considered the least toxic of the three 
cresol isomers.(10) Inhalation of aerosolized m-cresol in 
pulmonary insulin delivery formulations has been shown to 
be safe in animal models.(11) 
The PhEur 2005 contains a specification for cresol, crude. 
The EINECS number for cresol is 2035779. 
Cresol 209

19 Specific References 
1 FAO/WHO. WHO expert committee on biological standardization. 
Thirty-seventh report. World Health Organ Tech Rep Ser 
1987; No. 760. 
2 Denyer SP, Baird RM, eds. Guide to Microbiological Control in 
Pharmaceuticals. Chichester: Ellis Horwood, 1990: 261. 
3 Hugbo PG. Additive and synergistic actions of equipotent 
admixtures of some antimicrobial agents. Pharm Acta Helv 
1976; 51: 284288. 
4 McSherry TJ. Incompatibility between chlorpromazine and 
metacresol [letter]. Am J Hosp Pharm 1987; 44: 1574. 
5 Cresol. In: The Pharmaceutical Codex, 11th edn. London: 
Pharmaceutical Press, 1979: 232. 
6 Co. te. MA, Lyonnais J, Leblond PF. Acute Heinz-body anemia due 
to severe cresol poisoning: successful treatment with erythrocytapheresis. 
Can Med Assoc J 1984; 130: 13191322. 
7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1003. 
8 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: HSE Books, 2002. 
9 NIOSH. Recommendations for occupational safety and health 
standard. MMWR 1988; 37(Suppl S-7): 129. 
10 Deichmann WB, Keplinger ML. Phenols and phenolic compounds. 
In: Clayton GD, Clayton FE, eds. Pattys Industrial Hygiene and 
Toxicology, 3rd edn. New York: Wiley, 1981: 25972600. 
11 Gopalakrishnan V, Uster P, Rajendran N, Yoshida M. Inhalation 
safety of phenol and m-cresol in rodents: a fourteen-day repeat 
dose study. Presented at ISAM congress 2001, Interlaken, Switzerland. 
20 General References 
Chapman DG. o-Cresol. In: Board RG, Allwood MC, Banks JG, eds. 
Preservatives in the Food, Pharmaceutical and Environmental 
Industries. Oxford: Blackwell Scientific, 1987: 184. 
Russell AD, Jones BD, Milburn P. Reversal of the inhibition of bacterial 
spore germination and outgrowth by antibacterial agents. Int J 
Pharm 1985; 25: 105112. 
21 Authors 
LY Galichet. 
22 Date of Revision 
17 August 2005. 
210 Cresol

Croscarmellose Sodium 
1 Nonproprietary Names 
BP: Croscarmellose sodium 
PhEur: Carmellosum natricum conexum 
USPNF: Croscarmellose sodium 
2 Synonyms 
Ac-Di-Sol; crosslinked carboxymethylcellulose sodium; Explocel; 
modified cellulose gum; Nymcel ZSX; Pharmacel XL; 
Primellose; Solutab; Vivasol. 
3 Chemical Name and CAS Registry Number 
Cellulose, carboxymethyl ether, sodium salt, crosslinked 
[74811-65-7] 
4 Empirical Formula and Molecular Weight 
Croscarmellose sodium is a crosslinked polymer of carboxymethylcellulose 
sodium. 
See Carboxymethylcellulose sodium. 
5 Structural Formula 
See Carboxymethylcellulose sodium. 
6 Functional Category 
Tablet and capsule disintegrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Croscarmellose sodium is used in oral pharmaceutical formulations 
as a disintegrant for capsules,(1,2) tablets,(313) and 
granules. 
In tablet formulations, croscarmellose sodium may be used 
in both direct-compression and wet-granulation processes. 
When used in wet granulations, the croscarmellose sodium 
should be added in both the wet and dry stages of the process 
(intra- and extragranularly) so that the wicking and swelling 
ability of the disintegrant is best utilized.(11,12) Croscarmellose 
sodium at concentrations up to 5% w/w may be used as a tablet 
disintegrant, although normally 2% w/w is used in tablets 
prepared by direct compression and 3% w/w in tablets 
prepared by a wet-granulation process. See Table I. 
Table I: Uses of croscarmellose sodium. 
Use Concentration (%) 
Disintegrant in capsules 1025 
Disintegrant in tablets 0.55.0 
SEM: 1 
Excipient: Croscarmellose sodium (Ac-Di-Sol) 
Manufacturer: FMC Biopolymer 
Magnification: 100 
SEM: 2 
Excipient: Croscarmellose sodium (Ac-Di-Sol) 
Manufacturer: FMC Biopolymer 
Magnification: 1000

8 Description 
Croscarmellose sodium occurs as an odorless, white or grayishwhite 
powder. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for croscarmellose sodium. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
pH (1% w/v dispersion) 5.07.0 5.07.0 
Loss on drying 410.0% 410.0% 
Heavy metals 410 ppm 40.001% 
Sodium chloride and sodium glycolate 40.5% 40.5% 
Sulfated ash 14.028.0%  
Degree of substitution 0.600.85 0.600.85 
Content of water-soluble material 410.0% 1.010.0% 
Settling volume 10.030.0 ml 10.030.0 ml 
Microbial contamination .  
Aerobic 103/g 103/g 
Fungi 102/g 102/g 
Organic volatile impurities  . 
10 Typical Properties 
Acidity/alkalinity: pH = 5.07.0 in aqueous dispersions. 
Bonding index: 0.0456 
Brittle fracture index: 0.1000 
Density (bulk): 0.529 g/cm3 for Ac-Di-Sol(7) 
Density (tapped): 0.819 g/cm3 for Ac-Di-Sol(7) 
Density (true): 1.543 g/cm3 for Ac-Di-Sol(7) 
Particle size distribution: 
Ac-Di-Sol: not more than 2% retained on a #200 (73.7 mm) 
mesh and not more than 10% retained on a #325 (44.5 mm) 
mesh. 
Pharmacel XL: more than 90% less than 45 mm, and more 
than 98% less than 100 mm in size. 
Solubility: insoluble in water, although croscarmellose sodium 
rapidly swells to 48 times its original volume on contact 
with water. Practically insoluble in acetone, ethanol and 
toluene. 
Specific surface area: 0.810.83m2/g 
11 Stability and Storage Conditions 
Croscarmellose sodium is a stable though hygroscopic material. 
A model tablet formulation prepared by direct compression, 
with croscarmellose sodium as a disintegrant, showed no 
significant difference in drug dissolution after storage at 308C 
for 14 months.(9) 
Croscarmellose sodium should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
The efficacy of disintegrants, such as croscarmellose sodium, 
may be slightly reduced in tablet formulations prepared by 
either the wet-granulation or direct-compression process that 
contain hygroscopic excipients such as sorbitol.(10) 
Croscarmellose sodium is not compatible with strong acids 
or with soluble salts of iron and some other metals such as 
aluminum, mercury, and zinc. 
13 Method of Manufacture 
Alkali cellulose is prepared by steeping cellulose, obtained from 
wood pulp or cotton fibers, in sodium hydroxide solution. The 
alkali cellulose is then reacted with sodium monochloroacetate 
to obtain carboxymethylcellulose sodium. After the substitution 
reaction is completed and all of the sodium hydroxide has 
been used, the excess sodium monochloroacetate slowly 
hydrolyzes to glycolic acid. The glycolic acid changes a few of 
the sodium carboxymethyl groups to the free acid and catalyzes 
the formation of crosslinks to produce croscarmellose sodium. 
The croscarmellose sodium is then extracted with aqueous 
alcohol and any remaining sodium chloride or sodium glycolate 
is removed. After purification, croscarmellose sodium of purity 
greater than 99.5% is obtained.(4) The croscarmellose sodium 
may be milled to break the polymer fibers into shorter lengths 
and hence improve its flow properties. 
14 Safety 
Croscarmellose sodium is mainly used as a disintegrant in oral 
pharmaceutical formulations and is generally regarded as an 
essentially nontoxic and nonirritant material. However, oral 
consumption of large amounts of croscarmellose sodium may 
have a laxative effect, although the quantities used in solid 
dosage formulations are unlikely to cause such problems. 
In the UK, croscarmellose sodium is accepted for use in 
dietary supplements. 
The WHO has not specified an acceptable daily intake for 
the related substance carboxymethylcellulose sodium, used as a 
food additive, since the levels necessary to achieve a desired 
effect were not considered sufficient to be a hazard to health.(14) 
See also Carboxymethylcellulose sodium. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Croscarmellose sodium may 
be irritant to the eyes; eye protection is recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
granules, sublingual tablets, and tablets). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian 
List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Carboxymethylcellulose calcium; carboxymethylcellulose 
sodium. 
18 Comments 
Typically, the degree of substitution (DS) for croscarmellose 
sodium is 0.7. 
19 Specific References 
1 Botzolakis JE, Augsburger LL. Disintegrating agents in hard 
gelatin capsules. Part I: mechanism of action. Drug Dev Ind Pharm 
1988; 14(1): 2941. 
212 Croscarmellose Sodium

2 Dahl TC, Sue IT, Yum A. The influence of disintegrant level and 
capsule size on dissolution of hard gelatin capsules stored in high 
humidity conditions. Drug Dev Ind Pharm 1991; 17(7): 1001 
1016. 
3 Gissinger D, Stamm A. A comparative evaluation of the properties 
of some tablet disintegrants. Drug Dev Ind Pharm 1980; 6(5): 
511536. 
4 Shangraw R, Mitrevej A, Shah M. A new era of tablet 
disintegrants. Pharm Technol 1980; 4(10): 4957. 
5 Rudnic EM, Rhodes CT, Bavitz JF, Schwartz JB. Some effects of 
relatively low levels of eight tablet disintegrants on a direct 
compression system. Drug Dev Ind Pharm 1981; 7(3): 347358. 
6 Gorman EA, Rhodes CT, Rudnic EM. An evaluation of 
croscarmellose as a tablet disintegrant in direct compression 
systems. Drug Dev Ind Pharm 1982; 8: 397410. 
7 Rudnic EM, Rhodes CT, Welch S, Bernado P. Evaluations of the 
mechanism of disintegrant action. Drug Dev Ind Pharm 1982; 8: 
87109. 
8 Gordon MS, Chowhan ZT. Effect of tablet solubility and 
hygroscopicity on disintegrant efficiency in direct compression 
tablets in terms of dissolution. J Pharm Sci 1987; 76: 907909. 
9 Gordon MS, Chowhan ZT. The effect of aging on disintegrant 
efficiency in direct compression tablets with varied solubility and 
hygroscopicity, in terms of dissolution. Drug Dev Ind Pharm 1990; 
16: 437447. 
10 Johnson JR, Wang L-H, Gordon MS, Chowhan ZT. Effect of 
formulation solubility and hygroscopicity on disintegrant efficiency 
in tablets prepared by wet granulation, in terms of 
dissolution. J Pharm Sci 1991; 80: 469471. 
11 Gordon MS, Rudraraju VS, Dani K, Chowhan ZT. Effect of the 
mode of super disintegrant incorporation on dissolution in wet 
granulated tablets. J Pharm Sci 1993; 82(2): 220226. 
12 Khattab I, Menon A, Sakr A. Effect of mode of incorporation of 
disintegrants on the characteristics of fluid-bed wet-granulated 
tablets. J Pharm Pharmacol 1993; 45(8): 687691. 
13 Ferrero C, Mun. oz N, Velasco MV, et al. Disintegrating efficiency 
of croscarmellose sodium in a direct compression formulation. Int 
J Pharm 1997; 147: 1121. 
14 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 1990; No. 
789. 
20 General References 
DMV International. Technical literature: Pharmacel XL, 1997. 
DMV International. Primellose and Primojel. 
http://www.dmv-international.com (accessed 26 August 2005). 
FMC Corporation. Technical literature: Ac-Di-Sol, 2003. 
J. Rettenmaier and So.hne GmbH. Technical literature: Vivasol, 2001. 
Metsa. -Serla Chemicals BV. Technical literature: Nymcel ZSX, 1995. 
21 Authors 
RT Guest. 
22 Date of Revision 
23 August 2005. 
Croscarmellose Sodium 213

Crospovidone 
1 Nonproprietary Names 
BP: Crospovidone 
PhEur: Crospovidonum 
USPNF: Crospovidone 
2 Synonyms 
Crosslinked povidone; E1202; Kollidon CL; Kollidon CL-M; 
Polyplasdone XL; Polyplasdone XL-10; polyvinylpolypyrrolidone; 
PVPP; 1-vinyl-2-pyrrolidinone homopolymer. 
3 Chemical Name and CAS Registry Number 
1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8] 
4 Empirical Formula and Molecular Weight 
(C6H9NO)n >1 000 000 
The USPNF 23 describes crospovidone as a water-insoluble 
synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidinone. 
An exact determination of the molecular weight has 
not been established because of the insolubility of the material. 
5 Structural Formula 
See Povidone. 
6 Functional Category 
Tablet disintegrant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Crospovidone is a water-insoluble tablet disintegrant and 
dissolution agent used at 25% concentration in tablets 
prepared by direct-compression or wet- and dry-granulation 
methods.(16) It rapidly exhibits high capillary activity and 
pronounced hydration capacity, with little tendency to form 
gels. Studies suggest that the particle size of crospovidone 
strongly influences disintegration of analgesic tablets.(7) Larger 
particles provide a faster disintegration than smaller particles. 
Crospovidone can also be used as a solubility enhancer. With 
the technique of co-evaporation, crospovidone can be used to 
enhance the solubility of poorly soluble drugs. The drug is 
adsorbed on to crospovidone in the presence of a suitable 
solvent and the solvent is then evaporated. This technique 
results in faster dissolution rate. 
8 Description 
Crospovidone is a white to creamy-white, finely divided, freeflowing, 
practically tasteless, odorless or nearly odorless, 
hygroscopic powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for crospovidone. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
pH (1% suspension)  5.08.0 
Water  45.0% 
Residue on ignition 40.1% 40.4% 
Water-soluble 
substances 
41.0% 41.50% 
Peroxides 4400 ppm  
Heavy metals 410 ppm 40.001% 
Vinylpyrrolidinone  40.1% 
Loss on drying 45.0%  
Nitrogen content 
(anhydrous basis) 
11.012.8% . 
10 Typical Properties 
Acidity/alkalinity: pH = 5.08.0 (1% w/v aqueous slurry) 
Density: 1.22 g/cm3 
Density (bulk): see Table II. 
Density (tapped): see Table II. 
Table II: Density values of commercial grades of crospovidone. 
Commercial grade Density (bulk) 
g/cm3 
Density (tapped) 
g/cm3 
Kollidon CL 0.30.4 0.40.5 
Kollidon CL-M 0.150.25 0.30.5 
Polyplasdone XL 0.213 0.273 
Polyplasdone XL-10 0.323 0.461 
Moisture content: maximum moisture sorption is approximately 
60%. 
Particle size distribution: less than 400 mm for Polyplasdone 
XL; less than 74 mm for Polyplasdone XL-10. Approximately 
50% greater than 50 mm and maximum of 3% 
greater than 250 mm in size for Kollidon CL. Minimum of 
90% of particles are below 15 mm for Kollidon CL-M. 
Solubility: practically insoluble in water and most common 
organic solvents. 
Specific surface area: see Table III. 
Table III: Specific surface areas for commercial grades of 
crospovidone. 
Commercial grade Surface area 
(m2/g) 
Kollidon CL 1.0 
Kollidon CL-M 3.06.0 
Polyplasdone XL 0.60.8 
Polyplasdone XL-10 1.21.4

SEM 1 
Excipient: Crospovidone (Polyplasdone XL-10) 
Manufacturer: ISP Corp. 
Lot No.: S81031 
Magnification: 400 Voltage: 10 kV 
11 Stability and Storage Conditions 
Since crospovidone is hygroscopic, it should be stored in an 
airtight container in a cool, dry place. 
12 Incompatibilities 
Crospovidone is compatible with most organic and inorganic 
pharmaceutical ingredients. When exposed to a high water 
level, crospovidone may form molecular adducts with some 
materials; see Povidone. 
13 Method of Manufacture 
Acetylene and formaldehyde are reacted in the presence of a 
highly active catalyst to form butynediol, which is hydrogenated 
to butanediol and then cyclodehydrogenated to form 
butyrolactone. Pyrrolidone is produced by reacting butyrolactone 
with ammonia. This is followed by a vinylation reaction in 
which pyrrolidone and acetylene are reacted under pressure. 
The monomer vinylpyrrolidone is then polymerized in solution, 
using a catalyst. Crospovidone is prepared by a popcorn 
polymerization process. 
14 Safety 
Crospovidone is used in oral pharmaceutical formulations and 
is generally regarded as a nontoxic and nonirritant material. 
Short-term animal toxicity studies have shown no adverse 
effects associated with crospovidone.(8) However, owing to the 
lack of available data, an acceptable daily intake in humans has 
not been specified by the WHO.(8) 
LD50 (mouse, IP): 12 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection, gloves, and a 
dust mask are recommended. 
16 Regulatory Status 
Accepted for use as a food additive in Europe. Included in the 
FDA Inactive Ingredients Guide (IM injections, oral capsules 
and tablets; topical, transdermal, and vaginal preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Copovidone; povidone. 
18 Comments 
Crospovidone has been studied as a superdisintegrant. The 
ability of the compound to swell has been examined directly 
using scanning electron microscopy.(9) The impact of crospovidone 
on percolation has also been examined.(10) The 
impact of crospovidone on dissolution of poorly soluble drugs 
in tablets has also been investigated.(11) 
A specification for crospovidone is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Kornblum SS, Stoopak SB. A new tablet disintegrating agent: 
crosslinked polyvinylpyrrolidone. J Pharm Sci 1973; 62: 4349. 
2 Rudnic EM, Lausier JM, Chilamkurti RN, Rhodes CT. Studies of 
the utility of cross linked polyvinylpolypyrrolidine as a tablet 
disintegrant. Drug Dev Ind Pharm 1980; 6: 291309. 
3 Gordon MS, Chowhan ZT. Effect of tablet solubility and 
hygroscopicity on disintegrant efficiency in direct compression 
tablets in terms of dissolution. J Pharm Sci 1987; 76: 907909. 
4 Gordon MS, Rudraraju VS, Dani K, Chowhan ZT. Effect of the 
mode of super disintegrant incorporation on dissolution in wet 
granulated tablets. J Pharm Sci 1993; 82: 220226. 
5 Tagawa M, Chen R, Chen P, et al. Effect of various disintegrants on 
drug release behavior from tablets. J Pharm Sci Tech Yakuzaigaku 
2003; 63(4): 238248. 
6 Hipasawa N, Ishise S, Miyata M, Danjo K. Application of 
nilvadipine solid dispersion to tablet formulation and manufacturing 
using crospovidone and methylcellulose on dispersion carriers. 
Chem Pharm Bull 2004; 52(2): 244247. 
7 Schiermeier S, Schmidt PC. Fast dispersible ibuprofen tablets. Eur J 
Pharm Sci 2002; 15(3): 295305. 
8 FAO/WHO. Evaluation of certain food additives and contaminants. 
Twenty-seventh report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1983; No. 696. 
9 Thibert R, Hancock BC. Direct visualization of superdisintegrant 
hydration using environmental scanning electron microscopy. J 
Pharm Sci 1996; 85: 12551258. 
10 Caraballo I, Fernandez-Arevalo M, Millan M, et al. Influence of 
disintegrant on the drug percolation threshold in tablets. Drug Dev 
Ind Pharm 1997; 23(7): 665669. 
11 Yen SY, Chen CR, Lee MT, Chen LC. Investigation of dissolution 
enhancement of nifedipine by deposition on superdisintegrants. 
Drug Dev Ind Pharm 1997; 23(3): 313317. 
Crospovidone 215

20 General References 
Barabas ES, Adeyeye CM. Crospovidone. In: Brittain HG, ed. 
Analytical Profiles of Drug Substances and Excipients, vol. 24. 
London: Academic Press, 1996: 87163. 
BASF. Technical literature: Insoluble Kollidon grades, 1996. 
ISP. Technical literature: Polyplasdone crospovidone NF, 1999. 
Wan LSC, Prasad KPP. Uptake of water by excipients in tablets. Int J 
Pharm 1989; 50: 147153. 
21 Authors 
AH Kibbe. 
22 Date of Revision 
25 August 2005. 
216 Crospovidone

Cyclodextrins 
1 Nonproprietary Names 
BP: Betadex 
PhEur: Betadexum 
USPNF: Betadex 
Note: b-cyclodextrin (betadex) is the only cyclodextrin to be 
currently described in a pharmacopeia. Alfadex is the rINN for 
a-cyclodextrin. 
2 Synonyms 
Cyclodextrin: Cavitron; cyclic oligosaccharide; cycloamylose; 
cycloglucan; Encapsin; Schardinger dextrin. 
a-Cyclodextrin: alfadex; alpha-cycloamylose; alpha-cyclodextrin; 
alpha-dextrin; Cavamax W6 Pharma; cyclohexaamylose; 
cyclomaltohexose. 
b-Cyclodextrin: beta-cycloamylose; beta-dextrin; Cavamax 
W7 Pharma; cycloheptaamylose; cycloheptaglucan; cyclomaltoheptose; 
Kleptose. 
g-Cyclodextrin: Cavamax W8 Pharma; cyclooctaamylose; 
gamma cyclodextrin. 
3 Chemical Name and CAS Registry Number 
a-Cyclodextrin [10016-20-3] 
b-Cyclodextrin [7585-39-9] 
g-Cyclodextrin [17465-86-0] 
4 Empirical Formula and Molecular Weight 
a-Cyclodextrin C36H60O30 972 
b-Cyclodextrin C42H70O35 1135 
g-Cyclodextrin C48H80O40 1297 
5 Structural Formula 
Note: the structure of b-cyclodextrin (7 glucose units) is 
shown. 
R0, R00 = H for natural a-, b- and g-cyclodextrins 
R0, R00 = CH3 for methyl cyclodextrins 
R0, R00 = CHOHCH3 for 2-hydroxyethyl cyclodextrins 
R0, R00 = CH2CHOHCH3 for 2-hydroxypropyl cyclodextrins 
6 Functional Category 
Solubilizing agent; stabilizing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cyclodextrins are crystalline, nonhygroscopic, cyclic oligosaccharides 
derived from starch. Among the most commonly used 
forms are a-, b-, and g-cyclodextrin, which have respectively 6, 
7, and 8 glucose units; see Section 5. 
Substituted cyclodextrin derivatives are also available; see 
Section 17. 
Cyclodextrins are bucketlike or conelike toroid molecules, 
with a rigid structure and a central cavity, the size of 
which varies according to the cyclodextrin type; see Section 8. 
The internal surface of the cavity is hydrophobic and the 
outside of the torus is hydrophilic; this is due to the 
arrangement of hydroxyl groups within the molecule. This 
arrangement permits the cyclodextrin to accommodate a guest 
molecule within the cavity, forming an inclusion complex. 
Cyclodextrins may be used to form inclusion complexes 
with a variety of drug molecules, resulting primarily in 
improvements to dissolution and bioavailability owing to 
enhanced solubility and improved chemical and physical 
stability; see Section 18. 
Cyclodextrin inclusion complexes have also been used to 
mask the unpleasant taste of active materials and to convert a 
liquid substance into a solid material. 
b-Cyclodextrin is the most commonly used cyclodextrin, 
although it is the least soluble; see Section 10. It is the least 
expensive cyclodextrin; is commercially available from a 
number of sources; and is able to form inclusion complexes 
with a number of molecules of pharmaceutical interest. 
However, b-cyclodextrin is nephrotoxic and should not be 
used in parenteral formulations; see Section 14. 
b-Cyclodextrin is considered to be nontoxic when administered 
orally, and is primarily used in tablet and capsule 
formulations. b-Cyclodextrin derivatives tend to be nontoxic 
when used either orally or parenterally, and the derivatives 2- 
hydroxypropyl-b-cyclodextrin and 3-hydroxypropyl-b-cyclodextrin 
are becoming increasingly important in pharmaceutical 
formulations.(15) 
a-Cyclodextrin is used mainly in parenteral formulations. 
However, as it has the smallest cavity of the cyclodextrins it can 
form inclusion complexes with only relatively few, small-sized 
molecules. In contrast, g-cyclodextrin has the largest cavity and 
can be used to form inclusion complexes with large molecules; 
it has low toxicity and enhanced water solubility. 
In oral tablet formulations, b-cyclodextrin may be used in 
both wet-granulation and direct-compression processes. The 
physical properties of b-cyclodextrin vary depending on the 
manufacturer. However, b-cyclodextrin tends to possess poor

flow properties and requires a lubricant, such as 0.1% w/w 
magnesium stearate, when it is directly compressed.(6,7) 
In parenteral formulations, cyclodextrins have been used to 
produce stable and soluble preparations of drugs that would 
otherwise have been formulated using a nonaqueous solvent. 
In eye drop formulations, cyclodextrins form water-soluble 
complexes with lipophilic drugs such as corticosteroids. They 
have been shown to increase the water solubility of the drug; to 
enhance drug absorption into the eye; to improve aqueous 
stability; and to reduce local irritation.(8) 
Cyclodextrins have also been used in the formulation of 
solutions,(9,10) suppositories,(11,12) and cosmetics.(13,14) 
8 Description 
Cyclodextrins are cyclic oligosaccharides containing at least six 
D-(.)-glucopyranose units attached by a(1!4) glucoside 
bonds. The three natural cyclodextrins, a, b, and g, differ in 
their ring size and solubility. They contain 6, 7, or 8 glucose 
units, respectively. 
Cyclodextrins occur as white, practically odorless, fine 
crystalline powders, having a slightly sweet taste. Some 
cyclodextrin derivatives occur as amorphous powders. 
The PhEur 2005 lists a-cyclodextrin and g-cyclodextrin as 
potential impurities in b-cyclodextrin. 
See also Table I. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for b-cyclodextrin (betadex). 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Color and clarity of solution . . 
pH 5.08.0  
Specific rotation .160 to .1648 .160 to .1648 
Microbial limits  41000/g(a) 
Sulfated ash 40.1% 40.1% 
Heavy metals 410 ppm 45 ppm 
Light-absorbing impurities .  
Loss on drying 416.0% 414.0% 
Related substances .  
Residual solvents .  
Reducing sugars 40.2% 41.0% 
Assay (anhydrous basis) 98.0101.0% 98.0101.0% 
(a) Tests for Salmonella and Escherichia coli are negative. 
10 Typical Properties 
Compressibility: 21.044.0% for b-cyclodextrin. 
Density (bulk): 
a-cyclodextrin: 0.526 g/cm3; 
b-cyclodextrin: 0.523 g/cm3; 
g-cyclodextrin: 0.568 g/cm3. 
Density (tapped): 
a-cyclodextrin: 0.685 g/cm3; 
b-cyclodextrin: 0.754 g/cm3; 
g-cyclodextrin: 0.684 g/cm3. 
Density (true): 
a-cyclodextrin: 1.521 g/cm3; 
g-cyclodextrin: 1.471 g/cm3. 
Melting point: 
a-cyclodextrin: 2502608C; 
b-cyclodextrin: 2552658C; 
g-cyclodextrin: 2402458C. 
Moisture content: 
a-cyclodextrin: 10.2% w/w; 
b-cyclodextrin: 13.015.0% w/w; 
g-cyclodextrin: 818% w/w. 
Particle size distribution: 
b-cyclodextrin: 7.045.0 mm 
Physical characteristics: see Table II. 
Table II: Physical characteristics of cyclodextrins. 
Characteristic Cyclodextrin 
a b g 
Cavity diameter (A) 4.75.3 6.06.5 7.58.3 
Height of torus (A) 7.9 7.9 7.9 
Diameter of periphery (A) 14.6 15.4 17.5 
Approximate volume of cavity (A3) 174 262 472 
Approximate cavity volume 
Per mol cyclodextrin (mL) 104 157 256 
Per g cyclodextrin (mL) 0.1 0.14 0.20 
Note: 1A = 0.1 nm. 
Solubility: 
a-cyclodextrin: soluble 1 in 7 parts of water at 208C, 1 in 3 
at 508C. 
b-cyclodextrin: soluble 1 in 200 parts of propylene glycol, 1 
in 50 of water at 208C, 1 in 20 at 508C; practically insoluble 
in acetone, ethanol (95%), and methylene chloride. 
g-cyclodextrin: soluble 1 in 4.4 parts of water at 208C, 1 in 2 
at 458C. 
Specific rotation [a]D
25: 
a-cyclodextrin: .150.58; 
b-cyclodextrin: .162.08; 
g-cyclodextrin: .177.48. 
Surface tension (at 258C): 
a-cyclodextrin: 71mN/m (71 dynes/cm); 
b-cyclodextrin: 71mN/m (71 dynes/cm); 
g-cyclodextrin: 71mN/m (71 dynes/cm). 
11 Stability and Storage Conditions 
b-Cyclodextrin and other cyclodextrins are stable in the solid 
state if protected from high humidity. 
Cyclodextrins should be stored in a tightly sealed container, 
in a cool, dry place. 
12 Incompatibilities 
The activity of some antimicrobial preservatives in aqueous 
solution can be reduced in the presence of hydroxypropyl-bcyclodextrin.(
1517) 
13 Method of Manufacture 
Cyclodextrins are manufactured by the enzymatic degradation 
of starch using specialized bacteria. For example, b-cyclodextrin 
is produced by the action of the enzyme cyclodextrin 
glucosyltransferase upon starch or a starch hydrolysate. An 
organic solvent is used to direct the reaction that produces bcyclodextrin, 
and to prevent the growth of microorganisms 
218 Cyclodextrins

during the enzymatic reaction. The insoluble complex of bcyclodextrin 
and organic solvent is separated from the 
noncyclic starch, and the organic solvent is removed in vacuo 
so that less than 1 ppm of solvent remains in the b-cyclodextrin. 
The b-cyclodextrin is then carbon treated and crystallized from 
water, dried, and collected. 
Hydroxyethyl-b-cyclodextrin is made by reacting b-cyclodextrin 
with ethylene oxide; hydroxypropyl-b-cyclodextrin is 
made by reacting b-cyclodextrin with propylene oxide. 
14 Safety 
Cyclodextrins are starch derivatives and are mainly used in oral 
and parenteral pharmaceutical formulations. They are also 
used in topical and ophthalmic formulations.(8) 
Cyclodextrins are also used in cosmetics and food products, 
and are generally regarded as essentially nontoxic and 
nonirritant materials. However, when administered parenterally, 
b-cyclodextrin is not metabolized but accumulates in the 
kidneys as insoluble cholesterol complexes, resulting in severe 
nephrotoxicity.(18) Other cyclodextrins, such as 2-hydroxypropyl-
b-cyclodextrin, have been the subject of extensive toxicological 
studies. They are not associated with nephrotoxicity and 
are reported to be safe for use in parenteral formulations.(3) 
Cyclodextrin administered orally is metabolized by microflora 
in the colon, forming the metabolites maltodextrin, 
maltose, and glucose; which are themselves further metabolized 
before being finally excreted as carbon dioxide and water. 
Although a study published in 1957 suggested that orally 
administered cyclodextrins were highly toxic,(19) more recent 
animal toxicity studies in rats and dogs have shown this not to 
be the case, and cyclodextrins are now approved for use in food 
products and orally administered pharmaceuticals in a number 
of countries. 
Cyclodextrins are not irritant to the skin and eyes, or upon 
inhalation. There is also no evidence to suggest that cyclodextrins 
are mutagenic or teratogenic. 
a-Cyclodextrin: 
LD50 (rat, IP): 1.0 g/kg(20) 
LD50 (rat, IV): 0.79 g/kg 
b-Cyclodextrin: 
LD50 (mouse, IP): 0.33 g/kg(21) 
LD50 (mouse, SC): 0.41 g/kg 
LD50 (rat, IP): 0.36 g/kg 
LD50 (rat, IV): 1.0 g/kg 
LD50 (rat, oral): 18.8 g/kg 
LD50 (rat, SC): 3.7 g/kg 
g-Cyclodextrin: 
LD50 (rat, IP): 4.6 g/kg(20) 
LD50 (rat ,IV): 4.0 g/kg 
LD50 (rat, oral): 8.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Cyclodextrins are fine 
organic powders and should be handled in a well-ventilated 
environment. Efforts should be made to limit the generation of 
dust, which can be explosive. 
16 Regulatory Status 
b-cyclodextrin is included in the FDA Inactive Ingredients guide 
(IM, IV injections, and other injection preparations). 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients (stabilizing agent; solubilizing agent ); and in oral 
and rectal pharmaceutical formulations licensed in Europe, 
Japan, and the USA. 
17 Related Substances 
Dimethyl-b-cyclodextrin; 2-hydroxyethyl-b-cyclodextrin; 
2-hydroxypropyl-b-cyclodextrin; 3-hydroxypropyl-b-cyclodextrin; 
trimethyl-b-cyclodextrin. 
Dimethyl-b-cyclodextrin 
Molecular weight: 1331 
Synonyms: DM-b-CD. 
Appearance: white crystalline powder. 
Cavity diameter: 6 A. 
Melting point: 295.0300.08C 
Moisture content: 41% w/w 
Solubility: soluble 1 in 135 parts of ethanol (95%), and 1 in 
1.75 of water at 258C. Solubility decreases with increasing 
temperature. 
Surface tension: 62mN/m (62 dynes/cm) at 258C 
Method of manufacture: dimethyl-b-cyclodextrin is prepared 
from b-cyclodextrin by the selective methylation of all C2 
secondary hydroxyl groups and all C6 primary hydroxyl 
groups (C3 secondary hydroxyl groups remain unsubstituted). 
Comments: used in applications similar to those for bcyclodextrin.(
2,3) 
2-Hydroxyethyl-b-cyclodextrin 
CAS number: [98513-20-3] 
Synonyms: 2-HE-b-CD. 
Appearance: white crystalline powder. 
Density (bulk): 0.681 g/cm3 
Density (tapped): 0.916 g/cm3 
Density (true): 1.378 g/cm3 
Solubility: greater than 1 in 2 parts of water at 258C. 
Surface tension: 68.071.0mN/m (6871 dynes/cm) at 258C. 
Comments: used in applications similar to those for 
b-cyclodextrin. The degree of substitution of hydroxyethyl 
groups can vary.(2,3,22) 
2-Hydroxypropyl-b-cyclodextrin 
CAS number: [128446-35-5] 
Synonyms: 2-HP-b-CD; Kleptose HPB. 
Appearance: white crystalline powder. 
Solubility: greater than 1 in 2 parts of water at 258C. 
Surface tension: 52.069.0mN/m (5269 dynes/cm) at 258C. 
Comments: used in applications similar to those for bcyclodextrin. 
However, as it is not nephrotoxic it has been 
suggested for use in parenteral formulations. Included in 
oral and parenteral pharmaceutical formulations licensed in 
Europe and the USA. The degree of substitution of 
hydroxypropyl groups can vary.(15) 
3-Hydroxypropyl-b-cyclodextrin 
Synonyms: 3-HP-b-CD. 
Appearance: white crystalline powder. 
Solubility: greater than 1 in 2 parts of water at 258C. 
Surface tension: 70.071.0mN/m (7071 dynes/cm) at 258C. 
Cyclodextrins 219

Comments: used in applications similar to those for bcyclodextrin. 
However, as it is not nephrotoxic it has been 
suggested for use in parenteral formulations. The degree of 
substitution of hydroxypropyl groups can vary.(2,3) 
Trimethyl-b-cyclodextrin 
Molecular weight: 1429 
Synonyms: TM-b-CD. 
Appearance: white crystalline powder. 
Cavity diameter: 4.07.0 A .
Melting point: 1578C 
Moisture content: 41% w/w 
Solubility: soluble 1 in 3.2 parts of water at 258C. Solubility 
decreases with increasing temperature. 
Surface tension: 56mN/m (56 dynes/cm) at 258C. 
Method of manufacture: trimethyl-b-cyclodextrin is prepared 
from b-cyclodextrin by the complete methylation of all C2 
and C3 secondary hydroxyl groups along with all C6 
primary hydroxyl groups. 
Comments: used in applications similar to those for bcyclodextrin.(
2,3) 
18 Comments 
In addition to their use in pharmaceutical formulations, 
cyclodextrins have also been investigated for use in various 
industrial applications. Analytically, cyclodextrin polymers are 
used in chromatographic separations, particularly of chiral 
materials. 
b-Cyclodextrin derivatives are more water-soluble than bcyclodextrin, 
and studies have shown that they have greater 
solubilizing action with some drugs such as ibuproxam, a 
poorly water-soluble anti-inflammatory agent.(23,24) 
The EINECS number for cyclodextrin is 231-493-2. 
19 Specific References 
1 Brewster ME, Simpkins JW, Hora MS, et al. The potential use of 
cyclodextrins in parenteral formulations. J Parenter Sci Technol 
1989; 43: 231240. 
2 Duche.ne D, Wouessidjewe D. Physicochemical characteristics and 
pharmaceutical uses of cyclodextrin derivatives, part I. Pharm 
Technol 1990; 14(6): 26, 28, 34. 
3 Duche.ne D, Wouessidjewe D. Physicochemical characteristics and 
pharmaceutical uses of cyclodextrin derivatives, part II. Pharm 
Technol 1990; 14(8): 14, 22, 24, 26. 
4 Brewster ME, Hora MS, Simpkins JW, Bodor N. Use of 2- 
hydroxypropyl-b-cyclodextrin as a solubilizing and stabilizing 
excipient for protein drugs. Pharm Res 1991; 8(6): 792795. 
5 Choudhury S, Nelson KF. Improvement of oral bioavailability of 
carbamazepine by inclusion in 2-hydroxypropyl-b-cyclodextrin. 
Int J Pharm 1992; 85: 175180. 
6 El Shaboury MH. Physical properties and dissolution profiles of 
tablets directly compressed with b-cyclodextrin. Int J Pharm 1990; 
63: 95100. 
7 Shangraw RF, Pande GS, Gala P. Characterization of the tableting 
properties of b-cyclodextrin and the effects of processing variables 
on inclusion complex formation, compactibility and dissolution. 
Drug Dev Ind Pharm 1992; 18(17): 18311851. 
8 Loftsson T, Stefansson E. Cyclodextrins in eye drop formulations: 
enhanced topical delivery of corticosteroids to the eye. Acta 
Ophthamol Scand 2002; 80(2): 144150. 
9 Prankerd RJ, Stone HW, Sloan KB, Perrin JH. Degradation of 
aspartame in acidic aqueous media and its stabilization by 
complexation with cyclodextrins or modified cyclodextrins. Int J 
Pharm 1992; 88: 189199. 
10 Palmieri GF, Wehrle. P, Stamm A. Inclusion of vitamin D2 in bcyclodextrin. 
Evaluation of different complexation methods. Drug 
Dev Ind Pharm 1993; 19(8): 875885. 
11 Szente L, Apostol I, Szejtli J. Suppositories containing bcyclodextrin 
complexes, part 1: stability studies. Pharmazie 
1984; 39: 697699. 
12 Szente L, Apostol I, Gerloczy A, Szejtli J. Suppositories containing 
b-cyclodextrin complexes, part 2: dissolution and absorption 
studies. Pharmazie 1985; 40: 406407. 
13 Amann M, Dressnandt G. Solving problems with cyclodextrins in 
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14 Buschmann HJ, Schollmeyer E. Applications of cyclodextrins in 
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15 Loftsson T, Stefa.nsdo. ttir O.
, Fridriksdo. ttir H, Gudmundsson O.
. 
Interactions between preservatives and 2-hydroxypropyl-b-cyclodextrin. 
Drug Dev Ind Pharm 1992; 18(13): 14771484. 
16 Lehner SJ, Mu. ller BW, Seydel JK. Interactions between phydroxybenzoic 
acid esters and hydroxypropyl-b-cyclodextrin 
and their antimicrobial effect against Candida albicans. Int J 
Pharm 1993; 93: 201208. 
17 Lehner SJ, Mu. ller BW, Seydel JK. Effect of hydroxypropyl-bcyclodextrin 
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18 Frank DW, Gray JE, Weaver RN. Cyclodextrin nephrosis in the 
rat. Am J Pathol 1976; 83: 367382. 
19 French D. The Schardinger dextrins. Adv Carbohydr Chem 1957; 
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20 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
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21 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1031. 
22 Menard FA, Dedhiya MG, Rhodes CT. Potential pharmaceutical 
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23 Mura P, Zerrouk N, Faucci M, et al. Comparative study of 
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24 Liu X, Lin HS, Chan SY, Ho PC. Biopharmaceuticals of betacyclodextrin 
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20 General References 
Bekers O, Uijtendaal EV, Beijnen JH, et al. Cyclodextrins in the 
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Bender ML, Komiyama M. Cyclodextrin Chemistry. New York: 
Springer-Verlag, 1978. 
Carpenter TO, Gerloczy A, Pitha J. Safety of parenteral hydroxypropyl 
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Chaubal MV. Drug delivery applications of cyclodextrins Part I. Drug 
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Darrouzet H. Preparing cyclodextrin inclusion compounds. Manuf 
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Fenyvest E.
, Antal B, Zsadon B, Szejtli J. Cyclodextrin polymer, a new 
tablet disintegrating agent. Pharmazie 1984; 39: 473475. 
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cytotoxicity of cyclodextrins and hydroxypropylated derivatives. 
Int J Pharm 1994; 101: 97103. 
Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins 
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10171025. 
Loftsson T, Brewster ME. Cyclodextrins as pharmaceutical excipients. 
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Loftsson T. Pharmaceutical applications of b-cyclodextrin. Pharm 

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220 Cyclodextrins

Pande GS, Shangraw RF. Characterization of b-cyclodextrin for direct 
compression tableting. Int J Pharm 1994; 101: 7180. 
Pande GS, Shangraw RF. Characterization of b-cyclodextrin for direct 
compression tableting II: the role of moisture in the compactibility 
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Pitha J, Szente L, Szejtli J. Molecular encapsulation by cyclodextrin and 
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Pharm Res 1997; 14(5): 556567. 
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21 Authors 
RA Nash. 
22 Date of Revision 
23 August 2005. 
Cyclodextrins 221

Cyclomethicone 
1 Nonproprietary Names 
USPNF: Cyclomethicone 
2 Synonyms 
Dimethylcyclopolysiloxane; Dow Corning 245 Fluid; Dow 
Corning 246 Fluid; Dow Corning 345 Fluid. 
3 Chemical Name and CAS Registry Number 
Cyclopolydimethylsiloxane [69430-24-6] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes cyclomethicone as a fully methylated 
cyclic siloxane containing repeating units of the formula 
[(CH3)2SiO]n in which n is 4, 5, or 6, or a mixture of them. 
5 Structural Formula 
6 Functional Category 
Emollient; humectant; viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Cyclomethicone is mainly used in topical pharmaceutical and 
cosmetic formulations such as water-in-oil creams.(13) 
Cyclomethicone has been used in cosmetic formulations, at 
concentrations of 0.150%, since the late 1970s and is now the 
most widely used silicone in the cosmetics industry. Its high 
volatility, and mild solvent properties, make it ideal for use in 
topical formulations because its low heat of vaporization means 
that when applied to skin it has a dry feel. 
See also Dimethicone. 
8 Description 
Cyclomethicone occurs as a clear, colorless and tasteless volatile 
liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for cyclomethicone. 
Test USPNF 23 
Identification . 
Limit of nonvolatile residue 40.15% 
Assay of (C2H6OSi)n calculated as the sum of 
cyclomethicone 4, cyclomethicone 5, and 
cyclomethicone 6 
598.0% 
Assay of individual cyclomethicone components 95.0105.0% 
10 Typical Properties 
Solubility: soluble in ethanol (95%), isopropyl myristate, 
isopropyl palmitate, mineral oil, and petrolatum at 808C; 
practially insoluble in glycerin, propylene glycol, and water. 
See also Table II. 
11 Stability and Storage Conditions 
Cyclomethicone should be stored in an airtight container in a 
cool, dry, place. 
12 Incompatibilities 

13 Method of Manufacture 
Cyclomethicone is manufactured by the distillation of crude 
polydimethylsiloxanes. 
14 Safety 
Cyclomethicone is generally regarded as a relatively nontoxic 
and nonirritant material. Although it has been used in oral 
pharmaceutical applications, cyclomethicone is mainly used in 
topical pharmaceutical formulations. It is also widely used in 
cosmetics. Studies of the animal and human toxicology of 
cyclomethicone suggest that it is nonirritant and not absorbed 
through the skin. Only small amounts are absorbed orally; an 
acute oral dose in rats produced no deaths.(4,5) 
See also Dimethicone. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral powder 
for reconstitution). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients.

17 Related Substances 
Dimethicone; simethicone. 
18 Comments 

19 Specific References 
1 Goldenberg RL, Tassof JA, DiSapio AJ. Silicones in clear 
formulations. Drug Cosmet Ind 1986; 138(Feb): 34, 38, 40, 44. 
2 Chandra D, DiSapio A, Frye C, Zellner D. Silicones for cosmetics 
and toiletries: environmental update. Cosmet Toilet 1994; 
109(Mar): 6366. 
3 Forster AH, Herrington TM. Rheology of siloxane-stabilized 
water in silicone emulsions. Int J Cosmet Sci 1997; 19(4): 173 
191. 
4 Anonymous. Final report on the safety assessment of cyclomethicone. 
J Am Coll Toxicol 1991; 10(1): 919. 
5 Christopher SM, Myers RC, Ballantyne B. Acute toxicologic 
evaluation of cyclomethicone. J Am Coll Toxicol 1994; 12(6): 578. 
20 General References 

21 Authors 
RT Guest. 
22 Date of Revision 
22 August 2005. 
Table II: Typical physical properties of selected commercially available cyclomethicones. 
Grade Boiling 
point (8C) 
Flash 
point (8C) 
Freezing 
point (8C) 
Refractive 
index at 258C 
Surface tension 
(mN/m) 
Specific gravity 
at 258C 
Viscosity 
(kinematic) 
(mm2/s) 
Water 
content 
(%) 
Dow Corning 245 Fluid 205 77 <50 1.397 18.0 0.95 4.0 0.025 
Dow Corning 246 Fluid 245 93 <40 1.402 18.8 0.96 6.8 0.025 
Dow Corning 345 Fluid 217 77 <50 1.398 20.8 0.957 6.0 0.025 
Cyclomethicone 223

Denatonium Benzoate 
1 Nonproprietary Names 
USPNF: Denatonium benzoate 
2 Synonyms 
Bitrex; Bitterguard; N-[2-(2,6-dimethylphenyl)amino]-2- 
oxoethyl]-N,N-diethylbenzenemethanaminium benzoate 
monohydrate; lignocaine benzyl benzoate. 
3 Chemical Name and CAS Registry Number 
Benzyldiethyl[(2,6-xylylcarbamolyl)methyl]ammonium benzoate 
anhydrous [3734-33-6] 
Benzyldiethyl[(2,6-xylylcarbamolyl)methyl]ammonium benzoate 
monohydrate [86398-53-0] 
4 Empirical Formula and Molecular Weight 
C28H34N2O3 446.59 (for anhydrous) 
C28H34N2O3H2O 464.60 (for monohydrate) 
5 Structural Formula 
6 Functional Category 
Alcohol denaturant; flavoring agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Denatonium benzoate is among the most bitter of substances 
known and is detectable at concentrations of approximately 
10 ppb. In pharmaceutical and other industrial applications it is 
added to some products as a deterrent to accidental ingestion.(
14) It is most commonly used at levels of 5500 ppm. 
Denatonium benzoate may also be used to replace brucine or 
quassin as a denaturant for ethanol. 
In pharmaceutical formulations, denatonium benzoate has 
been used as a flavoring agent in placebo tablets, and in a 
topical formulation it has been used in an anti-nailbiting 
preparation.(5) 
8 Description 
Denatonium benzoate occurs as an odorless, very bitter tasting, 
white crystalline powder or granules. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for denatonium benzoate. 
Test USPNF 23 
Identification . 
Melting range 1631708C 
pH (3% aqueous solution) 6.57.5 
Loss on drying (monohydrate) 43.54.5% 
Loss on drying (anhydrous) 41.0% 
Residue on ignition 40.1% 
Chloride 40.2% 
Assay (dried substance) 99.5101.0% 
10 Typical Properties 
Density (bulk): 0.30.6 g/cm3 
Density (tapped): 0.40.7 g/cm3 
Solubility: very soluble in chloroform, and methanol; soluble in 
ethanol (95%), and water; sparingly soluble in acetone; 
practically insoluble in ether. 
11 Stability and Storage Conditions 
Denatonium benzoate is stable up to 1408C and over a wide pH 
range. It should be stored in a well-closed container (such as 
polythene-lined steel) in a cool, dry place. Aqueous or alcoholic 
solutions retain their bitterness for several years even when 
exposed to light. 
12 Incompatibilities 
Denatonium benzoate is incompatible with strong oxidizing 
agents. 
13 Method of Manufacture 
Denatonium benzoate was first synthesized in the 1950s and is 
usually prepared by reacting denatonium chloride with benzyl 
benzoate. 
14 Safety 
Denatonium benzoate is generally regarded as a nonirritant and 
nonmutagenic substance. However, there has been a single 
report of contact urticaria attributed to denatonium benzoate 
occurring in a 30-year-old man who developed asthma and 
pruritus after using an insecticidal spray denatured with 
denatonium benzoate.(6) 
LD50 (rabbit, oral): 0.508 g/kg(7) 
LD50 (rat, oral): 0.584 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Containers should be kept 
tightly closed and handled in areas with good ventilation. Eye 
protection, gloves, and a dust mask are recommended. 
Denatonium benzoate is moderately toxic by ingestion and 
when heated to decomposition emits toxic vapors of NOx. 
Denatonium benzoate may also cause hypersensitization. 
16 Regulatory Status 
Denatonium benzoate is used worldwide as a denaturant for 
alcohol. It is included in the FDA Inactive Ingredients Guide 
(topical gel and solution). 
17 Related Substances 

18 Comments 
Several HPLC methods of analysis for denatonium benzoate 
have been reported.(810) The EINECS number for denatonium 
benzoate is 223-095-2. 
19 Specific References 
1 Klein-Schwartz W. Denatonium benzoate: review of efficacy and 
safety. Vet Hum Toxicol 1991; 33(6): 545547. 
2 Sibert JR, Frude N. Bittering agents in the prevention of accidental 
poisoning: childrens reactions to denatonium benzoate (Bitrex). 
Arch Emerg Med 1991; 8(1): 17. 
3 Hansen SR, Janssen C, Beasley VR. Denatonium benzoate as a 
deterrent to ingestion of toxic substances: toxicity and efficacy. Vet 
Hum Toxicol 1993; 35(3): 234236. 
4 Rodgers GC, Tenenbein M. Role of aversive bittering agents in the 
prevention of pediatric poisonings. Pediatrics 1994; 93(Jan): 68 
69. 
5 Anonymous. Relief for warts; none for nail biters. FDA Consum 
1981; 15(Feb): 13. 
6 Bjo. rkner B. Contact urticaria and asthma from denatonium 
benzoate (Bitrex). Contact Dermatitis 1980; 6(7): 466471. 
7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1087. 
8 Sugden K, Mayne TG, Loscombe CR. Determination of denaturants 
in alcoholic toilet preparations 1: denatonium benzoate 
(Bitrex) by high performance liquid chromatography. Analyst 
1978; 103(Jun): 653656. 
9 Faulkner A, DeMontigny P. High-performance liquid chromatographic 
determination of denatonium benzoate in ethanol with 5% 
polyvinylpyrrolidone. J Chromatogr-A 1995; 715(1): 189194. 
10 Henderson MC, Neumann CM, Buhler DR. Analysis of denatonium 
benzoate in Oregon consumer products by HPLC. Chemosphere 
1998; 36(1): 203210. 
20 General References 
Payne HAS. Bitrex  a bitter solution to safety. Chem Ind 1988; 22: 
721723. 
Payne HAS. Bitrex  a bitter solution to product safety. Drug Cosmet 
Ind 1989; 144(May): 30, 32, 34. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
Denatonium Benzoate 225

Dextrates 
1 Nonproprietary Names 
USPNF: Dextrates 
2 Synonyms 
Candex; Emdex. 
3 Chemical Name and CAS Registry Number 
Dextrates [39404-33-6] 
4 Empirical Formula and Molecular Weight 
The USPNF 23 describes dextrates as a purified mixture of 
saccharides resulting from the controlled enzymatic hydrolysis 
of starch. It may be either hydrated or anhydrous. Its dextrose 
equivalent is not less than 93.0% and not more than 99.0%, 
calculated on the dried basis. 
5 Structural Formula 
See Section 4. 
6 Functional Category 
Tablet binder; tablet and capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dextrates is a directly compressible tablet diluent used in 
chewable, nonchewable, soluble, dispersible, and effervescent 
tablets.(13) It is a free-flowing material and glidants are thus 
unnecessary. Lubrication with magnesium stearate (0.51.0% 
w/w) is recommended.(4) Dextrates may also be used as a 
binding agent by the addition of water, no further binder being 
required.(4) 
Tablets made from dextrates increase in crushing strength in 
the first few hours after manufacture, but no further increase 
occurs on storage.(5) 
8 Description 
Dextrates is a purified mixture of saccharides resulting from the 
controlled enzymatic hydrolysis of starch. It is either anhydrous 
or hydrated. In addition to dextrose, dextrates contains 35% 
w/w maltose and higher polysaccharides. 
Dextrates comprises white spray-crystallized free-flowing 
porous spheres. It is odorless with a sweet taste (about half as 
sweet as sucrose). 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dextrates. 
Test USPNF 23 
pH (20% aqueous solution) 3.85.8 
Loss on drying 
Anhydrous 42.0% 
Hydrated 7.89.2% 
Residue on ignition 40.1% 
Heavy metals 45 ppm 
Organic volatile impurities . 
Dextrose equivalent (dried basis) 93.099.0% 
10 Typical Properties 
Angle of repose: 26.48 (6) 
Compressibility: see Figure 1.(6) 
Density (bulk): 0.68 g/cm3(6) 
Density (tapped): 0.72 g/cm3(6) 
Density (true): 1.539 g/cm3 
Hausner ratio: 1.05 
Flowability: 9.3 g/s (6) 
Heat of combustion: 16.818.8 J/g (4.04.5 cal/g) 
Heat of solution: 105 J/g (25 cal/g) 
Melting point: 1418C. 
Moisture content: 7.89.2% w/w (hydrated form). See also 
Figure 2.(7) 
Particle size distribution: not more than 3% retained on a 
840 mm sieve; not more than 25% passes through a 150 mm 
sieve. Mean particle size 190220 mm. 
Solubility: soluble 1 in 1 part of water; insoluble in ethanol 
(95%), propan-2-ol, and common organic solvents. 
Specific surface area: 0.70m2/g 
11 Stability and Storage Conditions 
Dextrates may be heated to 508C without any appreciable 
darkening of color. Dextrates should be stored in a well-closed 
container in conditions that do not exceed 258C and 60% 
relative humidity. When correctly stored in unopened containers, 
dextrates has a shelf-life of 3 years. 
12 Incompatibilities 
At high temperatures and humidities, dextrates may react with 
substances containing a primary amino group (Maillard 
reaction).(8,9) Also incompatible with oxidizing agents. 
13 Method of Manufacture 
Dextrates is produced by controlled enzymatic hydrolysis of 
starch. The product is spray-crystallized, and may be dried to 
produce an anhydrous form.

Figure 1: Crushing strength for dextrates. 
&: Dextrates, Emdex (Lot # L-53X, Mendell) at V = 
100 mm/s 
~: Dextrates, Emdex (Lot # L-53X, Mendell) at V = 
300 mm/s 
Figure 2: Equilibrium moisture content of dextrates at 258C.(7) 
14 Safety 
Dextrates is used in oral pharmaceutical formulations and is 
generally regarded as a relatively nontoxic and nonirritant 
material. 
15 Handling Precautions 
Observe normal handling precautions appropriate to the 
circumstances and quantity of material handled. Eye protection, 
gloves, and a dust mask are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredient Guide 
(oral; tablets, sustained action). Included in nonparenteral 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dextrose. 
18 Comments 
Only the hydrated form of dextrates is currently commercially 
available. 
19 Specific References 
1 Henderson NL, Bruno AJ. Lactose USP (Beadlets) and Dextrose 
(PAF 2011): two new agents for direct compression. J Pharm Sci 
1970; 59: 13361340. 
2 Shukla AJ, Price JC. Effect of moisture content on compression 
properties of two dextrose-based directly compressible diluents. 
Pharm Res 1991; 8(3): 336340. 
3 Allen LV. Featured excipient: capsule and tablet diluents. Int J 
Pharm Compound 2000; 4(4): 306310, 324325. 
4 Penwest. Technical Literature: Emdex, 2004. 
5 Shangraw RF, Wallace JW, Bowers FM. Morphology and 
functionality in tablet excipients by direct compression: Part I. 
Pharm Technol 1981; 5(9): 6978. 
6 Celik M, Okutgen E. A feasibility study for the development of a 
prospective compaction functionality test and the establishment of 
a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309 
2334. 
7 Callahan JC, Cleary GW, Elefant M, et al. Equilibrium moisture 
content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 
8(3): 355369. 
8 Blang SM, Huang WT. Interaction of dexamphetamine sulphate 
with dextrates in solution. J Pharm Sci 1973; 62(4): 652655. 
9 Blaug SM, Huang WT. Browning of dextrates in solid-solid 
mixtures containing dexamphetamine sulfate. J Pharm Sci 1974; 
63(9): 14151418. 
20 General References 
Armstrong NA. Tablet manufacture. In: Swarbrick J, Boylan JC, eds. 
Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. New 
York: Marcel Dekker, 2002: 27132732. 
Shangraw RF. Direct compression tabletting. In: Swarbrick J, Boylan 
JC, eds. Encyclopedia of Pharmaceutical Technology, vol. 4. New 
York: Marcel Dekker, 1988: 85106. 
21 Authors 
NA Armstrong. 
22 Date of Revision 
16 August 2005. 
Dextrates 227

Dextrin 
1 Nonproprietary Names 
BP: Dextrin 
JP: Dextrin 
PhEur: Dextrinum 
USPNF: Dextrin 
2 Synonyms 
Avedex; British gum; Caloreen; canary dextrin; C*Pharm; 
Crystal Gum; dextrinum album; Primogran W; starch gum; 
yellow dextrin; white dextrin. 
3 Chemical Name and CAS Registry Number 
Dextrin [9004-53-9] 
4 Empirical Formula and Molecular Weight 
(C6H10O5)nxH2O (162.14)n 
The molecular weight of dextrin is typically 450085 000 
and depends on the number of (C6H10O5) units in the polymer 
chain. 
5 Structural Formula 
6 Functional Category 
Stiffening agent; suspending agent; tablet binder; tablet and 
capsule diluent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dextrin is a dextrose polymer used as an adhesive and stiffening 
agent for surgical dressings. It is also used as a tablet and 
capsule diluent; as a binder for tablet granulation; as a sugarcoating 
ingredient that serves as a plasticizer and adhesive; and 
as a thickening agent for suspensions. 
Additionally, dextrin has been used as a source of 
carbohydrate by people with special dietary requirements 
because it has a low electrolyte content and is free of lactose 
and sucrose.(1) 
Dextrin is also used in cosmetics. 
8 Description 
Dextrin is partially hydrolyzed maize (corn) or potato starch. It 
is a white, pale yellow or brown-colored powder with a slight 
characteristic odor. 
SEM: 1 
Excipient: Dextrin 
Manufacturer: Matheson Colleman & Bell 
Magnification: 600 
SEM: 2 
Excipient: Dextrin 
Manufacturer: Matheson Colleman & Bell 
Magnification: 2400

9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dextrin. 
Test JP 2001 PhEur 2005 USPNF 23 
Identification . . . 
Characters  .  
Appearance of solution .   
Loss on drying 410.0% 413.0% 413.0% 
Acidity . . . 
Residue on ignition 40.5% 40.5% 40.5% 
Chloride 40.013% 40.2% 40.2% 
Sulfate 40.019%   
Oxalate .   
Calcium .   
Heavy metals 450 ppm 420 ppm 420 mg/g 
Protein   41.0% 
Organic volatile impurities   . 
Reducing sugars/substances 
(calculated as C6H12O6) 
 410.0% 410.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.88.0 for a 5% w/v aqueous 
solution. 
Density (bulk): 0.80 g/cm3 
Density (tapped): 0.91 g/cm3 
Density (true): 1.4951.589 g/cm3 
Melting point: 1788C (with decomposition) 
Moisture content: 5% w/w 
Particle size distribution: see Figure 1. 
Solubility: practically insoluble in chloroform, ethanol (95%), 
ether, and propan-2-ol; slowly soluble in cold water; very 
soluble in boiling water, forming a mucilaginous solution. 
Specific surface area: 0.14m2/g 
11 Stability and Storage Conditions 
Physical characteristics of dextrin may vary slightly depending 
on the method of manufacture and on the source material. In 
aqueous solutions, dextrin molecules tend to aggregate as 
density, temperature, pH, or other characteristics change. An 
increase in viscosity is caused by gelation or retrogradation as 
dextrin solutions age, and is particularly noticeable in the lesssoluble 
maize starch dextrins. Dextrin solutions are thixotropic, 
becoming less viscous when sheared but changing to a soft 
paste or gel when allowed to stand. However, acids that are 
present in dextrin as residues from manufacturing can cause 
further hydrolysis, which results in a gradual thinning of 
solutions. Residual acid, often found in less-soluble dextrins 
such as pyrodextrin, will also cause a reduction in viscosity 
during dry storage. To eliminate these problems, dextrin 
manufacturers neutralize dextrins of low solubility with 
ammonia or sodium carbonate in the cooling vessel. 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing agents. 
Figure 1: Particle size distribution of dextrin. 
13 Method of Manufacture 
Dextrin is prepared by the incomplete hydrolysis of starch by 
heating in the dry state with or without the aid of suitable acids 
and buffers; moisture may be added during heating. The PhEur 
2005 specifies that dextrin is derived from maize (corn) or 
potato starch. A specification for cassava is included in the 
USPNF 23. 
14 Safety 
Dextrin is generally regarded as a nontoxic and nonirritant 
material at the levels employed as an excipient. Larger 
quantities are used as a dietary supplement without adverse 
effects, although ingestion of very large quantities may be 
harmful. 
LD50 (mouse, IV): 0.35 g/kg(2) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Dextrin may be irritant to the 
eyes. Eye protection, gloves, and a dust mask are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(IV injections, oral tablets and topical preparations). Included 
in nonparenteral medicines licensed in the UK. Included in the 
Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dextrates; dextrose; glucose liquid; maltodextrin. 
See also Section 18. 
Dextrin 229

18 Comments 
Dextrin is available from suppliers in a number of modified 
forms and mixtures such as dextrimaltose, a mixture of maltose 
and dextrin obtained by the enzymatic action of barley malt on 
corn flour. It is a light, amorphous powder, readily soluble in 
milk or water. 
Crystal Gum is a grade of dextrin containing carbohydrate 
not less than 98% of dry weight. Caloreen(1) is a water-soluble 
mixture of dextrins consisting predominantly of polysaccharides 
containing an average of 5 dextrose molecules, with a 
mean molecular weight of 840, that does not change after 
heating. A 22% w/v solution of Caloreen is isoosmotic with 
serum. 
A specification for dextrin is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for dextrin is 232-675-4. 
19 Specific References 
1 Berlyne GM, Booth EM, Brewis RAL, et al. A soluble glucose 
polymer for use in renal failure and calorie-deprivation states. 
Lancet 1969; i: 689692. 
2 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 1859. 
20 General References 
French D. Chemical and physical properties of starch. J Animal Sci 
1973; 37: 10481061. 
Satterthwaite RW, Iwinski DJ. Starch dextrins. In: Whistler RL, 
Bemiller JN, eds. Industrial Gums. New York: Academic Press, 
1973: 577599. 
21 Authors 
A Day. 
22 Date of Revision 
17 August 2005. 
230 Dextrin

Dextrose 
1 Nonproprietary Names 
BP: Glucose monohydrate 
JP: Glucose 
PhEur: Glucosum monohydricum 
USP: Dextrose 
2 Synonyms 
Blood sugar; Caridex; corn sugar; C*PharmDex; Dextrofin; 
D-(.)-glucopyranose monohydrate; grape sugar; Lycadex PF; 
Roferose; starch sugar; Tabfine D-100. 
3 Chemical Name and CAS Registry Number 
D-(.)-Glucose monohydrate [5996-10-1] 
See also Section 17. 
4 Empirical Formula and Molecular Weight 
C6H12O6H2O 198.17 (for monohydrate) 
See also Section 17. 
5 Structural Formula 
Anhydrous material shown. 
6 Functional Category 
Tablet and capsule diluent; therapeutic agent; tonicity agent; 
sweetening agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dextrose is widely used in solutions to adjust tonicity and as a 
sweetening agent. Dextrose is also used as a wet granulation 
diluent and binder, and as a direct-compression tablet diluent 
and binder, primarily in chewable tablets. Although dextrose is 
comparable as a tablet diluent to lactose, tablets produced with 
dextrose monohydrate require more lubrication, are less 
friable, and have a tendency to harden.(13) The mildly reducing 
properties of dextrose may be used when tableting to improve 
the stability of active materials that are sensitive to oxidation. 
Dextrose is also used therapeutically and is the preferred 
source of carbohydrate in parenteral nutrition regimens. 
8 Description 
Dextrose occurs as odorless, sweet-tasting, colorless crystals or 
as a white crystalline or granular powder. The JP 2001 
describes dextrose as dextrose anhydrous; the PhEur 2005 
specifies dextrose as either dextrose anhydrous or dextrose 
monohydrate; and the USP 28 specifies dextrose as dextrose 
monohydrate. 
SEM: 1 
Excipient: Dextrose anhydrous (granular) 
Manufacturer: Mallinckrodt Specialty Chemicals Co. 
Lot No.: KLKZ 
Magnification: 180 
9 Pharmacopeial Specifications 
See Table I. 
10 Typical Properties 
Data are shown for dextrose monohydrate; see Section 17 for 
data for dextrose anhydrous. 
Acidity/alkalinity: pH = 3.55.5 (20% w/v aqueous solution) 
Density (bulk): 0.826 g/cm3 
Density (tapped): 1.020 g/cm3 
Density (true): 1.54 g/cm3 
Heat of solution: 105.4 J/g (25.2 cal/g) 
Melting point: 838C 
Moisture content: anhydrous dextrose absorbs significant 
amounts of moisture at 258C and a relative humidity of 
about 85% to form the monohydrate. The monohydrate 
similarly only absorbs moisture at around 85% relative 
humidity and 258C. See Figure 1.

Table II: Solubility of dextrose monohydrate. 
Solvent Solubility at 208C 
Chloroform Practically insoluble 
Ethanol (95%) 1 in 60 
Ether Practically insoluble 
Glycerin Soluble 
Water 1 in 1 
Osmolarity: a 5.51% w/v aqueous solution is isoosmotic with 
serum. However, it is not isotonic since dextrose can pass 
through the membrane of red cells and cause hemolysis. 
Solubility: see Table II. 
11 Stability and Storage Conditions 
Dextrose has good stability under dry storage conditions. 
Aqueous solutions may be sterilized by autoclaving. However, 
excessive heating can cause a reduction in pH and caramelization 
of solutions.(47) 
The bulk material should be stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Dextrose solutions are incompatible with a number of drugs 
such as cyanocobalamin, kanamycin sulfate, novobiocin 
sodium, and warfarin sodium.(8) Erythromycin gluceptate is 
unstable in dextrose solutions at a pH less than 5.05.(9) 
Decomposition of B-complex vitamins may occur if they are 
warmed with dextrose. 
In the aldehyde form, dextrose can react with amines, 
amides, amino acids, peptides, and proteins. Brown coloration 
and decomposition occur with strong alkalis. 
Dextrose may cause browning of tablets containing amines 
(Maillard reaction). 
13 Method of Manufacture 
Dextrose, a monosaccharide sugar, occurs widely in plants and 
is manufactured on a large scale by the acid or enzymatic 
hydrolysis of starch, usually maize (corn) starch. Below 508C a- 
D-dextrose monohydrate is the stable crystalline form produced; 
above 508C the anhydrous form is obtained; and at still 
higher temperatures b-D-dextrose is formed, which has a 
melting point of 1481558C. 
14 Safety 
Dextrose is rapidly absorbed from the gastrointestinal tract. It 
is metabolized to carbon dioxide and water with the release of 
energy. 
Concentrated dextrose solutions given by mouth may cause 
nausea and vomiting. Dextrose solutions of concentration 
greater than 5% w/v are hyperosmotic and are liable to cause 
local vein irritation following intravenous administration. 
Thrombophlebitis has been observed following the intravenous 
infusion of isoosmotic dextrose solution with low pH, probably 
owing to the presence of degradation products formed by 
overheating during sterilization. The incidence of phlebitis may 
be reduced by adding sufficient sodium bicarbonate to raise the 
pH of the infusion above pH 7. 
LD50 (mouse, IV): 9 g/kg(10) 
LD50 (rat, oral): 25.8 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. Dust generation should be minimized to reduce 
the risk of explosion. 
Table I: Pharmacopeial specifications for dextrose. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters  .  
Color of solution . . . 
Specific optical rotation  .52.58 to 
.53.38 
.52.68 to 
.53.28 
Acidity . . . 
Organic volatile impurities   . 
Water 
for monohydrate  7.09.5% 7.59.5% 
for anhydrous 41.0%  40.5% 
Residue on ignition 40.1% 40.1% 40.1% 
Chloride 40.018% 4125 ppm 40.018% 
Sulfate 40.024% 4200 ppm 40.025% 
Arsenic 41.3 ppm 41 ppm 41 ppm 
Barium  .  
Calcium  4200 ppm  
Heavy metals 44 ppm  45 ppm 
Lead  40.5 ppm  
Dextrin . . . 
Soluble starch, and sulfites . . . 
Pyrogens(a)  .  
Assay (dried basis) 599.5%   
(a) If intended for large volume parenteral use. 
Figure 1: Sorptiondesorption isotherm for anhydrous dextrose 
granules. 
^: Sorption 
&: Desorption 
232 Dextrose

16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (capsules; 
inhalations; IM, IV, and SC injections; tablets, oral solutions, 
and syrups). Included in nonparenteral and parenteral medicines 
licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Dextrates; dextrin; dextrose anhydrous; fructose; glucose 
liquid; polydextrose; sucrose. 
Dextrose anhydrous 
Empirical formula: C6H12O6 
Molecular weight: 180.16 
CAS number: [50-99-7] 
Synonyms: anhydrous dextrose; anhydrous D-(.)-glucopyranose; 
anhydrous glucose; dextrosum anhydricum. 
Appearance: white, odorless, crystalline powder with a sweet 
taste. 
Acidity/alkalinity: pH = 5.9 (10% w/v aqueous solution) 
Density (bulk): 1.31.4 g/cm3 
Density (tapped): 1.11.2 g/cm3 
Melting point: 1468C 
Moisture content: see Section 10. 
Osmolarity: a 5.05% w/v aqueous solution is isoosmotic with 
serum. See also Section 10. 
Refractive index: nD
20 = 1.3479 (10% w/v aqueous solution) 
Solubility: see Table III. 
Specific gravity: see Table IV. 
Specific surface area: 0.220.29m2/g 
Table III: Solubility of dextrose anhydrous. 
Solvent Solubility at 208C 
unless otherwise stated 
Ethanol (95%) Sparingly soluble 
Ether Sparingly soluble 
Methanol 1 in 120 
Water 1 in 1.1 at 258C 
1 in 0.8 at 308C 
1 in 0.41 at 508C 
1 in 0.28 at 708C 
1 in 0.18 at 908C 
Table IV: Specific gravity of dextrose anhydrous aqueous solutions. 
Concentration of aqueous dextrose 
solution (% w/v) 
Specific gravity at 17.58C 
5 1.019 
10 1.038 
20 1.076 
30 1.113 
40 1.149 
18 Comments 
The way in which the strengths of dextrose solutions are 
expressed varies from country to country. The JP 2001 requires 
strengths to be expressed in terms of dextrose monohydrate, 
while the BP 2004 and USP 28 require strengths to be expressed 
in terms of anhydrous dextrose. Approximately 1.1 g of 
dextrose monohydrate is equivalent to 1 g of anhydrous 
dextrose. 
A specification for dextrose is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for dextrose is 200-075-1. 
19 Specific References 
1 DuVall RN, Koshy KT, Dashiell RE. Comparative evaluation of 
dextrose and spray-dried lactose in direct compression systems. J 
Pharm Sci 1965; 54: 11961200. 
2 Henderson NL, Bruno AJ. Lactose USP (beadlets) and dextrose 
(PAF 2011): two new agents for direct compression. J Pharm Sci 
1970; 59: 13361340. 
3 Armstrong NA, Patel A, Jones TM. The compressional properties 
of dextrose monohydrate and anhydrous dextrose of varying 
water contents. In: Rubinstein MH, ed. Pharmaceutical Technology: 
Tableting Technology, vol. 1. Chichester: Ellis Horwood, 
1987: 127138. 
4 Wing WT. An examination of the decomposition of dextrose 
solution during sterilisation. J Pharm Pharmacol 1960; 12: 191T 
196T. 
5 Murty BSR, Kapoor JN, Smith FX. Levels of 5-hydroxymethylfurfural 
in dextrose injection. Am J Hosp Pharm 1977; 34: 205 
206. 
6 Sturgeon RJ, Athanikar NK, Harbison HA, et al. Degradation of 
dextrose during heating under simulated sterilization. J Parenter 
Drug Assoc 1980; 34: 175182. 
7 Durham DG, Hung CT, Taylor RB. Identification of some acids 
produced during autoclaving of D-glucose solutions using HPLC. 
Int J Pharm 1982; 12: 3140. 
8 Patel JA, Phillips GL. A guide to physical compatibility of intravenous 
drug admixtures. Am J Hosp Pharm 1966; 23: 409411. 
9 Edward M. pH  an important factor in the compatibility of 
additives in intravenous therapy. Am J Hosp Pharm 1967; 24: 
440449. 
10 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 18601861. 
20 General References 

21 Authors 
A Day. 
22 Date of Revision 
9 June 2005. 
Dextrose 233

Dibutyl Phthalate 
1 Nonproprietary Names 
BP: Dibutyl phthalate 
PhEur: Dibutylis phthalas 
2 Synonyms 
Araldite 502; benzenedicarboxylic acid; benzene-o-dicarboxylic 
acid di-n-butyl ester; butyl phthalate; Celluflex DBP; 
DBP; dibutyl 1,2-benzenedicarboxylate; dibutyl benzene 1,2- 
dicarboxylate; dibutyl ester of 1,2-benzenedicarboxylic acid; 
dibutyl-o-phthalate; di-n-butyl phthalate; Elaol; Ergoplast 
FDB; Genoplast B; Hatcol DBP; Hexaplast M/B; Kodaflex 
DBP; Monocizer DBP; Palatinol C; phthalic acid dibutyl ester; 
Polycizer DBP; PX 104; RC Plasticizer DBP; Staflex DBP; 
Unimoll DB; Vestimol C; Witcizer 300. 
3 Chemical Name and CAS Registry Number 
Dibutyl benzene-1,2-dicarboxylate [84-74-2] 
4 Empirical Formula and Molecular Weight 
C16H22O4 278.34 
5 Structural Formula 
6 Functional Category 
Film-former; plasticizer; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dibutyl phthalate is used in pharmaceutical formulations as a 
plasticizer in film-coatings. It is also used extensively as a 
solvent particularly in cosmetic formulations such as antiperspirants, 
hair shampoos and hair sprays. In addition to a 
number of industrial applications, dibutyl phthalate is used as 
an insect repellent, although it is not as effective as dimethyl 
phthalate. 
8 Description 
Dibutyl phthalate occurs as an odorless, oily, colorless, or very 
slightly yellow-colored, viscous liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dibutyl phthalate. 
Test PhEur 2005 
Identification . 
Characters . 
Appearance . 
Relative density 1.0431.048 
Refractive index 1.4901.495 
Acidity . 
Related substances . 
Water 40.2% 
Sulfated ash 40.1% 
Assay 99.0101.0% 
10 Typical Properties 
Boiling point: 3408C 
Density: see Table II. 
Flash point: 1718C open cup. 
Melting point: 358C 
Partition coefficient: 
Octanol : water log kow = 4.50 
Refractive index: nD
20 = 1.4911.495 
Solubility: very soluble in acetone, benzene, ethanol (95%), and 
ether; soluble 1 in 2500 of water at 208C. 
Viscosity (dynamic): see Table II. 
Table II: Density and dynamic viscosity of dibutyl phthalate at 
specified temperatures. 
Temperature (8C) Density (g/cm3) Dynamic viscosity (mPa s) 
0 1.0627 59 
10 1.0546 33 
20 1.0465 20 
30 1.0384 13 
40 1.0303 9 
50 1.0222 7 
11 Stability and Storage Conditions 
Dibutyl phthalate should be stored in a well-closed container in 
a cool, dry, location. Containers may be hazardous when empty 
since they can contain product residues such as vapors and 
liquids. 
12 Incompatibilities 
Dibutyl phthalate reacts violently with chlorine. It also reacts 
with oxidizing agents, acids, bases, and nitrates.

13 Method of Manufacture 
Dibutyl phthalate is produced from n-butanol and phthalic 
anhydride in an ester formation reaction. 
14 Safety 
Dibutyl phthalate is generally regarded as a relatively nontoxic 
material, although it has occasionally been reported to cause 
hypersensitivity reactions. It is widely used in topical cosmetic 
and some oral pharmaceutical formulations. 
LD50 (mouse, IV): 0.72 g/kg(1) 
LD50 (mouse, oral): 5.3 g/kg 
LD50 (rat, oral): 8.0 g/kg 
LD50 (rat, IP): 3.05 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Contact with the skin and 
eyes should be avoided. Decomposition produces toxic fumes, 
carbon monoxide and carbon dioxide. 
In the USA, the permitted 8-hour exposure limit for dibutyl 
phthalate is 5 mg/m3. In the UK, the long-term (8-hour TWA) 
exposure limit for dibutyl phthalate is 5 mg/m3. The short-term 
(15-minute) exposure limit is 10 mg/m3.(2) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral delayed 
action, enteric coated, tablets). Included in nonparenteral 
medicines licensed in the UK (oral capsules, tablets, granules; 
topical creams and solutions). 
17 Related Substances 
Diethyl phthalate; dimethyl phthalate; dioctyl phthalate. 
Dioctyl phthalate 
Empirical formula: C24H38O4 
Molecular weight: 390.55 
CAS number: dioctyl phthalate occurs commercially in two 
isomeric forms: di-n-octyl phthalate [117-84-0] and di(2- 
ethylhexyl) phthalate [117-81-7]. 
Synonyms: 1,2-benzenedicarboxylic acid bis(2-ethylhexyl) 
ester; bis(2-ethylhexyl) phthalate; di(2-ethyl-hexyl)phthalate; 
DEHP; DOP; Octoil. 
Description: clear, colorless, odorless, and anhydrous liquid. 
Boiling point: 3848C 
Flash point: 2068C (closed cup). 
Melting point: 508C 
Refractive index: nD
20 = 1.50 
Solubility: soluble in conventional organic solvents; practically 
insoluble in water. 
Comments: the EINECS number for dioctyl phthalate is 204- 
214-7. 
18 Comments 
The EINECS number for dibutyl phthalate is 201-557-4. 
19 Specific References 
1 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1164. 
2 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Wilson AS. Plasticisers  Principles and Practice. London: Institute of 
Materials, 1995. 
21 Authors 
RT Guest. 
22 Date of Revision 
21 August 2005. 
Dibutyl Phthalate 235

Dibutyl Sebacate 
1 Nonproprietary Names 
USPNF: Dibutyl sebacate 
2 Synonyms 
Butyl sebacate; decanedioic acid, dibutyl ester; dibutyl decanedioate; 
dibutyl 1,8-octanedicarboxylate; Kodaflex DBS. 
3 Chemical Name and CAS Registry Number 
Decanedioic acid, di-n-butyl ester [109-43-3] 
4 Empirical Formula and Molecular Weight 
C18H34O4 314.47 
The USPNF 23 describes dibutyl sebacate as consisting of 
the esters of n-butyl alcohol and saturated dibasic acids, 
principally sebacic acid. 
5 Structural Formula 
6 Functional Category 
Plasticizer. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dibutyl sebacate is used in oral pharmaceutical formulations as 
a plasticizer for film coatings on tablets, beads, and granules, at 
concentrations of 1030% by weight of polymer.(1,2) It is also 
used as a plasticizer in controlled-release tablets and microcapsule 
preparations.(3,4) 
Dibutyl sebacate is also used as a synthetic flavor and flavor 
adjuvant in food products; for example, up to 5 ppm is used in 
ice cream and nonalcoholic beverages. 
8 Description 
Dibutyl sebacate is a clear, colorless, oily liquid with a bland to 
slight butyl odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dibutyl sebacate. 
Test USPNF 23 
Specific gravity 0.9350.939 
Refractive index 1.4291.441 
Acid value 40.1 
Saponification value 352357 
Assay (of C18H34O4) 592.0% 
10 Typical Properties 
Acid value: 0.02 
Boiling point: 3443498C 
Flash point: 1938C 
Melting point: 108C 
Refractive index: nD
25 = 1.4401 
Solubility: soluble in ethanol (95%), isopropanol, and mineral 
oil; practically insoluble in water. 
Specific gravity: 0.937 at 208C 
Vapor density (relative): 10.8 (air = 1) 
Vapor pressure: 0.4 kPa (3 mmHg) at 1808C 
11 Stability and Storage Conditions 
Dibutyl sebacate is stable. It is not reactive with water and 
hazardous polymerization does not occur. Dibutyl sebacate 
should be stored in a closed container in a cool, dry location. 
12 Incompatibilities 
Dibutyl sebacate is incompatible with strong oxidizing 
materials and strong alkalis. 
13 Method of Manufacture 
Dibutyl sebacate is manufactured by the esterification of nbutanol 
and sebacic acid in the presence of a suitable catalyst, 
and by the distillation of sebacic acid with n-butanol in the 
presence of concentrated acid. 
14 Safety 
Dibutyl sebacate is used in cosmetics, foods, and oral 
pharmaceutical formulations, and is generally regarded as a 
nontoxic and nonirritant material. Following oral administration, 
dibutyl sebacate is metabolized in the same way as fats. In 
humans, direct eye contact and prolonged or repeated contact 
with the skin may cause very mild irritation. Acute animal 
toxicity tests and long-term animal feeding studies have shown 
no serious adverse effects to be associated with orally 
administered dibutyl sebacate. 
LD50 (rat, oral): 16 g/kg(5) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. It is recommended that eye

protection be used at all times. When heating this product, it is 
recommended to have a well-ventilated area, and the use of a 
respirator is advised. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
granules, film-coated, sustained action, and tablets). Included 
in the Canadian List of Acceptable Non-medicinal Ingredients. 
17 Related Substances 

18 Comments 
As dibutyl sebacate is an emollient ester, the personal care grade 
is recommended for use in cosmetics, hair products, lotions, 
and creams. 
The EINECS number for dibutyl sebacate is 203-672-5. 
19 Specific References 
1 Goodhart FW, Harris MR, Murthy KS, Nesbitt RU. An evaluation 
of aqueous film-forming dispersions for controlled release. Pharm 
Technol 1984; 8(4): 64, 66, 68, 70, 71. 
2 Iyer U, Hong W-H, Das N, Ghebre-Sellassie I. Comparative 
evaluation of three organic solvent and dispersion-based ethylcellulose 
coating formulations. Pharm Technol 1990; 14(9): 68, 70, 
72, 74, 76, 78, 80, 82, 84, 86. 
3 Lee BJ, Ryn SG, Cui JH. Controlled release of dual drug loaded 
hydroxypropyl methylcellulose matrix tablet using drug containing 
polymeric coatings. Int J Pharm 1999; 188: 7180. 
4 Zhang ZY, Ping QN, Xiao B. Microencapsulation and characterization 
of tramadol-resin complexes. J Control Release 2000; 66: 
107113. 
5 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1165. 
20 General References 
Appel LE, Zentner GM. Release from osmotic tablets coated with 
modified Aquacoat lattices. Proc Int Symp Control Rel Bioact 
Mater 1990; 17: 335336. 
Ozturk AG, Ozturk SS, Palsson BO, et al. Mechanism of release from 
pellets coated with an ethylcellulose-based film. J Control Release 
1990; 14: 203213. 
Rowe RC. Materials used in the film coating of oral dosage forms. In: 
Florence AT, ed. Materials Used in Pharmaceutical Formulation: 
Critical Reports on Applied Chemistry, vol. 6. Oxford: Blackwell 
Scientific, 1984: 136. 
Wheatley TA, Steurnagel CR. Latex emulsions for controlled drug 
delivery. In: McGinity JC, ed. Aqueous Polymeric Coatings for 
Pharmaceutical Dosage Forms, 2nd edn. New York: Marcel 
Dekker, 1996: 1341. 
21 Authors 
SW Kennedy. 
22 Date of Revision 
15 August 2005. 
Dibutyl Sebacate 237

Diethanolamine 
1 Nonproprietary Names 
USPNF: Diethanolamine 
2 Synonyms 
Bis(hydroxyethyl)amine; DEA; diethylolamine; 2,20-dihydroxydiethylamine; 
diolamine; 2,20-iminodiethanol. 
3 Chemical Name and CAS Registry Number 
2,20-Iminobisethanol [111-42-2] 
4 Empirical Formula and Molecular Weight 
C4H11NO2 105.14 
5 Structural Formula 
6 Functional Category 
Alkalizing agent; emulsifying agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Diethanolamine is primarily used in pharmaceutical formulations 
as a buffering agent, such as in the preparation of 
emulsions with fatty acids. In cosmetics and pharmaceuticals it 
is used as a pH adjuster and dispersant. 
Diethanolamine has also been used to form the soluble salts 
of active compounds, such as iodinated organic acids that are 
used as contrast media. As a stabilizing agent, diethanolamine 
prevents the discoloration of aqueous formulations containing 
hexamethylenetetramine-1,3-dichloropropene salts. 
Diethanolamine is also used in cosmetics. 
8 Description 
The USPNF 23 describes diethanolamine as a mixture of 
ethanolamines consisting largely of diethanolamine. At about 
room temperature it is a white, deliquescent solid. Above room 
temperature diethanolamine is a clear, viscous liquid with a 
mildly ammoniacal odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for diethanolamine. 
Test USPNF 23 
Identification . 
Limit of triethanolamine 41.0% 
Organic volatile impurities . 
Refractive index at 308C 1.4731.476 
Water 40.15% 
Assay (anhydrous basis) 98.5101.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 11.0 for a 0.1 N aqueous solution. 
Autoignition temperature: 6628C 
Boiling point: 268.88C 
Density: 
1.0881 g/cm3 at 308C; 
1.0693 g/cm3 at 608C. 
Dissociation constant: pKa = 8.88 
Flash point (open cup): 1388C 
Hygroscopicity: very hygroscopic. 
Melting point: 288C 
Refractive index: nD
30 = 1.4753 
Solubility: see Table II. 
Table II: Solubility of diethanolamine. 
Solvent Solubility at 208C 
Acetone Miscible 
Benzene 1 in 24 
Chloroform Miscible 
Ether 1 in 125 
Glycerin Miscible 
Methanol Miscible 
Water 1 in 1 
Surface tension: 49.0mN/m (49.0 dynes/cm) at 208C. 
Vapor density (relative): 3.65 (air = 1) 
Vapor pressure: >1Pa at 208C. 
Viscosity (dynamic): 
351.9 mPa s (351.9 cP) at 308C; 
53.85 mPa s (53.85 cP) at 608C. 
11 Stability and Storage Conditions 
Diethanolamine is hygroscopic and light- and oxygen-sensitive; 
it should be stored in an airtight container, protected from light, 
in a cool, dry place. 
See Monoethanolamine for further information. 
12 Incompatibilities 
Diethanolamine is a secondary amine that contains two 
hydroxy groups. It is capable of undergoing reactions typical 
of secondary amines and alcohols. The amine group usually

exhibits the greater activity whenever it is possible for a 
reaction to take place at either the amine or a hydroxy group. 
Diethanolamine will react with acids, acid anhydrides, acid 
chlorides, and esters to form amide derivatives, and with 
propylene carbonate or other cyclic carbonates to give the 
corresponding carbonates. As a secondary amine, diethanolamine 
reacts with aldehydes and ketones to yield aldimines and 
ketimines. Diethanolamine also reacts with copper to form 
complex salts. Discoloration and precipitation will take place in 
the presence of salts of heavy metals. 
13 Method of Manufacture 
Diethanolamine is prepared commercially by the ammonolysis 
of ethylene oxide. The reaction yields a mixture of monoethanolamine, 
diethanolamine, and triethanolamine which is 
separated to obtain the pure products. 
14 Safety 
Diethanolamine is used in topical and parenteral pharmaceutical 
formulations, with up to 1.5% w/v being used in 
intravenous infusions. Experimental studies in dogs have 
shown that intravenous administration of larger doses of 
diethanolamine results in sedation, coma, and death. 
Animal toxicity studies suggest that diethanolamine is less 
toxic than monoethanolamine, although in rats the oral acute 
and subacute toxicity is greater.(1) Diethanolamine is said to be 
heptacarcinogenic in mice and has also been reported to induce 
hepatic choline deficiency in mice.(2) 
Diethanolamine is an irritant to the skin, eyes, and mucous 
membranes when used undiluted or in high concentration. 
However, in rabbits, aqueous solutions containing 10% w/v 
diethanolamine produce minor irritation. The lethal human 
oral dose of diethanolamine is estimated to be 515 g/kg bodyweight. 
The US Cosmetic Ingredient Review Expert Panel evaluated 
diethanolamine and concluded that it is safe for use in cosmetic 
formulations designed for discontinuous, brief use followed by 
thorough rinsing from the surface of the skin. In products 
intended for prolonged contact with the skin, the concentration 
of ethanolamines should not exceed 5%. Diethanolamine 
should not be used in products containing N-nitrosating 
agents.(1) See also Section 18. 
LD50 (guinea pig, oral): 2.0 g/kg(3) 
LD50 (mouse, IP): 2.3 g/kg 
LD50 (mouse, oral): 3.3 g/kg 
LD50 (rabbit, skin): 12.2 g/kg 
LD50 (rat, IM): 1.5 g/kg 
LD50 (rat, IP): 0.12 g/kg 
LD50 (rat, IV): 0.78 g/kg 
LD50 (rat, oral): 0.71 g/kg 
LD50 (rat, SC): 2.2 g/kg 
15 Handling Precautions 
Diethanolamine is irritating to the skin, eyes, and mucous 
membranes. Protective clothing, gloves, eye protection, and a 
respirator are recommended. Ideally, diethanolamine should be 
handled in a fume cupboard. In the UK, the long-term (8-hour 
TWA) exposure limit for diethanolamine is 13 mg/m3 
(3 ppm).(4) Diethanolamine poses a slight fire hazard when 
exposed to heat or flame. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IV infusions, 
ophthalmic solutions, and topical preparations). Included in 
medicines licensed in the UK. Included in the Canadian List of 
Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Monoethanolamine; triethanolamine. 
18 Comments 
Through a standard battery of rodent studies, diethanolamine 
has been identified by the US National Toxicology Program as a 
potential carcinogen following topical administration. Several 
possible confounding issues have been noted during the review 
of these studies, which may affect the ultimate conclusion made 
regarding the carcinogenicity of diethanolamine and the 
relevance of these findings to humans. Diethanolamine is not 
permitted for use in cosmetics sold within the EU. 
19 Specific References 
1 Neudahl GA. Diethanolamine (DEA) and diethanolamides toxicology. 
Drug Cosmet Ind 1998; 162(4): 2629. 
2 Lehman-McKeeman LD, Gamsky EA, Hicks SM, et al. Diethanolamine 
induces hepatic choline deficiency in mice. Toxicol Sci 2002; 
67(1): 3845. 
3 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1235. 
4 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 

21 Authors 
K Fowler. 
22 Date of Revision 
17 August 2005. 
Diethanolamine 239

Diethyl Phthalate 
1 Nonproprietary Names 
BP: Diethyl phthalate 
PhEur: Diethylis phthalas 
USPNF: Diethyl phthalate 
2 Synonyms 
DEP; ethyl benzene-1,2-dicarboxylate; ethyl phthalate; Kodaflex 
DEP; phthalic acid diethyl ester. 
3 Chemical Name and CAS Registry Number 
1,2-Benzenedicarboxylic acid, diethyl ester [84-66-2] 
4 Empirical Formula and Molecular Weight 
C12H14O4 222.24 
5 Structural Formula 
6 Functional Category 
Film-former; plasticizer; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Diethyl phthalate is used as a plasticizer for film coatings on 
tablets, beads, and granules at concentrations of 1030% by 
weight of polymer. 
Diethyl phthalate is also used as an alcohol denaturant and 
as a solvent for cellulose acetate in the manufacture of varnishes 
and dopes. In perfumery, diethyl phthalate is used as a perfume 
fixative at a concentration of 0.10.5% of the weight of the 
perfume used. 
8 Description 
Diethyl phthalate is a clear, colorless, oily liquid. It is practically 
odorless, or with a very slight aromatic odor and a bitter, 
disagreeable taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for diethyl phthalate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Specific gravity 1.1171.121 1.1181.122 
Refractive index 1.5001.505 1.5001.505 
Acidity . . 
Related substances .  
Water 40.2% 40.2% 
Residue on ignition  40.02% 
Sulfated ash 40.1%  
Assay (anhydrous basis) 99.0101.0% 98.0102.0% 
10 Typical Properties 
Boiling point: 2958C 
Flash point: 1608C (open cup) 
Melting point: 408C 
Refractive index: nD
25 = 1.501 
Solubility: miscible with ethanol (95%), ether, and many other 
organic solvents; practically insoluble in water. 
Specific gravity: 1.120 at 258C 
Vapor density (relative): 7.66 (air = 1) 
Vapor pressure: 1.87 kPa (14 mmHg) at 1638C 
11 Stability and Storage Conditions 
Diethyl phthalate is stable when stored in a well-closed 
container in a cool, dry place. 
12 Incompatibilities 
Incompatible with strong oxidizing materials. 
13 Method of Manufacture 
Diethyl phthalate is produced by the reaction of phthalic 
anhydride with ethanol in the presence of sulfuric acid. 
14 Safety 
Diethyl phthalate is used in oral pharmaceutical formulations 
and is generally regarded as a nontoxic and nonirritant material 
at the levels employed as an excipient. However, if consumed in 
large quantities it can act as a narcotic and cause paralysis of 
the central nervous system. 
Although some animal studies have suggested that high 
concentrations of diethyl phthalate may be teratogenic, other 
studies have shown no adverse effects.(1) 
LD50 (guinea pig, oral): 8.6 g/kg(2) 
LD50 (mouse, IP): 2.7 g/kg 
LD50 (mouse, oral): 6.2 g/kg 
LD50 (rat, IP): 5.1 g/kg 
LD50 (rat, oral): 8.6 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Diethyl phthalate is irritant 
to the skin, eyes, and mucous membranes. Protective clothing, 
eye protection, and nitrile gloves are recommended. Diethyl 
phthalate should be handled in a fume cupboard or a wellventilated 
environment; a respirator is recommended. In the 
UK, the long-term (8-hour TWA) exposure limit for diethyl 
phthalate is 5 mg/m3. The short-term (15-minute) exposure 
limit is 10 mg/m3.(3) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
delayed action, enteric coated, and sustained action tablets). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Dibutyl phthalate; dimethyl phthalate. 
18 Comments 
The EINECS number for diethyl phthalate is 201-550-6. 
19 Specific References 
1 Field EA, Price CJ, Sleet RB, et al. Developmental toxicity 
evaluation of diethyl and dimethyl phthalate in rats. Teratology 
1993; 48(1): 3344. 
2 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 12841285. 
3 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 
Banker GS. Film coating theory and practice. J Pharm Sci 1966; 55: 81 
89. 
Berg JA, Mayor GH. Diethyl phthalate not dangerous [letter]. Am J 
Hosp Pharm 1991; 48: 14481449. 
Cafmeyer NR, Wolfson BB. Possible leaching of diethyl phthalate into 
levothyroxine sodium tablets. Am J Hosp Pharm 1991; 48: 735 
739. 
Chambliss WG. The forgotten dosage form: enteric-coated tablets. 
Pharm Technol 1983; 7(9): 124, 126, 128, 130, 132, 138. 
Health and Safety Executive. Review of the toxicity of the esters of 
phthalic acid (phthalate esters). Toxicity Reviews 14. London: 
HMSO, 1986. 
Kamrin MA, Mayor GH. Diethyl phthalate: a perspective. J Clin 
Pharmacol 1991; 31: 484489. 
Porter SC, Ridgway K. The permeability of enteric coatings and the 
dissolution rates of coated tablets. J Pharm Pharmacol 1982; 34: 5 
8. 
Rowe RC. Materials used in the film coating of oral dosage forms. In: 
Florence AT, ed. Materials Used in Pharmaceutical Formulation: 
Critical Reports on Applied Chemistry, volume 6. Oxford: Blackwell 
Scientific, 1984: 136. 
Wheatley TA, Steurernagel CR. Latex emulsions for controlled drug 
delivery. In: McGinity JW, ed. Aqueous Polymeric Coatings for 
Pharmaceutical Dosage Forms, 2nd edn. New York: Marcel 
Dekker, 1996: 4159. 
21 Authors 
RT Guest. 
22 Date of Revision 
21 August 2005. 
Diethyl Phthalate 241

Difluoroethane (HFC) 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Dymel 152a; ethylene fluoride; Genetron 152a; halocarbon 
152a; HFC 152a; P-152a; propellant 152a; refrigerant 152a; 
Solkane 152a. 
3 Chemical Name and CAS Registry Number 
1,1-Difluoroethane [75-37-6] 
4 Empirical Formula and Molecular Weight 
C2H4F2 66.05 
5 Structural Formula 
6 Functional Category 
Aerosol propellant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Difluoroethane, a hydrofluorocarbon (HFC), is an aerosol 
propellant used in topical pharmaceutical formulations.(1) 
Difluoroethane may be used as a vehicle for dispersions and 
emulsions. 
Under the terms of the Montreal Protocol, aimed at reducing 
damage to the ozone layer, the use of chlorofluorocarbons has 
been prohibited since January 1996. Since difluoroethane does 
not contain chlorine, there are no environmental controls on 
the use of this material as a propellant, since it does not deplete 
the ozone layer and is not a greenhouse gas. 
8 Description 
Difluoroethane is a liquefied gas and exists as a liquid at room 
temperature when contained under its own vapor pressure, or 
as a gas when exposed to room temperature and atmospheric 
pressure. The liquid is practically odorless and colorless. 
Difluoroethane is noncorrosive and nonirritating. 
9 Pharmacopeial Specifications 
 
10 Typical Properties 
Boiling point: 24.78C 
Critical temperature: 113.58C 
Density: 
0.90 g/cm3 for liquid at 258C; 
0.81 g/cm3 for liquid at 54.58C. 
Flammability: flammable. Limits of flammability 3.718.0% 
v/v in air. 
Melting point: 1178C 
Solubility: soluble 1 in 357 parts of water at 258C. 
Surface tension: 11.25mN/m (11.25 dynes/cm) for liquid at 
208C. 
Vapor density (absolute): 2.949 g/m3 at standard temperature 
and pressure. 
Vapor density (relative): 2.29 (air = 1) 
Vapor pressure: 
600 kPa (61.7 psig) at 21.18C; 
1317 kPa (191 psia) at 54.58C. 
Viscosity (dynamic): 0.243 mPa s (0.243 cP) for liquid at 208C. 
11 Stability and Storage Conditions 
Difluoroethane is a nonreactive and stable material. The 
liquefied gas is stable when used as a propellant and should 
be stored in a metal cylinder in a cool, dry place. 
12 Incompatibilities 
Compatible with the usual ingredients used in the formulation 
of pharmaceutical aerosols. 
13 Method of Manufacture 
Difluoroethane is prepared from ethyne by the addition of 
hydrogen fluoride in the presence of a suitable catalyst. The 
difluoroethane formed is purified to remove all traces of water, 
as well as traces of the starting materials. 
14 Safety 
Difluoroethane may be used as an aerosol propellant in topical 
pharmaceutical formulations. It is generally regarded as an 
essentially nontoxic and nonirritant material. 
Deliberate inhalation of excessive quantities of this propellant 
may result in death, and the following warning statements 
must appear on the label of all aerosols: 
WARNING: Avoid inhalation. Keep away from eyes or 
other mucous membranes. 
(Aerosols designed specifically for oral and nasal inhalation 
need not contain this statement.) 
WARNING: Do not inhale directly; deliberate inhalation of 
contents can cause death. 
or

WARNING: Use only as directed; intentional misuse by 
deliberately concentrating and inhaling the contents can be 
harmful or fatal. 
Additionally, the label should contain the following information: 
WARNING: Contents under pressure. Do not puncture or 
incinerate container. Do not expose to heat or store at room 
temperature above 1208F (498C). Keep out of the reach of 
children. 
When propellants are used in topical aerosols they may cause a 
chilling effect on the skin, although this effect has been 
somewhat overcome by the use of vapor-tap valves. The 
propellants quickly vaporize from the skin, and are nonirritating 
when used as directed. 
15 Handling Precautions 
Difluoroethane is usually encountered as a liquefied gas and 
appropriate precautions for handling such materials should be 
taken. Eye protection, gloves, and protective clothing are 
recommended. Difluoroethane should be handled in a wellventilated 
environment. Fluorocarbon vapors are heavier than 
air and do not support life; therefore, when cleaning large tanks 
that have contained these propellants, adequate provision for 
oxygen supply in the tanks must be made in order to protect 
workers cleaning the tanks. 
Difluoroethane is flammable; see Section 10. When it is 
heated to decomposition, toxic fumes of hydrogen fluoride may 
be formed. 
16 Regulatory Status 
Accepted in the USA, by the FDA, for use as a topical aerosol 
propellant. 
17 Related Substances 
Tetrafluoroethane. 
18 Comments 
Difluoroethane is useful as an aerosol propellant in that it 
shows greater miscibility with water than some other fluorocarbons 
and when combined with chlorodifluoroethane will 
produce a mixture with a specific gravity of 1. For a discussion 
of the numerical nomenclature applied to this aerosol 
propellant, see Chlorofluorocarbons. 
19 Specific References 
1 Sheridan V. Propelling VOCs down. Manuf Chem 1995; 66(10): 
57. 
20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. Caldwell: WE 
Dorland, 1982: 305335. 
Johnson MA. Flammability aspects of dimethy ether, p-22, p-142b, p- 
152a. Aerosol Age 1988; 33(8): 32, 34, 36, 3839. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 1935. 
Sciarra JJ. Aerosols. In: Gennaro AR, ed. Remington: The Science and 
Practice of Pharmacy, 19th edn. Easton, PA: Mack Publishing Co., 
1995: 16761692. 
Sciarra JJ. Aerosol suspensions and emulsions. In: Lieberman H, Rieger 
J, Banker G, eds. Pharmaceutical Dosage Forms: Disperse Systems, 
vol. 2, 2nd edn. New York: Marcel Dekker, 1996: 319356. 
Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. 
Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 
547574. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 137145. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Difluoroethane (HFC) 243

Dimethicone 
1 Nonproprietary Names 
BP: Dimeticone 
PhEur: Dimeticonum 
USPNF: Dimethicone 
2 Synonyms 
ABIL; dimethylpolysiloxane; dimethylsilicone fluid; dimethylsiloxane; 
Dow Corning Q7-9120; E900; methyl polysiloxane; 
poly(dimethylsiloxane); Sentry. 
3 Chemical Name and CAS Registry Number 
a-(Trimethylsilyl)-o-methylpoly[oxy(dimethylsilylene)] [9006- 
65-9] 
4 Empirical Formula and Molecular Weight 
The PhEur 2005 describes dimethicone as a polydimethylsiloxane 
obtained by hydrolysis and polycondensation of dichlorodimethylsilane 
and chlorotrimethylsilane. The degree of 
polymerization (n = 20400) is such that materials with 
kinematic viscosities nominally 201300mm2/s (201300 cSt) 
are produced. Dimethicones with a nominal viscosity of 
50mm2/s (50 cSt) or lower are intended for external use only. 
The USPNF 23 describes dimethicone as a mixture of fully 
methylated linear siloxane polymers containing repeating units 
of the formula [(CH3)2SiO]n stabilized with trimethylsiloxy 
end-blocking units of the formula [(CH3)3SiO], where n has 
an average value such that the corresponding nominal viscosity 
is in a discrete range 2030 000mm2/s (2030 000 cSt). 
5 Structural Formula 
6 Functional Category 
Antifoaming agent; emollient. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dimethicones of various viscosities are widely used in cosmetic 
and pharmaceutical formulations. In topical oil-in-water 
emulsions dimethicone is added to the oil phase as an 
antifoaming agent. Dimethicone is hydrophobic and is also 
widely used in topical barrier preparations. Therapeutically, 
dimethicone may be used with simethicone in oral pharmaceutical 
formulations used in the treatment of flatulence. Dimethicone 
is also used to form a water-repellent film on glass 
containers. See Table I. 
Table I: Uses of dimethicone. 
Use Concentration (%) 
Creams, lotions and ointments 1030 
Oilwater emulsions 0.55.0 
8 Description 
Dimethicones are clear, colorless liquids available in various 
viscosities; see Section 4. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for dimethicone. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Acidity . . 
Specific gravity  .(a) 
Viscosity (kinematic) of the 
nominal stated value 
90110% .(a) 
Refractive index  .(a) 
Mineral oils .  
Phenylated compounds .  
Heavy metals 45 ppm 45 mg/g 
Volatile matter (for dimethicones 
with a viscosity greater than 
50mm2/s (50 cSt) 
40.3%  
Loss on heating  .(a) 
Bacterial endotoxins (coating of 
containers for parenteral use) 
 . 
Assay (of polydimethylsiloxane)  97.0103.0% 
(a) The USPNF 23 specifies limits for these tests specific to the nominal viscosity of the 
dimethicone. 
10 Typical Properties 
Acid value: <0.01 
Density: 0.940.98 g/cm3 at 258C 
Refractive index: nD
25 = 1.4011.405 
Solubility: miscible with ethyl acetate, methyl ethyl ketone, 
mineral oil, and toluene; soluble in isopropyl myristate, very 
slightly soluble in ethanol (95%); practically insoluble in 
glycerin, propylene glycol, and water. 
Surface tension: 20.521.2mN/m at 258C 
11 Stability and Storage Conditions 
Dimethicones should be stored in an airtight container in a 
cool, dry, place; they are stable to heat and are resistant to most 
chemical substances although they are affected by strong acids. 
Thin films of dimethicone may be sterilized by dry heat for at 
least 2 hours at 1608C. Sterilization of large quantities of

dimethicone by steam autoclaving is not recommended since 
excess water diffuses into the fluid causing it to become hazy. 
However, thin films may be sterilized by this method. Gamma 
irradiation may also be used to sterilize dimethicone. Gamma 
irradiation can, however, cause cross-linking with a consequent 
increase in the viscosity of fluids. 
12 Incompatibilities 

13 Method of Manufacture 
Dimethicone is a poly(dimethylsiloxane) obtained by hydrolysis 
and polycondensation of dichlorodimethylsilane and 
chlorotrimethylsilane. The hydrolysis products contain active 
silanol groups through which condensation polymerization 
proceeds. By varying the proportions of chlorotrimethylsilane, 
which acts as a chain terminator, silicones of varying molecular 
weight may be prepared. Different grades of dimethicone are 
produced that may be distinguished by a number placed after 
the name indicating the nominal viscosity. For example, ABIL 
20 (Goldschmidt UK Ltd) has a nominal kinematic viscosity of 
1822mm2/s (1822 cSt). See also Section 4. 
14 Safety 
Dimethicone is generally regarded as a relatively nontoxic and 
nonirritant material although it can cause temporary irritation 
to the eyes. In pharmaceutical formulations it may be used in 
oral and topical preparations. Dimethicones are also used 
extensively in cosmetic formulations and in certain food 
applications. 
The WHO has set a tentative estimated acceptable daily 
intake of dimethicone with a relative molecular mass in the 
range of 200300 at up to 1.5 mg/kg body-weight.(1) 
Injection of silicones into tissues may cause granulomatous 
reactions. Accidental intravascular injection has been associated 
with fatalities. 
LD50 (mouse, oral): >20 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Dimethicone is flammable 
and should not be exposed to naked flames or heat. 
16 Regulatory Status 
Accepted for use as a food additive in Europe. Included in the 
FDA Inactive Ingredients Guide (oral capsules and tablets, 
topical creams, emulsions, lotions, and transdermal preparations). 
Included in nonparenteral medicines licensed in the UK. 
Included in the Canadian List of Acceptable Non-medicinal 
Ingredients. 
17 Related Substances 
Cyclomethicone; simethicone. 
18 Comments 

19 Specific References 
1 FAO/WHO. Evaluation of certain food additives. Twenty-third 
report of the joint FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1980; No. 648. 
20 General References 
Calogero AV. Regulatory review. Cosmet Toilet 2000; 115(May): 24, 
26, 27. 
21 Authors 
RT Guest. 
22 Date of Revision 
21 August 2005. 
Dimethicone 245

Dimethyl Ether 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Dimethyl oxide; DME; Dymel A; methoxymethane; methyl 
ether; oxybismethane; wood ether. 
3 Chemical Name and CAS Registry Number 
Dimethyl ether [115-10-6] 
4 Empirical Formula and Molecular Weight 
C2H6O 46.07 
5 Structural Formula 
6 Functional Category 
Aerosol propellant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dimethyl ether may be used as an aerosol propellant for topical 
aerosol formulations in combination with hydrocarbons and 
other propellants.(14) Generally, it cannot be used alone as a 
propellant owing to its high vapor pressure. Dimethyl ether is a 
good solvent and has the unique property of high water 
solubility, compared to other propellants. It has frequently been 
used with aqueous aerosols. A coarse, wet, spray is formed 
when dimethyl ether is used as a propellant. 
Dimethyl ether is also used as a propellant in cosmetics such 
as hair sprays, and in other aerosol products such as air 
fresheners and fly sprays. 
Dimethyl ether is additionally used as a refrigerant. 
8 Description 
Dimethyl ether is a liquefied gas and exists as a liquid at room 
temperature when contained under its own vapor pressure, or 
as a gas when exposed to room temperature and pressure. 
It is a clear, colorless, virtually odorless liquid. In high 
concentrations, the gas has a faint etherlike odor. 
9 Pharmacopeial Specifications 

10 Typical Properties 
Autoignition temperature: 3508C 
Boiling point: 23.68C 
Critical temperature: 126.98C 
Density: 0.66 g/cm3 for liquid at 258C. 
Flammability: the pure material is flammable; limit of flammability 
is 3.418.2% v/v in air. Aqueous mixtures are 
nonflammable. 
Freezing point: 138.58C 
Flash point: 418C 
Heat of combustion: 28.9 kJ/g (6900 cal/g) 
Kauri-butanol value: 60 
Solubility: soluble in acetone, chloroform, ethanol (95%), 
ether, and 1 in 3 parts of water. Dimethyl ether is generally 
miscible with water, nonpolar materials, and some semipolar 
materials. For pharmaceutical aerosols, ethanol (95%) 
is the most useful cosolvent. Glycols, oils, and other similar 
materials exhibit varying degrees of miscibility with 
dimethyl ether. 
Surface tension: 16mN/m (16 dynes/cm) at 108C 
Vapor density (absolute): 2.058 g/m3 at standard temperature 
and pressure. 
Vapor density (relative): 1.596 (air = 1) 
Vapor pressure: 
592 kPa at 258C (63 psig at 21.18C); 
1301 kPa at 548C. 
11 Stability and Storage Conditions 
The liquefied gas is stable when used as a propellant. However, 
exposure to the air for long periods of time may result in 
explosive peroxides being slowly formed. 
Solutions of liquid dimethyl ether should not be concentrated 
either by distillation or by evaporation. Dimethyl ether 
should be stored in tightly closed metal cylinders in a cool, dry 
place. 
12 Incompatibilities 
Dimethyl ether is an aggressive solvent and may affect the 
gasket materials used in aerosol packaging. Oxidizing agents, 
acetic acid, organic acids, and anhydrides should not be used 
with dimethyl ether. See also Section 10. 
13 Method of Manufacture 
Dimethyl ether is prepared by the reaction of bituminous or 
lignite coals with steam in the presence of a finely divided nickel 
catalyst. This reaction produces formaldehyde, which is then 
reduced to methanol and dimethyl ether. Dimethyl ether may 
also be prepared by the dehydration of methanol. 
14 Safety 
Dimethyl ether may be used as a propellant and solvent in 
topical pharmaceutical aerosols, and is generally regarded as an 
essentially nontoxic and nonirritant material when used in such 
applications. However, inhalation of high concentrations of 
dimethyl ether vapor is harmful. Additionally, skin contact with 
dimethyl ether liquid may result in freezing of the skin and 
severe frostbite. 
When used in topical formulations, dimethyl ether may 
exert a chilling effect on the skin, although if it is used as 
directed the propellant quickly vaporizes and is nonirritating.

LD50 (mouse, inhalation): 386 000 ppm/30 min(5) 
LD50 (rat, inhalation): 308 g/m3 
15 Handling Precautions 
Dimethyl ether is usually encountered as a liquefied gas, and 
appropriate precautions for handling such materials should be 
taken. Eye protection, gloves, and protective clothing are 
recommended. 
Dimethyl ether should be handled in a well-ventilated 
environment. 
Dimethyl ether vapor is heavier than air and does not 
support life; therefore, when cleaning large tanks that have 
contained this material, adequate provisions for oxygen supply 
in the tanks must be made in order to protect workers cleaning 
the tanks. 
In the UK, the long-term (8-hour TWA) exposure limit for 
dimethyl ether is 766 mg/m3 (400 ppm). The short-term (15- 
minute) exposure limit is 958 mg/m3 (500 ppm).(6) 
Dimethyl ether is flammable; see Section 10. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (topical 
aerosols). Included in nonparenteral medicines licensed in the 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Hydrocarbons (HC). 
18 Comments 
Since the solubility of dimethyl ether in water is about 35%, it 
can be used to good effect in aqueous aerosol products. It also 
has antimicrobial effects that are organism-dependent.(7) 
The EINECS number for dimethyl ether is 204-065-8. 
19 Specific References 
1 Bohnenn LJM. DME: an alternative propellant? Manuf Chem 
Aerosol News 1977; 48(9): 40. 
2 Bohnenn LJM. DME: further data on this alternative propellant. 
Manuf Chem Aerosol News 1978; 49(8): 39, 63. 
3 Bohnenn LJM. Alternative aerosol propellant. Drug Cosmet Ind 
1979; 125(Nov): 58, 60, 62, 66, 68, 70, 72, 74. 
4 Boulden ME. Use of dimethyl ether for reduction of VOC content. 
Spray Technol Market 1992; 2(May): 30, 32, 34, 36. 
5 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2442. 
6 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
7 Ibrahim YK, Sonntag HG. Preservative potentials of some aerosol 
propellants: effectiveness in some pharmaceutical oils. Drugs 
Made Ger 1995; 38(AprJun): 6265. 
20 General References 
Johnson MA. The Aerosol Handbook, 2nd edn. Mendham, NJ: WE 
Dorland, 1982: 305335. 
Johnson MA. Flammability aspects of dimethyl ether, p-22, p-142b, p- 
152a. Aerosol Age 1988; 33(8): 32, 34, 36, 3839. 
Sanders PA. Handbook of Aerosol Technology, 2nd edn. New York: 
Van Nostrand Reinhold, 1979: 4454. 
Sciarra JJ, Stoller L. The Science and Technology of Aerosol Packaging. 
New York: Wiley, 1974: 137145. 
Sciarra JJ. Pharmaceutical aerosols. In: Banker GS, Rhodes CT, eds. 
Modern Pharmaceutics, 3rd edn. New York: Marcel Dekker, 1996: 
547574. 
Sciarra JJ, Sciarra CJ. Aerosols. In: Gennaro AR, ed. Remington: The 
Science and Practice of Pharmacy, 20th edn. Baltimore, MD: 
Lippincott, Williams and Wilkins, 2000: 963979. 
21 Authors 
CJ Sciarra, JJ Sciarra. 
22 Date of Revision 
23 August 2005. 
Dimethyl Ether 247

Dimethyl Phthalate 
1 Nonproprietary Names 
BP: Dimethyl phthalate 
2 Synonyms 
Avolin; 1,2-benzenedicarboxylate; benzenedicarboxylic acid 
dimethyl ester; dimethyl 1,2-benzenedicarboxylate; dimethyl 
benzene-o-dicarboxylate; dimethyl benzeneorthodicarboxylate; 
dimethyl o-phthalate; o-dimethyl phthalate; DMP; Fermine; 
Kodaflex DMP; methyl benzene-1,2-dicarboxylate; 
Mipax; Palatinol M; phthalic acid dimethyl ester; phthalic 
acid methyl ester; Repeftal; Solvanom; Solvarone; Unimoll 
DM. 
3 Chemical Name and CAS Registry Number 
1,2-Benzene-dicarboxylic acid dimethyl ester [131-11-3] 
4 Empirical Formula and Molecular Weight 
C10H10O4 194.19 
5 Structural Formula 
6 Functional Category 
Film-former; plasticizer; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dimethyl phthalate is used in pharmaceutical applications as a 
solvent and plasticizer for film-coatings such as hydroxypropyl 
methylcellulose, cellulose acetate and cellulose acetatebutyrate 
mixtures.(1,2) 
In addition to a number of industrial applications, dimethyl 
phthalate is also widely used as an insect repellent with topical 
preparations typically applied as a 40% cream or lotion; it has 
also been applied as a tent fabric treatment.(3) 
8 Description 
Dimethyl phthalate occurs as a colorless, or faintly colored, 
odorless, viscous, oily liquid. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dimethyl phthalate. 
Test BP 2004 
Identification . 
Characters . 
Acidity . 
Refractive index 1.5151.517 
Weight per mL 1.1861.192 
Related substances . 
Sulfated ash 40.1% 
Water 40.1% 
Assay (dried basis) 99.0100.5% 
10 Typical Properties 
Boiling point: 2808C, with decomposition. 
Density: 1.1861.192 g/cm3 
Flash point: 1468C closed cup. 
Freezing point: the commercial product freezes at 08C. 
Melting point: 2.05.58C 
Partition coefficient: 
Octanol : water = 1.56(4) 
Refractive index: nD
20 = 1.5151.517 
Solubility: see Table II. 
Table II: Solubility of dimethyl phthalate. 
Solvent Solubility at 208C unless otherwise stated 
Benzene Miscible 
Chloroform Miscible 
Ethanol (95%) Miscible 
Ether Miscible 
Mineral oil 1 in 294 
Water 1 in 250 at 208C 
Surface tension: 41.9mN/m at 208C 
Vapor density (relative): 6.69 (air = 1) 
Vapor pressure: 120 Pa at 1008C 
Viscosity: 17.2 mPa s (17.2 cP) at 258C. 
11 Stability and Storage Conditions 
Dimethyl phthalate is sensitive to prolonged exposure to light 
and it should therefore be stored in a cool, dark, dry, wellventilated 
area that is protected from physical damage, and 
isolated from incompatible substances. Containers of dimethyl 
phthalate may be hazardous when empty as they may retain 
product residues such as vapors and liquids. There is a slight 
fire hazard when exposed to heat, and above the flash point (see 
Section 10); explosive vaporair mixtures may be formed. 
Carbon dioxide and carbon monoxide are released when 
dimethyl phthalate is heated to decomposition. Solutions of 
dimethyl phthalate in acetone, dimethyl sulfoxide, ethanol

(95%), and water are stable for 24 hours under normal 
laboratory conditions. 
12 Incompatibilities 
Dimethyl phthalate is incompatible with strong acids or bases, 
nitrates, and strong oxidizing agents. 
13 Method of Manufacture 
Dimethyl phthalate is produced industrially from phthalic 
anhydride and methanol. 
14 Safety 
In pharmaceutical applications, dimethyl phthalate is used in 
film-coating and as a topically applied insect repellent. Acute 
exposure to the eyes and mucous membranes can cause 
irritation although dimethyl phthalate is considered less irritant 
than diethyl phthalate. Inhalation of dimethyl phthalate can 
cause irritation of the respiratory tract; oral ingestion can cause 
a burning sensation in the mouth, vomiting, and diarrhea. 
Owing to the low water solubility and relatively high lipid 
solubility, dimethyl phthalate may accumulate in body tissues 
after chronic exposure, which may cause central nervous 
system depression. 
Although some animal studies have suggested that high 
concentrations of dimethyl phthalate may be teratogenic or 
cause mutagenic effects with bacteria,(5,6) other studies have 
shown no adverse effects.(7) There are no confirmed reports of 
human reproductive or developmental effects and the compound 
is not generally regarded as a carcinogenic material. 
LD50 (chicken, oral): 8.5 g/kg(8) 
LD50 (guinea pig, oral): 2.4 g/kg 
LD50 (mouse, IP): 1.38 g/kg 
LD50 (mouse, oral): 6.8 g/kg 
LD50 (rabbit, oral): 4.40 g/kg 
LD50 (rat, IP): 3.38 g/kg 
LD50 (rat, oral): 6.80 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Skin and eye contact should 
be avoided; eye goggles or a full face shield should be worn 
where splashing may occur. Respirators should be used if the 
compound is heated to decomposition. In the UK, the long-term 
(8-hour TWA) exposure limit for dimethyl phthalate is 
5 mg/m3. The short-term (15-minute) exposure limit is 
10 mg/m3.(9) 
16 Regulatory Status 
Dimethyl phthalate is included in a number of topical 
pharmaceutical formulations. As from 1992, dimethyl phthalate 
is no longer registered for use as a pesticide in California. 
17 Related Substances 
Dibutyl phthalate; diethyl phthalate. 
18 Comments 
The EINECS number for dimethyl phthalate is 205-011-6. 
19 Specific References 
1 Shah PS, Zatz JL. Plasticization of cellulose esters used in the 
coating of sustained release solid dosage forms. Drug Dev Ind 
Pharm 1992; 18: 17591772. 
2 Wolf B. Bead cellulose products with film formers and solubilisers 
for controlled drug release. Int J Pharm 1997; 156: 97107. 
3 Schreck CE. Permethrin and dimethyl phthalate as tent fabric 
treatments against Aedes aegypti. J Am Mosq Control Assoc 1991; 
7(4): 533535. 
4 Ellington JJ, Floyd TL. EPA/600/596: Octanol/water Partition 
Coefficients for Eight Phthalate Esters. Athens, GA: US Environmental 
Protection Agency, 1996. 
5 Kozumbo WJ, Rubin RJ. Mutagenicity and metabolism of 
dimethyl phthalate and its binding to epidermal and hepatic 
macromolecules. J Toxicol Environ Health 1991; 33(1): 2946. 
6 Niazi JH, Prasad DT, Karegoudar TB. Initial degradation of 
dimethyl phthalate by esterases from Bacillus species. FEMS 
Microbiol Lett 2001; 196(2): 201205. 
7 Field EA, Price CJ, Sleet RB, et al. Developmental toxicity 
evaluation of diethyl and dimethyl phthalate in rats. Teratology 
1993; 48(1): 3344. 
8 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1460. 
9 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 

21 Authors 
W Cook. 
22 Date of Revision 
4 August 2005. 
Dimethyl Phthalate 249

Dimethyl Sulfoxide 
1 Nonproprietary Names 
BP: Dimethyl sulfoxide 
PhEur: Dimethylis sulfoxidum 
USP: Dimethyl sulfoxide 
2 Synonyms 
Deltan; dimexide; dimethyl sulphoxide; DMSO; Kemsol; 
methylsulfoxide; Rimso-50; sulphinylbismethane 
3 Chemical Name and CAS Registry Number 
Sulfinylbismethane [67-68-5] 
4 Empirical Formula and Molecular Weight 
C2H6OS 78.13 
5 Structural Formula 
6 Functional Category 
Penetration enhancer; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dimethyl sulfoxide is a highly polar substance that is aprotic, 
therefore lacking acidic and basic properties. It has exceptional 
solvent properties for both organic and inorganic components, 
which are derived from its capacity to associate with both ionic 
species and neutral molecules that are either polar or 
polarizable. Dimethyl sulfoxide enhances the topical penetration 
of drugs owing to its ability to displace bound water from 
the stratum corneum; this is accompanied by the extraction of 
lipids and configurational changes of proteins.(1) The molecular 
interactions between dimethyl sulfoxide and the stratum 
corneum, as a function of depth and time, have been 
described.(2) Much of the enhancement capacity is lost if the 
solvent is diluted. Increases in drug penetration have been 
reported with dimethyl sulfoxide concentrations as low as 
15%, but significant increases in permeability generally require 
concentrations higher than 6080%. Furthermore, while low 
molecular weight substances can penetrate quickly into the 
deep layers of the skin, the appreciable transport of molecules 
with a molecular weight of more than 3000 is difficult. 
The use of dimethyl sulfoxide to improve transdermal 
delivery has been reported for ciclosporin,(3) timolol,(4) and a 
wide range of other drugs.(5,6) Dimethyl sulfoxide has also been 
used in the formulation of an injection containing allopurinol.(
7) It has also been investigated for use in an experimental 
parenteral preparation for the treatment of liver tumors.(8) 
In paint formulations of idoxuridine, dimethyl sulfoxide acts 
both as a solvent to increase drug solubility and a means of 
enabling penetration of the antiviral agent to the deeper levels 
of the epidermis. See Table I. 
Dimethyl sulfoxide has also been investigated as a potential 
therapeutic agent in conditions such as scleroderma, interstitial 
cystitis, rheumatoid arthritis, and acute musculoskeletal 
injuries, and as an analgesic.(913) It has also been recommended 
for the treatment of anthracycline extravasation(14,15) 
and has been investigated as a potential cryoprotectant.(16) 
Table I: Uses of dimethyl sulfoxide. 
Use Concentration (%) 
Solvent 4100 
Topical penetration enhancer 580 
8 Description 
Dimethyl sulfoxide occurs as a colorless, viscous liquid, or as 
colorless crystals that are miscible with water, alcohol, and 
ether. The material has a slightly bitter taste with a sweet 
aftertaste and is odorless, or has a slight odor characteristic of 
dimethyl sulfoxide. Dimethyl sulfoxide is extremely hygroscopic, 
absorbing up to 70% of its own weight in water with 
evolution of heat. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for dimethyl sulfoxide. 
Test PhEur 2005 USP 28 
Characters .  
Identification . . 
Specific gravity 1.1001.104 1.0951.101 
Freezing point 518.38C 518.38C 
Refractive index 1.4781.479 1.47551.4775 
Acidity . . 
Water 40.2% 40.1% 
Ultraviolet absorbance . . 
Substances darkened by potassium 
hydroxide 
 . 
Limit of dimethyl sulfone  . 
Limit of nonvolatile residue  45.0mg 
Related substances .  
Assay  599.9% 
10 Typical Properties 
Boiling point: 1898C 
Dielectric constant: 48.9 at 208C 
Dipole moment (D): 4.3 at 208C(17) 
Dissociation constant: pKa = 31.3(17) 
Enthalpy of fusion: 3.43 cal/mol(17)

Enthalpy of vaporization: 12.64 cal/mol at 258C(17) 
Flash point (open cup): 958C 
Specific heat: 0.7 cal/g (liquid) 
Solubility: miscible with water with evolution of heat; also 
miscible with ethanol (95%), ether and most organic 
solvents; immiscible with paraffins, hydrocarbons. Practically 
insoluble in acetone, chloroform, ethanol (95%), and 
ether. 
Vapor pressure: 0.37mm at 208C 
Viscosity (dynamic): 1.1 mPa s (1.1 cP) at 278C 
11 Stability and Storage Conditions 
Dimethyl sulfoxide is reasonably stable to heat but upon 
prolonged reflux it decomposes slightly to methyl mercaptan 
and bismethylthiomethane. This decomposition is aided by 
acids, and is retarded by many bases. When heated to 
decomposition, toxic fumes are emitted. 
At temperatures between 40608C, it has been reported that 
dimethyl sulfoxide suffers a partial breakdown, which is 
indicated by changes in physical properties such as refractive 
index, density, and viscosity.(18) 
Dimethyl sulfoxide should be stored in airtight, lightresistant 
containers. The PhEur 2005 states that glass containers 
should be used. Contact with plastics should be avoided. 
12 Incompatibilities 
Dimethyl sulfoxide can react with oxidizing materials. 
13 Method of Manufacture 
Dimethyl sulfoxide is prepared by air oxidation of dimethyl 
sulfide in the presence of nitrogen oxides. It can also be 
obtained as a by-product of wood pulp manufacture for the 
paper and allied industries. 
14 Safety 
Dimethyl sulfoxide has low systemic toxicity but causes local 
toxic effects.(1921) It is readily absorbed after injection or after 
oral or percutaneous administration and is widely distributed 
throughout the body. Dimethyl sulfoxide acts as a primary 
irritant on skin, causing redness, burning, itching, and scaling; 
it also causes urticaria. Systemic symptoms include nausea, 
vomiting, chills, cramps, and lethargy; dimethyl sulfoxide can 
also cause increases in intraocular pressure. Administration of 
dimethyl sulfoxide by any route is followed by a garlic-like 
odor on the breath. 
Intravascular hemolysis and biochemical changes(22) and 
reversible neurological deterioration(23) have been reported 
following intravenous administration; however, it has been 
questioned whether these findings were directly attributable to 
dimethyl sulfoxide rather than to concomitant drug therapy or 
contaminants.(24) Recently, a hypersensitivity reaction attributed 
to dimethyl sulfoxide has been reported.(25) 
In 1965, the FDA banned investigation in humans of 
dimethyl sulfoxide owing to the appearance of changes in the 
refractive index of the lens of the eye in experimental animals. 
However, in 1966, the FDA allowed the study of dimethyl 
sulfoxide in serious conditions such as scleroderma, persistent 
herpes zoster, and severe rheumatoid arthritis, and in 1968 
permitted studies using short-term topical application of the 
solvent. By 1980, the FDA no longer specifically regulated 
investigations of dimethyl sulfoxide.(10) 
Dimethyl sulfoxide enhances the skin penetration of several 
drugs, which may result in producing the adverse effects 
associated with those drugs. 
LD50 (dog, IV): 2.5 g/kg(26) 
LD50 (rat, IP): 8.2 g/kg 
LD50 (rat, IV): 5.3 g/kg 
LD50 (rat, oral): 14.5 g/kg 
LD50 (rat, SC): 12 g/kg 
LD50 (mouse, IP): 2.5 g/kg 
LD50 (mouse, IV): 3.8 g/kg 
LD50 (mouse, oral): 7.9 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Dimethyl sulfoxide may 
cause irritation to the skin. Gloves and eye protection are 
recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IV infusions, 
SC implants, and topical preparations). Available in the USA as 
a 50% solution for irrigation in the treatment of interstitial 
cystitis. Also available in Canada as a 70% solution for use as a 
topical antifibrotic and in Germany as a topical gel containing 
10% dimethyl sulfoxide for the treatment of musculoskeletal 
and joint disorders. Included in topical formulations of 
idoxuridine and diclofenac licensed in the UK. 
17 Related Substances 

18 Comments 
A 2.16% dimethyl sulfoxide solution in water is iso-osmotic 
with serum. Dimethyl sulfoxide has been used as a 50% 
aqueous solution for instillation into the bladder in the 
treatment of interstitial cystitis; it has also been tried clinically 
for a wide range of indications, including cutaneous and 
musculoskeletal disorders, but with little evidence of beneficial 
effects. 
Dimethyl sulfoxide has been shown to have bactericidal,(27) 
bacteriostatic,(27,28) and fungistatic(28) activity, although the 
concentration required is dependent on the organism present. 
19 Specific References 
1 Anigbogu ANC, Williams AC, Barry BW, Edwards HGM. Fourier 
transform Raman spectroscopy of interactions between the 
penetration enhancer dimethyl sulfoxide and human stratum 
corneum. Int J Pharm 1995; 125: 265282. 
2 Caspers PJ, Williams AC, Carter EA, et al. Monitoring the 
penetration enhancer dimethyl sulfoxide in human stratum 
corneum in vivo by confocal Raman spectroscopy. Pharm Res 
2002; 19(10): 15771580. 
3 Wang D-P, Lin C-Y, Chu D-L, Chang L-C. Effect of various 
physical/chemical properties on the transdermal delivery of 
ciclosporin through topical application. Drug Dev Ind Pharm 
1997; 23(1): 99106. 
4 Soni S, Jain SK, Jain NK. Effect of penetration enhancers on 
transdermal delivery of timolol maleate. Drug Dev Ind Pharm 
1992; 18(10): 11271135. 
5 Barry BW. Dermatological Formulations. New York: Marcel 
Dekker, 1983: 162167. 
Dimethyl Sulfoxide 251

6 Motlekar NA, Shah RB, Reddy IK, et al. Permeation of genistein 
through human skin. Pharm Technol 2003; 27(3): 140148. 
7 Lee DKT, Wang D-P. Formulation development of allopurinol 
suppositories and injectables. Drug Dev Ind Pharm 1999; 25(11): 
12051208. 
8 Komemushi A, Tanigawa N, Okuda Y, et al. A new liquid embolic 
material for liver tumors. Acta Radiol 2002; 43(2): 186191. 
9 Murdoch L-A. Dimethyl sulfoxide (DMSO): an overview. Can J 
Hosp Pharm 1982; 35(3): 7985. 
10 Fischer JM. DMSO: a review. US Pharm 1981; 6(Sept): 2528. 
11 Namaka M, Briggs C. DMSO revisited. Can Pharm J 1994; 
127(Jun): 248, 249, 255. 
12 Parker WA, Bailie GR. Current therapeutic status of DMSO. Can 
Pharm J 1982; 115(Jul): 247251. 
13 Ely A, Lockwood B. What is the evidence for the safety and 
efficiency of dimethyl sulfoxide and methylsulfanylmethane in 
pain relief? Pharm J 2002; 269: 685687. 
14 Bingham JM, Dooley MJ. EXTRA  Extravasation Treatment 
Record Database: a database to record and review cytotoxic drug 
extravasation events. Aust J Hosp Pharm 1998; 28(2): 8993. 
15 Bertelli G, Dini D, Forno G, et al. Dimethylsulphoxide and cooling 
after extravasation of antitumour agents [letter]. Lancet 1993; 
341: 10981099. 
16 Higgins J, Hodges NA, Olliff CJ, Phillips AJ. A comparative 
investigation of glycinebetaine and dimethylsulphoxide as liposome 
cryoprotectants. J Pharm Pharmacol 1987; 39: 577582. 
17 MacGregor WS. The chemical and physical properties of DMSO. 
Ann NY Acad Sci 1967; 141: 312. 
18 Jacob SW, Rosenbaum EE, Wood DC, eds. Dimethyl Sulfoxide, 
vol. 1. New York: Marcel Dekker, 1971: 81. 
19 Brobyn RD. The human toxicology of dimethyl sulfoxide. Ann NY 
Acad Sci 1975; 243: 497506. 
20 Willhite CC, Katz PI. Toxicology updates: dimethyl sulfoxide. J 
Appl Toxicol 1984; 4: 155160. 
21 Mottu F, Laurent A, Rufenacht DA, Doelker E. Organic solvents 
for pharmaceutical parenterals and embolic liquids: a review of 
toxicity data. PDA J Pharm Sci Technol 2000; 54(6): 456469. 
22 Yellowlees P, Greenfield C, McIntyre N. Dimethylsulphoxideinduced 
toxicity. Lancet 1980; ii: 10041006. 
23 Bond GR, Curry SC, Dahl DW. Dimethylsulphoxide-induced 
encephalopathy [letter]. Lancet 1989; i: 11341135. 
24 Knott LJ. Safety of intravenous dimethylsulphoxide [letter]. Lancet 
1980; ii: 1299. 
25 Creus N, Mateu J, Masso J, et al. Toxicity to topical dimethyl 
sulfoxide (DMSO) when used as an extravasation antidote. Pharm 
Wld Sci 2002; 24(5): 175176. 
26 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1466. 
27 Ansel HC, Norred WP, Roth IL. Antimicrobial activity of dimethyl 
sulfoxide against Escherichia coli, Pseudomonas aeruginosa, and 
Bacillus megaterium. J Pharm Sci 1969; 58(7): 836839. 
28 Placencia AM, Oxborrow GS, Danielson JW. Sterility testing of fat 
emulsions using membrane filtration and dimethyl sulfoxide. J 
Pharm Sci 1982; 71(6): 704705. 
20 General References 
Mottu F, Stelling M-J, Rufenacht DA. Comparative haemolytic activity 
of undiluted organic water-miscible solvents for intravenous and 
intra-arterial injection. PDA J Pharm Sci Technol 2001; 55(1): 16 
21. 
21 Authors 
CG Cable. 
22 Date of Revision 
19 August 2005. 
252 Dimethyl Sulfoxide

Dimethylacetamide 
1 Nonproprietary Names 
BP: Dimethylacetamide 
PhEur: Dimethylacetamidum 
2 Synonyms 
Acetdimethylamide; acetic acid dimethylamide; acetyldimethylamine; 
dimethylacetone amide; dimethylamide acetate; DMA; 
DMAC. 
3 Chemical Name and CAS Registry Number 
N,N-Dimethylacetamide [127-19-5] 
4 Empirical Formula and Molecular Weight 
C4H9NO 87.12 
5 Structural Formula 
6 Functional Category 
Solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Dimethylacetamide is used as a solvent in oral and injectable 
pharmaceutical formulations.(1) It has been used as a cosolvent 
to solubilize poorly soluble drugs.(24) The use of dimethylacetamide 
has also been investigated as a vehicle for the 
parenteral delivery of relatively small peptides.(5) 
The use of solvents such as dimethylacetamide has been 
shown to influence the size and rate of release of norfloxacin 
from nanoparticles.(6) 
Dimethylacetamide has also been used in topical formulations 
and has been evaluated as a permeation enhancer for 
transdermal drug delivery.(1) 
8 Description 
Dimethylacetamide occurs as a clear, colorless, slightly hygroscopic 
liquid. It has a weak ammonia-like or fishlike odor. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for dimethylacetamide. 
Test PhEur 2005 
(Suppl. 5.1) 
Identification . 
Characters . 
Appearance . 
Relative density 0.9410.944 
Refractive index 1.4351.439 
Acidity . 
Alkalinity . 
Related substances . 
Heavy metals 410 ppm 
Nonvolatile matter 420 ppm 
Water 40.1% 
10 Typical Properties 
Autoignition temperature: 4908C 
Boiling point: 1658C 
Dielectric constant: D20 = 37.8 
Flash point: 708C 
Refractive index: nD
22.5 = 1.4371 
Solubility: miscible with ethanol (95%), water, and most 
common solvents. 
Specific gravity: 0.943 
Surface tension: 35.7mN/m (35.7 dyne/cm) 
Vapor pressure: 0.33 kPa at 208C 
Viscosity (dynamic): 1.02 mPa s (1.02 cP) at 258C 
11 Stability and Storage Conditions 
Dimethylacetamide should be stored in an airtight container, 
protected from light, in a cool, dry, place. Dimethylacetamide 
has an almost unlimited shelf-life when kept in closed containers 
and under nitrogen. It is combustible. 
12 Incompatibilities 
Dimethylacetamide is incompatible with carbon tetrachloride, 
oxidizing agents, halogenated compounds, and iron. It attacks 
plastic and rubber. Contact with strong oxidizers may cause 
fire. 
13 Method of Manufacture 
Dimethylacetamide is manufactured from acetic acid and 
dimethylamine in a closed system. 
14 Safety 
Dimethylacetamide is used in pharmaceutical preparations as a 
solvent in parenteral formulations and is generally regarded as 
a nontoxic material when used as an excipient. Animal toxicity 
studies indicate that dimethylacetamide is readily absorbed into 
the bloodstream following inhalation or topical application. 
Repeated exposure to dimethylacetamide may be harmful and

can result in liver damage. High intravenous doses 
(>400 mg/kg/day for 3 days) may be hallucinogenic.(710) 
LD50 (rabbit, SC): 9.6 g/kg(11) 
LD50 (rat, IP): 2.75 g/kg 
LD50 (rat, IV): 2.64 g/kg 
LD50 (rat, oral): 4.93 g/kg 
LD50 (mouse, inhalation): 7.2 g/kg 
LD50 (mouse, IP): 2.8 g/kg 
LD50 (mouse, IV): 3.02 g/kg 
LD50 (mouse, SC): 9.6 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. Dimethylacetamide can 
be absorbed into the bloodstream by inhalation and through 
the skin; it is irritating to the skin and eyes. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (IM injections, 
IV injections and infusions). Included in parenteral medicines 
licensed in the UK. 
17 Related Substances 

18 Comments 
The EINECS number for dimethylacetamide is 204-826-4. A 
specification for dimethylacetamide is included in the Japanese 
Pharmaceutical Excipients (JPE) 2004.(12) 
19 Specific References 
1 Strickley RG. Solubilizing excipients in oral and injectable 
formulations. Pharm Res 2004; 21(2): 201230. 
2 Kawakami K, Miyoshi K, Ida Y. Solubilisation behavior of poorly 
soluble drugs with combined use of Gelucire 44/14 and cosolvent. J 
Pharm Sci 2004; 93(6): 14711479. 
3 Tesconi MS, Bramer SL, Yalkowsky SH. The preparation of soft 
gelatin capsules for a radioactive tracer study. Pharm Dev Technol 
1999; 4(4): 507513. 
4 Han SK, Kim GY, Park YH. Solubilization of biphenyl dimethyl 
dicarboxylate by cosolvency. Drug Dev Ind Pharm 1999; 25(11): 
11931197. 
5 Larsen SW, Ankersen M, Larsen C. Kinetics of degradation and oil 
solubility of ester prodrugs of a model dipeptide (Gly-Phe). Eur J 
Pharm Sci 2004; 22: 399408. 
6 Jeon HJ, Jeong YI, Jang MK, et al. Effect of solvent on the 
preparation of surfactant-free poly (DL-lactide-co-glycolide) 
nanoparticles and norfloxacin release characteristics. Int J Pharm 
2000; 207(12): 99108. 
7 Horn HJ. Toxicology of dimethylacetamide. Toxicol Appl 
Pharmacol 1961; 3: 1224. 
8 Anschel J. Solvents and solubilization in injections [in German]. 
Pharm Ind 1965; 27: 781787. 
9 Kennedy GL, Sherman H. Acute toxicity of dimethylformamide 
and dimethylacetamide following various routes of administration. 
Drug Chem Toxicol 1986; 9: 147170. 
10 Kim SN. Preclinical toxicology and pharmacology of dimethylacetamide, 
with clinical notes. Drug Metab Rev 1988; 19: 345 
368. 
11 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1371. 
12 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 244245. 
20 General References 
Sinha VR, Kaur MP. Permeation enhancers for transdermal drug 
delivery. Drug Dev Ind Pharm 2000; 26(11): 11311140. 
21 Authors 
RT Guest. 
22 Date of Revision 
21 August 2005. 
254 Dimethylacetamide

Disodium Edetate 
1 Nonproprietary Names 
BP: Disodium edetate 
JP: Disodium edetate 
PhEur: Dinatrii edetas 
USP: Edetate disodium 
2 Synonyms 
Disodium EDTA; disodium ethylenediaminetetraacetate; 
edathamil disodium; edetate disodium; edetic acid, disodium 
salt. 
3 Chemical Name and CAS Registry Number 
Ethylenediaminetetraacetic acid, disodium salt [139-33-3] 
Disodium ethylenediaminetetraacetate dihydrate [6381-92-6] 
4 Empirical Formula and Molecular Weight 
C10H14N2Na2O8 336.2 (for anhydrous) 
C10H18N2Na2O10 372.2 (for dihydrate) 
5 Structural Formula 
6 Functional Category 
Chelating agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Disodium edetate is used as a chelating agent in a wide range of 
pharmaceutical preparations, including mouthwashes, 
ophthalmic preparations, and topical preparations,(13) typically 
at concentrations between 0.005 and 0.1% w/v. 
Disodium edetate forms stable water-soluble complexes 
(chelates) with alkaline earth and heavy-metal ions. The 
chelated form has few of the properties of the free ion, and 
for this reason chelating agents are often described as 
removing ions from solution, a process known as sequestering. 
The stability of the metaledetate complex is dependent on 
the metal ion involved and the pH. 
Disodium edetate is also used as a water softener as it will 
chelate calcium and magnesium ions present in hard water. It is 
also used therapeutically as an anticoagulant as it will chelate 
calcium and prevent the coagulation of blood in vitro. 
Concentrations of 0.1% w/v are used in small volumes for 
hematological testing and 0.3% w/v in transfusions. 
See also Edetic acid. 
8 Description 
Disodium edetate occurs as a white crystalline, odorless powder 
with a slightly acidic taste. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for disodium edetate. 
Test JP 2001 PhEur 2005 USP 28 
Identification . . . 
Characters . .  
Appearance of 
solution 
. .  
pH 4.34.7 4.05.5 4.06.0 
Iron  480 ppm  
Calcium   . 
Heavy metals 410 ppm 420 ppm 40.005% 
Cyanide .   
Arsenic 42 ppm   
Limit of nitrilotriacetic 
acid 
 40.1% 40.1% 
Residue on ignition 37.039.0%   
Loss on drying   8.711.4% 
Assay 98.5101.0% 98.5101.0% 99.0101.0% 
10 Typical Properties 
Acidity/alkalinity: pH 4.34.7 (1% w/v solution in carbon 
dioxide-free water) 
Freezing point depression: 0.148C (1% w/v aqueous solution) 
Melting point: decomposition at 2528C for the dihydrate. 
Refractive index: 1.33 (1% w/v aqueous solution) 
Solubility: practically insoluble in chloroform and ether; 
slightly soluble in ethanol (95%); soluble 1 part in 11 parts 
water. 
Specific gravity: 1.004 (1% w/v aqueous solution) 
Viscosity (kinematic): 1.03mm2/s (1.03 cSt) (1% w/v aqueous 
solution). 
11 Stability and Storage Conditions 
Edetate salts are more stable than edetic acid (see also Edetic 
acid). However, disodium edetate dihydrate loses water of 
crystallization when heated to 1208C. Aqueous solutions of 
disodium edetate may be sterilized by autoclaving, and should 
be stored in an alkali-free container. 
Disodium edetate is hygroscopic and is unstable when 
exposed to moisture. It should be stored in a well-closed 
container in a cool, dry place.

12 Incompatibilities 
Disosium edetate behaves as a weak acid, displacing carbon 
dioxide from carbonates and reacting with metals to form 
hydrogen. It is incompatible with strong oxidizing agents, 
strong bases, metal ions, and metal alloys. 
See also Edetic acid. 
13 Method of Manufacture 
Disodium edetate may be prepared by the reaction of edetic 
acid and sodium hydroxide. 
14 Safety 
Disodium edetate is used widely in topical, oral, and parenteral 
pharmaceutical formulations; it is used extensively in cosmetic 
and food products. Disodium edetate and edetate calcium 
disodium are used in a greater number and variety of 
pharmaceutical formulations than is edetic acid. Both disodium 
edetate and edetate calcium disodium are poorly absorbed from 
the gastrointestinal tract and are associated with few adverse 
effects when used as excipients in pharmaceutical formulations. 
Disodium edetate, trisodium edetate, and edetic acid readily 
chelate calcium and can, in large doses, cause calcium depletion 
(hypocalcemia) if used over an extended period of time, or if 
administered too rapidly by intravenous infusion. If used in 
preparations for the mouth, they can also leach calcium from 
the teeth. However, edetate calcium disodium does not chelate 
calcium. 
Disodium edetate should be used with caution in patients 
with renal impairment, tuberculosis, and impaired cardiac 
function. 
Although disodium edetate is generally considered safe, 
there have been reports of disodium edetate toxicity in patients 
receiving chelation therapy.(4) 
Nasal formulations containing benzalkonium chloride and 
disodium edetate, both known to be local irritants, were shown 
to produce an inflammatory reaction, and microscopic 
examination showed an extended infiltration of the mucosa 
by eosinophils, and pronounced atrophy and disorganization 
of the epithelium, although these effects were subsequently 
shown to be reversible.(3) 
The WHO has set an estimated acceptable daily intake for 
disodium EDTA in foodstuffs of up to 2.5 mg/kg bodyweight.(
5) See also Edetic acid. 
LD50 (mouse, IP): 0.26 g/kg(6) 
LD50 (mouse, IV): 0.056 g/kg 
LD50 (mouse, OP): 2.05 g/kg 
LD50 (rabbit, IV): 0.047 g/kg 
LD50 (rabbit, OP): 2.3 g/kg 
LD50 (rat, OP): 2.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Disodium edetate and its 
derivatives are mild irritants to the mucous membranes. Eye 
protection, gloves, and dust masks are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(inhalations; injections; ophthalmic preparations; oral capsules, 
solutions, suspensions, syrups, and tablets; rectal topical, and 
vaginal preparations). Included in nonparenteral and parenteral 
medicines licensed in the UK. Included in the Canadian List 
of Acceptable Non-medicinal Ingredients. 
17 Related Substances 
Edetic acid. 
18 Comments 
Disodium edetate has been used experimentally to investigate 
the stability and skin penetration capacity of captopril gel, in 
which disodium edetate was shown to exert a potent stabilizing 
effect, and may be used in the development of a transdermal 
drug delivery system.(7) 
A chitosanEDTA conjugate has been investigated as a 
novel polymer for use in topical gels. The conjugate was shown 
to be stable, colorless, and transparent, and it also demonstrated 
antimicrobial effects.(8) 
The EINECS number for disodium edetate is 205-358-3. 
19 Specific References 
1 Ungphaiboon S, Maitani Y. In vitro permeation studies of 
triamcinolone acetonide mouthwashes. Int J Pharm 2001; 220: 
111117. 
2 Kaur IP, Singh M, Kanwar M. Formulation and evaluation of 
ophthalmic preparations of acetazolamide. Int J Pharm 2000; 199: 
119127. 
3 Bechgaard E, Bindseil E, Bagger M, Nielsen HW. Reversibility and 
clinical relevance of morphological changes after nasal application 
of ephedrine nasal drops 1%. Int J Pharm 1997; 152: 6773. 
4 Morgan BW, Singleton K, Thomas JD. Adverse effects in 5 patients 
receiving EDTA at an outpatient chelation clinic. Vet Hum Toxicol 
2002; 44(5): 274276. 
5 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
6 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1660. 
7 Huang YB, Tsai YH, Chang JS, et al. Effect of antioxidants and 
anti-irritants on the stability, skin irritation and penetration 
capacity of captopril gel. Int J Pharm 2002; 241: 345351. 
8 Valenta C, Christen B, Bernkop-Schnurch A. ChitosanEDTA 
conjugate: novel polymer for topical gels. J Pharm Pharmacol 
1998; 50: 445452. 
20 General References 

21 Authors 
S Shah, D Thassu. 
22 Date of Revision 
15 August 2005. 
256 Disodium Edetate

Docusate Sodium 
1 Nonproprietary Names 
BP: Docusate sodium 
PhEur: Docusatum natricum 
USP: Docusate sodium 
2 Synonyms 
Bis(2-ethylhexyl) sodium sulfosuccinate; dioctyl sodium sulfosuccinate; 
DSS; sodium dioctyl sulfosuccinate; sulfo-butanedioic 
acid 1,4-bis(2-ethylhexyl) ester, sodium salt. 
3 Chemical Name and CAS Registry Number 
Sodium 1,4-bis(2-ethylhexyl) sulfosuccinate [577-11-7] 
4 Empirical Formula and Molecular Weight 
C20H37NaO7S 444.56 
5 Structural Formula 
6 Functional Category 
Anionic surfactant; wetting agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Docusate sodium and docusate salts are widely used as anionic 
surfactants in pharmaceutical formulations. Docusate sodium 
is mainly used in capsule and direct-compression tablet 
formulations to assist in wetting and dissolution.(1) Docusate 
salts are also used in oral formulations as laxatives and fecal 
softeners; see Table I. 
Table I: Uses of docusate sodium. 
Use Concentration (%) 
IM injections 0.015 
Surfactant (wetting/dispersing/emulsifying agent) 0.011.0 
Tablet coating agent 20(a) 
Tablet disintegrant 0.5 
(a) Formulation of a tablet coating solution: 20% docusate sodium; 215% sodium benzoate; 
0.5% propylene glycol; solution made in ethanol (70%). 
8 Description 
Docusate sodium is a white or almost white, waxlike, bitter 
tasting, plastic solid with a characteristic octanol-like odor. It is 
hygroscopic and usually available in the form of pellets, flakes, 
or rolls of tissue-thin material. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for docusate sodium. 
Test PhEur 2005 USP 28 
Identification . . 
Characters .  
Alkalinity .  
Bis(2-ethylhexyl) maleate  40.4% 
Chlorides 4350 ppm  
Clarity of solution  . 
Heavy metals 410 ppm 40.001% 
Related nonionic 
substances 
.  
Residue on ignition  15.516.5% 
Sodium sulfate 42.0%  
Water 43.0% 42.0% 
Assay (dried basis) 98.0100.5% 99.0100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 5.86.9 (1% w/v aqueous solution). 
Acid value: 42.5 
Critical micelle concentration: 0.11% w/v aqueous solution at 
258C. 
Density: 1.16 g/cm3 
Hydroxyl value: 6.08.0 
Interfacial tension: in water versus mineral oil at 258C, see 
Table III. 
Table III: Interfacial tension of docusate sodium. 
Concentration (% w/v) Interfacial tension (mN/m) 
0.01 20.7 
0.1 5.9 
1.0 1.84 
Iodine number: 40.25 
Melting point: 1531578C 
Moisture content: 1.51% 
Saponification value: 240253 
Solubility: see Table IV. 
Surface tension: see Table V.

Table IV: Solubility of docusate sodium. 
Solvent Solubility at 208C 
unless otherwise stated 
Acetone Soluble 
Chloroform 1 in 1 
Ethanol (95%) 1 in 3 
Ether 1 in 1 
Glycerin Freely soluble 
Vegetable oils Soluble 
Water 1 in 70 at 258C(a) 
1 in 56 at 308C 
1 in 44 at 408C 
1 in 33 at 508C 
1 in 25 at 608C 
1 in 18 at 708C 
(a) In water, higher concentrations form a thick gel. 
Table V: Surface tension of docusate sodium. 
Concentration in water at 258C (% w/v) Surface tension (mN/m) 
0.001 62.8 
0.1 28.7 
1.0 26.0 
11 Stability and Storage Conditions 
Docusate sodium is stable in the solid state when stored at room 
temperature. Dilute aqueous solutions of docusate sodium 
between pH 110 are stable at room temperature. However, at 
very low pH (<1) and very high pH (>10) docusate sodium 
solutions are subject to hydrolysis. 
The solid material is hygroscopic and should be stored in an 
airtight container in a cool, dry place. 
12 Incompatibilities 
Electrolytes, e.g. 3% sodium chloride, added to aqueous 
solutions of docusate sodium can cause turbidity.(2,3) However, 
docusate sodium possesses greater tolerance to calcium, 
magnesium, and other polyvalent ions than do some other 
surfactants. Docusate sodium is incompatible with acids at pH 
<1 and with alkalis at pH >10. 
13 Method of Manufacture 
Maleic anhydride is treated with 2-ethylhexanol to produce 
dioctyl maleate, which is then reacted with sodium bisulfite. 
14 Safety 
Docusate salts are used in oral formulations as therapeutic 
agents for their fecal softening and laxative properties. As a 
laxative in adults, up to 500 mg of docusate sodium is 
administered daily in divided doses; in children over 6 months 
old, up to 75 mg in divided doses is used. The quantity of 
docusate sodium used as an excipient in oral formulations 
should therefore be controlled to avoid unintended laxative 
effects.(4) Adverse effects associated with docusate sodium 
include diarrhea, nausea, vomiting, abdominal cramps, and 
skin rashes. As with the chronic use of laxatives, the excessive 
use of docusate sodium may produce hypomagnesemia.(5) 
Docusate salts are absorbed from the gastrointestinal tract 
and excreted in bile; they may cause alteration of the 
gastrointestinal epithelium.(6,7) The gastrointestinal or hepatic 
absorption of other drugs may also be affected by docusate 
salts, enhancing activity and possibly toxicity. Docusate sodium 
should not be administered with mineral oil as it may increase 
the absorption of the oil. 
LD50 (mouse, IV): 0.06 g/kg(8) 
LD50 (mouse, oral): 2.64 g/kg 
LD50 (rat, IP): 0.59 g/kg 
LD50 (rat, oral): 1.9 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Docusate sodium may be 
irritant to the eyes and skin, and when inhaled. Eye protection, 
gloves, and a dust mask or respirator are recommended. When 
heated to decomposition, docusate sodium emits toxic fumes. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(IM injections, oral capsules, suspensions, and tablets, also 
topical formulations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
Docusate calcium; docusate potassium. 
Docusate calcium 
Empirical formula: C40H74CaO14S2 
Molecular weight: 883.23 
CAS number: [128-49-4] 
Synonyms: 1,4-bis(2-ethylhexyl) sulfosuccinate, calcium salt; 
dioctyl calcium sulfosuccinate. 
Appearance: white amorphous solid with a characteristic 
octanol-like odor. 
Solubility: soluble 1 in less than 1 of ethanol (95%), chloroform, 
and ether, and 1 in 3300 of water; very soluble in corn 
oil and polyethylene glycol 400. 
Docusate potassium 
Empirical formula: C20H37KO7S 
Molecular weight: 460.67 
CAS number: [7491-09-0] 
Synonyms: dioctyl potassium sulfosuccinate; potassium 1,4- 
bis(2-ethylhexyl) sulfosuccinate. 
Appearance: white amorphous solid with a characteristic 
octanol-like odor. 
Solubility: soluble in ethanol (95%) and glycerin; sparingly 
soluble in water. 
18 Comments 
A convenient way of making a 1% w/v aqueous solution of 
docusate sodium is to add 1 g of solid to about 50mL of water 
and to apply gentle heat. The docusate sodium dissolves in a 
short time and the resulting solution can be made up to 100mL 
with water. Alternatively, 1 g may be soaked overnight in 50mL 
of water and the additional water may then be added with 
gentle heating and stirring. 
258 Docusate Sodium

Docusate sodium may alter the dissolution characteristics of 
certain dosage forms and the bioavailability of some drugs. 
The EINECS number for docusate sodium is 209-406-4. 
19 Specific References 
1 Brown S, Rowley G, Pearson JT. Surface treatment of the 
hydrophobic drug danazol to improve drug dissolution. Int J 
Pharm 1998; 165: 227237. 
2 Ahuja S, Cohen J. Dioctyl sodium sulfosuccinate. In: Florey K, ed. 
Analytical Profiles of Drug Substances, volume 2. New York: 
Academic Press, 1973: 199219. 
3 Ahuja S, Cohen J. Dioctyl sodium sulfosuccinate. In: Florey K, ed. 
Analytical Profiles of Drug Substances, volume 12. New York: 
Academic Press, 1983: 713720. 
4 Guidott JL. Laxative components of a generic drug [letter]. Lancet 
1996; 347: 621. 
5 Rude RK, Siger FR. Magnesium deficiency and excess. Annu Rev 
Med 1981; 323: 245259. 
6 Chapman RW, Sillery J, Fontana DD, Matthys C. Effect of oral 
dioctyl sodium sulfosuccinate on intakeoutput studies of human 
small and large intestine. Gastroenterology 1985; 89: 489493. 
7 Moriarty KJ, Kelly MJ, Beetham R, Clark ML. Studies on the 
mechanism of action of dioctyl sodium sulfosuccinate in the 
human jejunum. Gut 1985; 26: 10081013. 
8 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1274. 
20 General References 
Chambliss WG, Cleary RW, Fischer R, et al. Effect of docusate sodium 
on drug release from a controlled release dosage form. J Pharm Sci 
1981; 70: 12481251. 
Hogue DR, Zimmardi JA, Shah KA. High-performance liquid 
chromatographic analysis of docusate sodium in soft gelatin 
capsules. J Pharm Sci 1992; 81: 359361. 
Shah DN, Feldkamp JR, White JL, Hem SL. Effect of the pH-zero point 
of charge relationship on the interaction of ionic compounds and 
polyols with aluminum hydroxide gel. J Pharm Sci 1982; 71: 266 
268. 
21 Authors 
S Murdande. 
22 Date of Revision 
15 August 2005. 
Docusate Sodium 259

Edetic Acid 
1 Nonproprietary Names 
BP: Edetic acid 
PhEur: Acidum edeticum 
USPNF: Edetic acid 
2 Synonyms 
Dissolvine; edathamil; EDTA; ethylenediaminetetraacetic acid; 
(ethylenedinitrilo)tetraacetic acid; Sequestrene AA; tetracemic 
acid; Versene Acid. 
3 Chemical Name and CAS Registry Number 
N,N-1,2-Ethanediylbis[N-(carboxymethyl)glycine] [60-00-4] 
4 Empirical Formula and Molecular Weight 
C10H16N2O8 292.24 
5 Structural Formula 
6 Functional Category 
Chelating agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Edetic acid and edetate salts are used in pharmaceutical 
formulations, cosmetics, and foods as chelating agents. They 
form stable water-soluble complexes (chelates) with alkaline 
earth and heavy metal ions. The chelated form has few of the 
properties of the free ion, and for this reason chelating agents 
are often described as removing ions from solution; this 
process is also called sequestering. The stability of the metal 
edetate complex depends on the metal ion involved and also on 
the pH. The calcium chelate is relatively weak and will 
preferentially chelate heavy metals, such as iron, copper, and 
lead, with the release of calcium ions. For this reason, edetate 
calcium disodium is used therapeutically in cases of lead 
poisoning; see also Section 18. 
Edetic acid and edetates are primarily used as antioxidant 
synergists, sequestering trace amounts of metal ions, particularly 
copper, iron, and manganese, that might otherwise 
catalyze autoxidation reactions. Edetic acid and edetates may 
be used alone or in combination with true antioxidants; the 
usual concentration employed being in the range 0.0050.1% 
w/v. Edetates have been used to stabilize ascorbic acid; 
corticosteroids; epinephrine; folic acid; formaldehyde; gums 
and resins; hyaluronidase; hydrogen peroxide; oxytetracycline; 
penicillin; salicylic acid, and unsaturated fatty acids. Essential 
oils may be washed with a 2% w/v solution of edetate to 
remove trace metal impurities. 
Edetic acid and edetates possess some antimicrobial activity 
but are most frequently used in combination with other 
antimicrobial preservatives owing to their synergistic effects. 
Many solutions used for the cleaning, storage, and wetting of 
contact lenses contain disodium edetate. Typically, edetic acid 
and edetates are used in concentrations of 0.010.1% w/v as 
antimicrobial preservative synergists; see Section 10. 
Edetic acid and disodium edetate may also be used as water 
softeners since they will chelate the calcium and magnesium 
ions present in hard water; edetate calcium disodium is not 
effective. Many cosmetic and toiletry products, e.g., soaps, 
contain edetic acid as a water softener. 
8 Description 
Edetic acid occurs as a white crystalline powder. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for edetic acid. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Appearance of solution .  
Residue on ignition  40.2% 
Sulfated ash 40.2%  
Heavy metals 420 ppm 40.003% 
Nitrilotriacetic acid 40.1% 40.3% 
Iron 480 ppm 40.005% 
Chloride 4200ppm  
Assay 98.0101.0% 98.0100.5% 
10 Typical Properties 
Acidity/alkalinity: pH = 2.2 for a 0.2% w/v aqueous solution. 
Antimicrobial activity: edetic acid has some antimicrobial 
activity against Gram-negative microorganisms, Pseudomonas 
aeruginosa, some yeasts, and fungi; although this 
activity is insufficient for edetic acid to be used effectively 
as an antimicrobial preservative on its own.(1,2) However, 
when used with other antimicrobial preservatives, edetic 
acid demonstrates a marked synergistic effect in its 
antimicrobial activity. Edetic acid and edetates are therefore 
frequently used in combination with such preservatives as 
benzalkonium chloride; bronopol; cetrimide; imidurea; 
parabens; and phenols, especially chloroxylenol. Typically, 
edetic acid is used at a concentration of 0.10.15% w/v. In 
the presence of some divalent metal ions, such as Ca2. or 
Mg2., the synergistic effect may be reduced or lost

altogether. The addition of disodium edetate to phenylmercuric 
nitrate(3) and thimerosal(3,4) has also been reported to 
reduce the antimicrobial efficacy of the preservative. Edetic 
acid and iodine form a colorless addition compound that is 
bactericidal. 
Dissociation constant: 
pKa1 = 2.00; 
pKa2 = 2.67; 
pKa3 = 6.16; 
pKa4 = 10.26. 
Melting point: melts above 2208C, with decomposition. 
Solubility: soluble in solutions of alkali hydroxides; soluble 1 in 
500 of water. 
11 Stability and Storage Conditions 
Although edetic acid is fairly stable in the solid state, edetate 
salts are more stable than the free acid, which decarboxylates if 
heated above 1508C. Disodium edetate dihydrate loses water of 
crystallization when heated to 1208C. Edetate calcium disodium 
is slightly hygroscopic and should be protected from 
moisture. 
Aqueous solutions of edetic acid or edetate salts may be 
sterilized by autoclaving, and should be stored in an alkali-free 
container. 
Edetic acid and edetates should be stored in well-closed 
containers in a cool, dry place. 
12 Incompatibilities 
Edetic acid and edetates are incompatible with strong oxidizing 
agents, strong bases, and polyvalent metal ions such as copper, 
nickel, and copper alloy. 
Edetic acid and disodium edetate behave as weak acids, 
displacing carbon dioxide from carbonates and reacting with 
metals to form hydrogen. 
Other incompatibilities include the inactivation of certain 
types of insulin due to the chelation of zinc, and the chelation of 
trace metals in total parenteral nutrition (TPN) solutions 
following the addition of TPN additives stabilized with 
disodium edetate. Calcium disodium edetate has also been 
reported to be incompatible with amphotericin and with 
hydralazine hydrochloride in infusion fluids. 
13 Method of Manufacture 
Edetic acid may be prepared by the condensation of ethylenediamine 
with sodium monochloroacetate in the presence of 
sodium carbonate. An aqueous solution of the reactants is 
heated to about 908C for 10 hours, then cooled, and 
hydrochloric acid is added to precipitate the edetic acid. 
Edetic acid may also be prepared by the reaction of 
ethylenediamine with hydrogen cyanide and formaldehyde 
with subsequent hydrolysis of the tetranitrile, or under alkaline 
conditions with continuous extraction of ammonia. 
See Section 17 for information on the preparation of edetate 
salts. 
14 Safety 
Edetic acid and edetates are widely used in topical, oral, and 
parenteral pharmaceutical formulations. They are also extensively 
used in cosmetics and food products. 
Edetic acid is generally regarded as an essentially nontoxic 
and nonirritant material, although it has been associated with 
dose-related bronchoconstriction when used as a preservative 
in nebulizer solutions. It has therefore been recommended that 
nebulizer solutions for bronchodilation should not contain 
edetic acid.(5) 
Edetates, particularly disodium edetate and edetate calcium 
disodium, are used in a greater number and variety of 
pharmaceutical formulations than the free acid. 
Disodium edetate, trisodium edetate, and edetic acid readily 
chelate calcium and can, in large doses, cause calcium depletion 
(hypocalcemia) if used over an extended period or if 
administered too rapidly by intravenous infusion. If used in 
preparations for the mouth, they can also leach calcium from 
the teeth. In contrast, edetate calcium disodium does not chelate 
calcium. 
Edetate calcium disodium is nephrotoxic and should be used 
with caution in patients with renal impairment. 
The WHO has set an estimated acceptable daily intake for 
disodium edetate in foodstuffs at up to 2.5 mg/kg bodyweight.(
6) 
See also Section 18. 
LD50 (mouse, IP): 0.25 g/kg(7) 
LD50 (rat, IP): 0.397 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Edetic acid and edetates are 
mildly irritant to the skin, eyes, and mucous membranes. 
Ingestion, inhalation, and contact with the skin and eyes should 
therefore be avoided. Eye protection, gloves, and a dust mask 
are recommended. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (otic, rectal, 
and topical preparations). Included in nonparenteral medicines 
licensed in the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
See also Section 17. 
17 Related Substances 
Dipotassium edetate; disodium edetate; edetate calcium disodium; 
sodium edetate; trisodium edetate. 
Dipotassium edetate 
Empirical formula: C10H14K2N2O8 
Molecular weight: 368.46 
CAS number: [2001-94-7] 
Synonyms: dipotassium edathamil; dipotassium ethylenediaminetetraacetate; 
edathamil dipotassium; edetate dipotassium; 
edetic acid dipotassium salt; EDTA dipotassium; 
N,N0-1,2-ethanediylbis[N-(carboxymethyl)glycine] dipotassium 
salt; ethylenebis(iminodiacetic acid) dipotassium salt; 
ethylenediaminetetraacetic acid dipotassium salt; (ethylenedinitrilo)
tetraacetic acid dipotassium salt; tetracemate dipotassium. 
Appearance: white crystalline powder. 
Comments: The EINECS number for dipotassium edetate is 
217-895-0. 
Edetate calcium disodium 
Empirical formula: C10H12CaN2Na2O8 
Molecular weight: 374.28 
CAS number: [62-33-9] for the anhydrous material and 
[23411-34-9] for the dihydrate 
Edetic Acid 261

Synonyms: calcium disodium edetate; calcium disodium 
ethylenediaminetetraacetate; calcium disodium (ethylenedinitrilo)
tetraacetate; E385; edathamil calcium disodium; 
edetic acid calcium disodium salt; EDTA calcium; ethylenediaminetetraacetic 
acid calcium disodium chelate; [(ethylenedinitrilo)
tetraacetato]calciate(2-) disodium; sodium 
calciumedetate; Versene CA. 
Appearance: white or creamy-white colored, slightly hygroscopic, 
crystalline powder or granules; odorless, or with a 
slight odor; tasteless, or with a faint saline taste. 
Acidity/alkalinity: pH = 45 for a 1% w/v aqueous solution. 
Density (bulk): 0.69 g/cm3 
Solubility: practically insoluble in chloroform, ether, and other 
organic solvents; very slightly soluble in ethanol (95%); 
soluble 1 in 2 of water. 
Method of manufacture: edetate calcium disodium may be 
prepared by the addition of calcium carbonate to a solution 
of disodium edetate. 
Safety: see also Section 14. 
LD50 (mouse, IP): 4.5 g/kg(7) 
LD50 (rabbit, IP): 6 g/kg 
LD50 (rabbit, oral): 7 g/kg 
LD50 (rat, IP): 3.85 g/kg 
LD50 (rat, IV): 3.0 g/kg 
LD50 (rat, oral): 10 g/kg 
Regulatory status: GRAS listed. Accepted for use as a food 
additive in Europe. Included in the FDA Inactive Ingredients 
Guide (injections, oral capsules, solutions, suspensions, 
syrups, and tablets). 
Comments: used in pharmaceutical formulations as a chelating 
agent in concentrations between 0.010.1% w/v. Usually 
edetate calcium disodium is used in pharmaceutical formulations 
in preference to disodium edetate or sodium 
edetate to prevent calcium depletion occurring in the body. 
In food products, edetate calcium disodium may also be 
used in flavors and as a color retention agent. Edetate 
calcium disodium occurs as the dihydrate, trihydrate, and 
anhydrous material. 
Some pharmacopeias specify that edetate calcium disodium 
is the dihydrate, others that it is the anhydrous 
material. The USP 28 specifies that edetate calcium 
disodium is a mixture of the dihydrate and trihydrate but 
that the dihydrate predominates. 
The EINECS number for edetate calcium disodium is 
200-529-9. 
Sodium edetate 
Empirical formula: C10H12N2Na4O8 
Molecular weight: 380.20 
CAS number: [64-02-8] 
Synonyms: edetate sodium; edetic acid tetrasodium salt; EDTA 
tetrasodium; N,N0-1,2-ethanediylbis[N-(carboxymethyl)- 
glycine] tetrasodium salt; ethylenebis(iminodiacetic acid) 
tetrasodium salt; ethylenediaminetetraacetic acid tetrasodium 
salt; (ethylenedinitrilo)tetraacetic acid tetrasodium 
salt; Sequestrene NA4; tetracemate tetrasodium; tetracemin; 
tetrasodium edetate; tetrasodium ethylenebis(iminodiacetate); 
tetrasodium ethylenediaminetetraacetate; Versene. 
Appearance: white crystalline powder. 
Acidity/alkalinity: pH = 11.3 for a 1% w/v aqueous solution. 
Melting point: >3008C 
Solubility: soluble 1 in 1 of water. 
Safety: see also Section 14. 
LD50 (mouse, IP): 0.33 g/kg(7) 
Regulatory status: included in the FDA Inactive Ingredients 
Guide (inhalations, injections, ophthalmic preparations, 
oral capsules and tablets, and topical preparations). 
Comments: sodium edetate reacts with most divalent and 
trivalent metallic ions to form soluble metal chelates and is 
used in pharmaceutical formulations in concentrations 
between 0.010.1% w/v. 
Trisodium edetate 
Empirical formula: C10H13N2Na3O8 
Molecular weight: 358.20 
CAS number: [150-38-9] 
Synonyms: edetate trisodium; edetic acid trisodium salt; EDTA 
trisodium; N,N0-1,2-ethanediylbis[N-(carboxymethyl)glycine] 
trisodium salt; ethylenediaminetetraacetic acid trisodium 
salt; (ethylenedinitrilo)tetraacetic acid trisodium 
salt; Sequestrene NA3; trisodium ethylenediaminetetraacetate; 
Versene-9. 
Appearance: white crystalline powder. 
Acidity/alkalinity: pH = 9.3 for a 1% w/v aqueous solution. 
Melting point: >3008C 
Method of manufacture: trisodium edetate may be prepared by 
adding a solution of sodium hydroxide to disodium edetate. 
Safety: see also Section 14. 
LD50 (mouse, IP): 0.3 g/kg(7) 
LD50 (mouse, oral): 2.15 g/kg 
LD50 (rat, oral): 2.15 g/kg 
Regulatory status: included in the FDA Inactive Ingredients 
Guide (topical preparations). 
Comments: more soluble in water than either the disodium salt 
or the free acid. Trisodium edetate also occurs as the 
monohydrate and is used in pharmaceutical formulations as 
a chelating agent. The EINECS number for trisodium 
edetate is 205-758-8. 
18 Comments 
Other salts of edetic acid that are commercially available 
include diammonium, dimagnesium, ferric sodium, and magnesium 
disodium edetates. Therapeutically, a dose of 50 mg/kg 
body-weight of disodium edetate, as a slow infusion over a 24- 
hour period, with a maximum daily dose of 3 g, has been used 
as a treatment for hypercalcemia. For the treatment of lead 
poisoning, a dose of 6080 mg/kg of edetate calcium disodium, 
as a slow infusion in two daily doses, for 5 days, has been used. 
Chelation therapy using edetic acid has been widely used for 
the treatment of ischemic heart disease. However, it has been 
suggested that the therapeutic benefits of this treatment may be 
due to the changes in lifestyle of the patient rather than the 
administration of edetic acid (40 mg/kg by infusion over a 3- 
hour period).(8) 
The EINECS number for edetic acid is 200-449-4. 
19 Specific References 
1 Richards RME, Cavill RH. Electron microscope study of effect of 
benzalkonium chloride and edetate disodium on cell envelope of 
Pseudomonas aeruginosa. J Pharm Sci 1976; 65: 7680. 
2 Whalley G. Preservative properties of EDTA. Manuf Chem 1991; 
62(9): 2223. 
3 Richards RME, Reary JME. Changes in antibacterial activity of 
thiomersal and PMN on autoclaving with certain adjuvants. J 
Pharm Pharmacol 1972; 24 (Suppl.): 84P89P. 
4 Morton DJ. EDTA reduces antimicrobial efficacy of thiomerosal. 
Int J Pharm 1985; 23: 357358. 
262 Edetic Acid

5 Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor properties 
of preservatives in ipratropium bromide (Atrovent) nebuliser 
solution. Br Med J 1987; 294: 11971198. 
6 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications. 
Seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1660. 
8 Knudtson ML, Wyse DG, Galbraith PD, et al. Chelation therapy 
for ischemic heart disease: a randomized controlled trial. J Am 
Med Assoc 2002; 287(4): 481486. 
20 General References 
Chalmers L. The uses of EDTA and other chelates in industry. Manuf 
Chem 1978; 49(3): 7980, 83. 
Hart JR. Chelating agents in cosmetic and toiletry products. Cosmet 
Toilet 1978; 93(12): 2830. 
Hart JR. EDTA-type chelating agents in personal care products. Cosmet 
Toilet 1983; 98(4): 5458. 
Lachman L. Antioxidants and chelating agents as stabilizers in liquid 
dosage forms. Drug Cosmet Ind 1968; 102(2): 4345, 146149. 
21 Authors 
SC Owen. 
22 Date of Revision 
27 August 2005. 
Edetic Acid 263

Erythorbic Acid 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Araboascorbic acid; d-araboascorbic acid; D-2,3-didehydroerythro-
hexono-1,4-lactone; E315; erycorbin; d-erythorbic 
acid; D-erythro-hex-2-enoic acid; D-erythro-3-ketohexonic 
acid lactone; glucosaccharonic acid; D-isoascorbic acid; isovitamin 
C; g-lactone; saccharosonic acid. 
3 Chemical Name and CAS Registry Number 
Isoascorbic acid [89-65-6] 
4 Empirical Formula and Molecular Weight 
C6H8O6 176.14 
5 Structural Formula 
6 Functional Category 
Antioxidant. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Erythorbic acid is a stereoisomer of L-ascorbic acid, and is used 
as an antioxidant in foods and oral pharmaceutical formulations. 
It has approximately 5% of the vitamin C activity of 
L-ascorbic acid. 
8 Description 
Erythorbic acid occurs as a white or slightly yellow-colored 
crystals or powder. It gradually darkens in color upon exposure 
to light. 
9 Pharmacopeial Specifications 
See Section 18. 
10 Typical Properties 
Acidity/alkalinity: pH = 2.1 (10% w/v aqueous solution at 
258C) 
Density (bulk): 0.704 g/cm3 
Melting point: 1641718C with decomposition at 1848C 
Solubility: see Table I. 
Specific rotation [a]D
20: 16.2 to 18.28 (10% w/v aqueous 
solution) 
Table I: Solubility of erythorbic acid. 
Solvent Solubility at 258C unless otherwise stated 
Acetone 1 in 70 
Ethanol (95%) 1 in 20 
Ether Practically insoluble 
Methanol 1 in 5.5 
Propylene glycol 1 in 6.7 
Water 1 in 2.3 
1 in 1.8 at 388C 
1 in 1.6 at 508C 
11 Stability and Storage Conditions 
Erythorbic acid should be stored in an airtight container, 
protected from light, in a cool, dry place. 
12 Incompatibilities 
Erythorbic acid is incompatible with chemically active metals 
such as aluminum, copper, magnesium, and zinc. It is also 
incompatible with strong bases and strong oxidizing agents. 
13 Method of Manufacture 
Erythorbic acid is synthesized by the reaction between methyl 
2-keto-D-gluconate and sodium methoxide. It can also be 
synthesized from sucrose, and produced from Penicillium spp. 
14 Safety 
Erythorbic acid is widely used in food applications as an 
antioxidant. It is also used in oral pharmaceutical applications 
as an antioxidant. Erythorbic acid is generally regarded as 
nontoxic and nonirritant when used as an excipient. Erythorbic 
acid is readily metabolized and does not affect the urinary 
excretion of ascorbic acid. 
The WHO has set an acceptable daily intake of erythorbic 
acid and its sodium salt in foods at up to 5 mg/kg bodyweight.(
1) 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. When heated to decomposition, 
erythorbic acid emits acrid smoke and irritating fumes.

16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral concentrate 
and tablets). 
17 Related Substances 
Ascorbic acid; sodium erythorbate 
Sodium erythorbate 
Empirical formula: C6H7NaO6 
Molecular weight: 198.11 
CAS number: [7378-23-6] 
Synonyms: E316; D-erythro-hex-2-enoic acid sodium salt; 
erythorbic acid sodium salt. 
Acidity/alkalinity: pH = 7.27.9 for 10% w/v aqueous 
solution. 
Melting point: 1728C 
Solubility: soluble 1 in 6.5 of water. The sodium salt is less 
soluble in water than the free acid. 
Comments: the EINECS number for sodium erythorbate is 228- 
973-6. 
18 Comments 
Although not currently included in any pharmacopeias, a 
specification for erythorbic acid is included in the Food 
Chemicals Codex and Japanese Pharmaceutical Excipients 
(JPE), see Table II. 
The EINECS number for erythorbic acid is 201-928-0. 
Table II: JPE 2004 specification for erythorbic acid.(2) 
Test JPE 2004 
Identification . 
Clarity and color of solution . 
Melting point 1661728C 
Heavy metals 420 ppm 
Arsenic 44 ppm 
Loss on drying 40.40% 
Residue on ignition 40.30% 
Optical rotation at 208C (10% w/v 
aqueous solution) 
16.2 to 18.28 
Assay >99.0% 
19 Specific References 
1 FAO/WHO. Toxicological evaluation of certain food additives 
with a review of general principles and of specifications: 
seventeenth report of the joint FAO/WHO expert committee on 
food additives.World Health Organ Tech Rep Ser 1974; No. 539. 
2 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 281282. 
20 General References 

21 Authors 
SC Owen, PJ Weller. 
22 Date of Revision 
25 May 2005. 
Erythorbic Acid 265

Erythritol 
1 Nonproprietary Names 
PhEur: Erythritolum 
2 Synonyms 
(2R,3S)-Butane 1,2,3,4-tetrol; C*Eridex; E968; erythrite; 
erythroglucin; meso-erythritol; phycite; tetrahydroxybutane. 
3 Chemical Name and CAS Registry Number 
Erythritol [149-32-6] 
4 Empirical Formula and Molecular Weight 
C4H10O4 122.12 
5 Structural Formula 
6 Functional Category 
Sweetening agent; tablet and capsule diluent; taste masking 
agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Erythritol is a noncariogenic excipient used in a variety of 
pharmaceutical preparations, including in solid dosage forms as 
a tablet filler,(1) and in coatings.(2) It is also used in sugar-free 
lozenges,(3,4) and medicated chewing gum.(3) 
Erythritol can also be used as a diluent in wet granulation in 
combination with moisture-sensitive drugs.(5) In buccal applications, 
such as medicated chewing gums, it is used because of 
its high negative heat of solution which provides a strong 
cooling effect.(3) 
Erythritol is also used as a noncaloric sweetener in syrups;(6) 
it is used to provide sensorial profile-modifying properties with 
intense sweeteners; and it is also used to mask unwanted 
aftertastes.(7) 
Erythritol is also used as a noncariogenic sweetener in 
toothpastes and mouthwash solutions. 
See Table I. 
Table I: Uses of erythritol. 
Use Concentration (%) 
Tablet filler and binder 30.090.0% 
Taste masking in solutions 0.53.0% 
Oral care products 5.010.0% 
8 Description 
Erythritol is a sugar alcohol (polyol) that occurs as a white or 
almost white powder or granular or crystalline substance. It is 
pleasant tasting with a mild sweetness approximately 6070% 
that of sucrose. It also has a high negative heat of solution that 
provides a strong cooling effect. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for erythritol. 
Test PhEur 2005 
Identification (melting point) 1191228C 
Identification (IR) . 
Appearance of solution . 
Conductivity . 
Related substances 42.0% 
Lead 40.5 ppm 
Water 40.5% 
Microbial contamination . 
Bacterial endotoxins . 
Assay (anhydrous basis) 96.0102.0% 
10 Typical Properties 
Acidity/alkalinity: pH = 57 at 258C for a 5% w/v aqueous 
solution. 
Boiling point: 3293318C 
Caloric value: 0.8 kJ/g 
Density: 1.45 g/cm3 
Heat of solution: 22 kJ/mol 
Hygroscopicity: erythritol is nonhygroscopic; it absorbs 
approximately 1% w/w of water at 95% relative humidity 
(RH). 
Melting point: 121.58C, with decomposition at 1608C. 
Solubility: soluble 1 in 3 of water; slightly soluble in ethanol 
(95%); practically insoluble in ether and fats. 
Viscosity (dynamic): 3 mPa s (3 cP) at 608C for a 30% w/w 
solution. 
11 Stability and Storage Conditions 
Erythritol has very good thermal and chemical stability. It is 
nonhygroscopic, and at 258C does not significantly absorb 
additional water up to a relative humidity (RH) of more than 
80%. Erythritol resists decomposition both in acidic and

alkaline media and remains stable for prolonged periods at pH 
210.(8) When stored for up to 4 years in ambient conditions 
(208C, 50% RH) erythritol has been shown to be stable.(5) 
12 Incompatibilities 
Erythritol is incompatible with strong oxidizing agents and 
strong bases. 
13 Method of Manufacture 
Erythritol is a starch-derived product. The starch is enzymatically 
hydrolyzed into glucose which is turned into erythritol via 
a fermentation process, using osmophilic yeasts or fungi (e.g. 
Moniliella, Trigonopsis, or Torulopsis).(9) 
14 Safety 
Erythritol is used in oral pharmaceutical formulations, confectionery, 
and food products. It is generally regarded as a 
nontoxic, nonallergenic, and nonirritant material.(10) 
The low molecular weight of erythritol allows more than 
90% of the ingested molecules to be rapidly absorbed from the 
small intestine;(11) it is not metabolized and is excreted 
unchanged in the urine. Erythritol has a low caloric value 
(0.8 kJ/g). The WHO has set an acceptable daily intake of not 
specified for erythritol.(10) 
Erythritol is noncariogenic; preliminary studies suggest that 
it may inhibit the formation of dental plaque.(12) 
In general, erythritol is well-tolerated;(13) furthermore, 
excessive consumption does not cause laxative effects. There 
is no significant increase in the blood glucose level after oral 
intake, and glycemic response is very low, making erythritol 
suitable for diabetics. 
LD50 (mouse, IP): 89 g/kg(10) 
LD50 (rat, IV): 6.6 g/kg 
LD50 (rat, oral): >13 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of the material handled. Eye protection and a dust 
mask or respirator are recommended. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
17 Related Substances 
Mannitol; sorbitol; xylitol. 
18 Comments 
Active ingredients can be granulated with erythritol and binders 
such as maltodextrin or carboxymethylcellulose, resulting in 
coarser granules with improved flowability.(3) Coprocessing 
erythritol with a small amount of maltodextrin results in a 
proprietary compound that is ideal for use in direct compression.(
14) 
A specification for erythritol is included in the Japanese 
Pharmaceutical Excipients (JPE).(15) 
The EINECS number for erythritol is 205-737-3. 
19 Specific References 
1 Bi YX, Sunada Y, Yonezawa Y, Danjo K. Evaluation of rapidly 
disintegrating tablets prepared by a direct compression method. 
Drug Dev Ind Pharm 1999; 25(5): 571581. 
2 Ohmori S, Ohno Y, Makino T, Kashihara T. Characteristics of 
erythritol and formulation of a novel coating with erythritol 
termed thin-layer sugarless coating. Int J Pharm 2004; 278(2): 
447457. 
3 Goossens J, Gonze M. Erythritol. Manuf Confect 2000; 80(1): 71 
75. 
4 de Cock P. Chewing gum coating with a healthier crunch thanks to 
erythritol. Confect Prod 2003; 6: 1011. 
5 Michaud J, Haest G. Erythritol: a new multipurpose excipient. 
Pharmaceut Technol Eur 2003; 15(10): 6972. 
6 de Cock P. Erythritol: a novel noncaloric sweetener ingredient. In: 
Corti A, ed. Low-Calorie Sweeteners: Present and Future. Basel: 
Karger, 1999: 110116. 
7 de Cock P, Bechert CL. Erythritol. Functionality in noncaloric 
functional beverages. Pure Appl Chem 2002; 74(7): 12811289. 
8 Leutner C, ed. Geigy Scientific Tables, vol. 1. Basel: Ciba Geigy, 
1993: 8485. 
9 Goossens J, Gonze M. Nutritional and application properties of 
erythritol: a unique combination? Part I: nutritional and functional 
properties. Agro Food Ind Hi-tech 1997; 4(8): 310. 
10 FAO/WHO. Evaluation of certain food additives and contaminants. 
Thirty-fifth report of the joint FAO/WHO expert committee 
on food additives. World Health Organ Tech Rep Ser 2000; No. 
896. 
11 Bornet FRJ, Blayo A, Dauchy F, Slama G. Plasma and urine 
kinetics of erythritol after oral ingestion by healthy humans. Regul 
Toxicol Pharmacol 1996; 24: 280286. 
12 Gonze M, Goossens J. Nutritional and application properties of 
erythritol: a unique combination? Part II: application properties. 
Agro Food Ind Hi-tech 1997; 8(5): 1216. 
13 Munro IC, Bernt WO, Borzella JF, et al. Erythritol: an interpretive 
summary of biochemical, metabolic, toxicologic and chemical 
data. Food Chem Toxicol 1998; 36(12): 11391174. 
14 De Sadeleer J, Gonze M. Erythritol compositions. European Patent 
No. 0497439; 1992. 
15 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 
Excipients 2004. Tokyo: Yakuji Nippo, 2004: 283284. 
20 General References 
Cerestar. Erythritol: the all-natural non-caloric bulk sweetener. 
http://www.eridex.com/english.html(accessed 24 May 2005). 
Endo K, Amikawa S, Matsumoto A, et al. Erythritol-based dry powder 
of glucagons for pulmonary administration. Int J Pharm 2005; 290: 
6371. 
OBrien Nabors L, Gelardi RC, eds. Alternative Sweeteners. New York: 
Marcel Dekker, 2001. 
21 Authors 
G Haest. 
22 Date of Revision 
24 May 2005. 
Erythritol 267

Ethyl Acetate 
1 Nonproprietary Names 
BP: Ethyl acetate 
PhEur: Ethylis acetas 
USPNF: Ethyl acetate 
2 Synonyms 
Acetic acid ethyl ester; acetic ester; acetic ether; acetoxyethane; 
aethylis acetas; aethylium aceticum; ethyl ethanoate; vinegar 
naphtha. 
3 Chemical Name and CAS Registry Number 
Ethyl acetate [141-78-6] 
4 Empirical Formula and Molecular Weight 
C4H8O2 88.1 
5 Structural Formula 
6 Functional Category 
Flavoring agent; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
In pharmaceutical preparations, ethyl acetate is primarily used 
as a solvent, although it has also been used as a flavoring agent. 
As a solvent, it is included in topical solutions and gels, and in 
edible printing inks used for tablets. 
Ethyl acetate has also been shown to increase the solubility 
of chlortalidone(1) and to modify the polymorphic crystal forms 
obtained for piroxicam pivalate(2) and mefenamic acid,(3) and 
has been used in the formulation of microspheres.(4,5) Its use as 
a chemical enhancer for the transdermal iontophoresis of 
insulin has been investigated.(6) 
In food applications, ethyl acetate is mainly used as a 
flavoring agent. It is also used in artificial fruit essence and as an 
extraction solvent in food processing. 
8 Description 
Ethyl acetate is a clear, colorless, volatile liquid with a pleasant 
fruity, fragrant, and slightly acetous odor, and has a pleasant 
taste when diluted. Ethyl acetate is flammable. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ethyl acetate. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Boiling point 76788C  
Appearance of solution .  
Acidity . . 
Specific gravity 0.8980.902 0.8940.898 
Refractive index 1.3701.373  
Readily carbonizable substances . . 
Reaction with sulfuric acid .  
Chromatographic purity .(a) . 
Residue on evaporation 430 ppm 40.02% 
Water 40.1%  
Limit of methyl compounds  . 
Organic volatile impurities  . 
Related substances .  
Assay  99.0100.5% 
(a) The PhEur 2005 lists impurities in ethyl acetate as methyl acetate, ethanol, and methanol. 
10 Typical Properties 
Autoignition temperature: 486.18C 
Boiling point: 778C 
Dielectric constant: 6.11 
Density: 0.902 g/cm3 at 208C 
Explosive limit: 2.211.5% (volume in air) 
Flash point: 
.7.28C (open cup); 
5.08C (closed cup). 
Freezing point: 83.68C 
Partition coefficient: Log P (octanol/water) = 0.7 
Refractive index: nD
20 = 1.3719 
Solubility: soluble 1 in 10 of water at 258C; ethyl acetate is 
more soluble in water at lower temperatures than at higher 
temperatures. Miscible with acetone, chloroform, dichloromethane, 
ethanol (95%), and ether, and with most other 
organic liquids. 
Vapor density: 3.04 (air = 1) 
11 Stability and Storage Conditions 
Ethyl acetate should be stored in an airtight container, 
protected from light and at a temperature not exceeding 
308C. Ethyl acetate is slowly decomposed by moisture and 
becomes acidic; the material can absorb up to 3.3% w/w water. 
Ethyl acetate decomposes on heating to produce ethanol and 
acetic acid, and will emit acrid smoke and irritating fumes. It is 
flammable and its vapor may travel a considerable distance to 
an ignition source and cause a flashback. 
The alkaline hydrolysis of ethyl acetate has been shown to 
be inhibited by polyethylene glycol and by mixed micelle 
systems.(7)

12 Incompatibilities 
Ethyl acetate can react vigorously with strong oxidizers, strong 
alkalis, strong acids, and nitrates to cause fires or explosions. It 
also reacts vigorously with chlorosulfonic acid, lithium 
aluminum hydride, 2-chloromethylfuran, and potassium tertbutoxide. 
13 Method of Manufacture 
Ethyl acetate can be manufactured by the slow distillation of a 
mixture of ethanol and acetic acid in the presence of 
concentrated sulfuric acid. It has also been prepared from 
ethylene using an aluminum alkoxide catalyst. 
14 Safety 
Ethyl acetate is used in foods and oral and topical pharmaceutical 
formulations. It is generally regarded as a relatively 
nontoxic and nonirritant material when used as an excipient. 
However, ethyl acetate may be irritant to mucous membranes 
and high concentrations may cause central nervous 
system depression. Potential symptoms of overexposure include 
irritation of the eyes, nose, and throat, narcosis, and dermatitis. 
Ethyl acetate has not been shown to be a human carcinogen 
or a reproductive or developmental toxin. 
The WHO has set an estimated acceptable daily intake of 
ethyl acetate at up to 25 mg/kg body-weight.(8) 
In the UK, it has been recommended that ethyl acetate be 
temporarily permitted for use as a solvent in food and that the 
maximum concentration consumed in food should be set at 
1000 ppm.(9) 
LD50 (cat, SC): 3.00 g/kg(10) 
LD50 (guinea-pig, oral): 5.50 g/kg 
LD50 (guinea-pig, SC): 3.00 g/kg 
LD50 (mouse, IP): 0.709 g/kg 
LD50 (mouse, oral): 4.10 g/kg 
LD50 (rabbit, oral): 4.935 g/kg 
LD50 (rat, oral): 5.62 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and gloves are 
recommended. In the UK, the occupational exposure limit for 
ethyl acetate is 400 ppm (short-term) and 200 ppm (longterm).(
11) 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (oral tablets 
and sustained-action tablets; topical and transdermal preparations). 
Included in nonparenteral medicines licensed in the UK 
(tablets, topical solutions, and gels). Ethyl acetate is also 
accepted for use in food applications in a number of countries 
including the UK. Included in the Canadian List of Acceptable 
Non-medicinal Ingredients. 
17 Related Substances 
 
18 Comments 
The following azeotropic mixtures have been reported: 
Ethyl acetate (93.9% w/w)water (6.1% w/w), boiling point 
70.48C 
Ethyl acetate (83.2% w/w)water (7.8% w/w)ethanol (9.0% 
w/w), boiling point 70.38C 
Ethyl acetate (69.4%)ethanol (30.6%), boiling point 71.88C 
Ethyl acetate (77%)propan-2-ol (23%), boiling point 74.88C 
A specification for ethyl acetate is contained in the Food 
Chemicals Codex (FCC). 
The EINECS number for ethyl acetate is 205-500-4. 
19 Specific References 
1 Lo. tter J, Kreig HM, Keizer K, Breytenbach JC. The influence of bcyclodextrin 
on the solubility of chlorthalidone and its enantiomers. 
Drug Dev Ind Pharm 1999; 25(8): 879884. 
2 Giordano F, Gazzaniga A, Moyano JR, et al. Crystal forms of 
piroxicam pivalate: preparation and characterization of two 
polymorphs. J Pharm Sci 1998; 87(3): 333337. 
3 Romero S, Escalera B, Bustamante P. Solubility behavior of 
polymorphs I and II of mefenamic acid in solvent mixtures. Int J 
Pharm 1999; 178: 193202. 
4 Abu-Izza K, Garcia-Contreras L, Lu DR. Preparation and 
evaluation of zidovudine-loaded sustained-release microspheres. 
2. Optimization of multiple response variables. J Pharm Sci 1996; 
85(6): 572576. 
5 Cleland JL, Jones AJS. Stable formulations of recombinant human 
growth hormone and interferon-g for microencapsulation and 
biodegradable microspheres. Pharm Res 1996; 13(10): 1464 
1475. 
6 Pillai O, Nair V, Panchagnula R. Transdermal iontophoresis of 
insulin: IV. Influence of chemical enhancers. Int J Pharm 2004; 
269(1): 109120. 
7 Xiancheng Z, Xiaonan C, Ziming Q, Qian W. The alkaline 
hydrolysis of ethyl acetate and ethyl propionate in single and 
mixed micellar solutions. J Disper Sci Technol 1996; 17(3): 339 
348. 
8 FAO/WHO. Specifications for the identity and purity of food 
additives and their toxicological evaluation: some flavouring 
substances and non-nutritive sweetening agents. Eleventh report 
of the Joint FAO/WHO Expert Committee on Food Additives. 
World Health Organ Tech Rep Ser 1968; No. 383. 
9 Ministry of Agriculture, Fisheries and Food. Report on the Review 
of Solvents in Food, FAC/REP/25. London: HMSO, 1978. 
10 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1625. 
11 Health and Safety Executive. EH40/2002: Occupational Exposure 
Limits 2002. Sudbury: Health and Safety Executive, 2002. 
20 General References 

21 Authors 
CG Cable. 
22 Date of Revision 
19 August 2005. 
Ethyl Acetate 269

Ethyl Lactate 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
Actylol; Acytol; ethyl a-hydroxypropionate; ethyl-2-hydroxypropanoate; 
ethyl-2-hydroxypropionate; ethyl-S-()-2-hydroxypropionate; 
2-hydroxypropanoic acid ethyl ester; lactic 
acid ethyl ester; propanoic acid 2-hydroxy-ethyl ester; Purasolv 
EL; Solactol. 
3 Chemical Name and CAS Registry Number 
2-Hydroxy-propanoic acid ethyl ester [97-64-3] 
4 Empirical Formula and Molecular Weight 
C5H10O3 118.13 
5 Structural Formula 
6 Functional Category 
Film-former; flavoring agent; solvent or co-solvent in liquid 
formulations. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethyl lactate is used as a solvent or co-solvent in liquid 
formulations(1,2) and recently as a co-solvent in emulsions and 
microemulsion technologies. It has also been used as a solvent 
for nitrocellulose, cellulose acetate, cellulose ethers, polyvinyl 
and other resins.(3) It has been applied topically in the treatment 
of acne vulgaris,(4,5) where it accumulates in the sebaceous 
glands and is hydrolyzed to ethanol and lactic acid, lowering 
the skin pH and exerting a bactericidal effect. 
8 Description 
Ethyl lactate occurs as a clear colorless liquid with a sharp 
characteristic odor. 
9 Pharmacopeial Specifications 

10 Typical Properties 
Acidity/alkalinity: pH = 7 (10% w/v aqueous solution) 
Boiling point: 1541558C 
Density: 1.0328 at 208C 
Explosion limits: 1.511.4% 
Flash point: 468C 
Heat of combustion: 6.5 kcal/g 
Melting point: 26.08C 
Refractive index: nD
20 = 1.4121.414 
Solubility: miscible with water (with partial decomposition), 
ethanol (95%), ether, chloroform, ketones, esters, and 
hydrocarbons. 
Viscosity (dynamic): 0.0261 mPa s at 208C 
Vapor density: 4.07 (air = 1) 
Vapor pressure: 0.732 kPa at 308C 
11 Stability and Storage Conditions 
Stable at normal temperature and pressure. Ethyl lactate is a 
flammable liquid and vapor. Store in a cool, dry, and wellventilated 
location away from any fire hazard area, in a tightly 
closed container. 
12 Incompatibilities 
Incompatible with bases or strong alkalis and may cause fire or 
explosion with strong oxidizing agents. 
13 Method of Manufacture 
Ethyl lactate is produced by the esterification of lactic acid with 
ethanol in the presence of a little mineral oil, or by combination 
of acetaldehyde with hydrocyanic acid to form acetaldehyde 
cyanhydrin. This is followed by treatment with ethanol (95%) 
and hydrochloric or sulfuric acid. Purification is achieved using 
fractional distillation. The commercial product is a racemic 
mixture. 
14 Safety 
Ethyl lactate is used as a flavoring agent in pharmaceutical 
preparations, and is found in food products. The estimated 
acceptable daily intake for lactic acid is 12.5 mg/kg bodyweight. 
In general, lactate esters have an oral LD50 > 2000 mg/kg; 
and the inhalation LC50 is generally above 5000 mg/m3. They 
have the potential of causing eye and skin irritation (on 
prolonged contact), but not sensitization.(6) Ethyl lactate is 
moderately toxic by intraperitoneal, subcutaneous, and intravenous 
routes. There is low oral and skin contact toxicity; 
although ingestion may cause nausea, stomach and throat pain, 
and narcosis. Inhalation of concentrated vapor of ethyl lactate 
may cause irritation of the mucous membranes, drowsiness, 
and narcosis. 
LD50 (rat, oral): >5.0 g/kg(7) 
LD50 (mouse, oral): 2.5 g/kg 
LD50 (mouse, SC): 2.5 g/kg 
LD50 (mouse, IV): 0.6 g/kg 
LD50 (rabbit, skin): >5.0 g/kg

15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Avoid skin and eye contact; 
eye goggles should be worn, or a full face shield where 
splashing may occur. 
There is a slight explosion hazard in the form of vapor when 
it is exposed to flame. Avoid ignition sources and use adequate 
ventilation to keep vapor and mist as low as possible. 
When heated to decomposition, it emits acrid smoke and 
irritating fumes. Facial respirators are recommended when 
dealing with excessive amounts or with prolonged exposure to 
the compound. 
16 Regulatory Status 
GRAS listed. Reported in the EPA TSCA Inventory. 
17 Related Substances 
n-Butyl lactate; methyl lactate. 
n-Butyl lactate 
Empirical formula: C7H14O3 
Molecular weight: 146.2 
CAS number: [138-22-7] 
Synonyms: butyl a-hydroxypropionate; propanoic acid 2- 
hydroxy butyl ester; lactic acid butyl ester; Purasolv BL. 
Boiling point: 1888C 
Melting point: 438C 
Solubility: partially miscible with water and most organic 
solvents. 
Comments: n-butyl lactate is used as a flavoring agent in 
pharmaceutical preparations. 
The EINECS number for n-butyl lactate is 205-316-4. 
Methyl lactate 
Empirical formula: C4H8O3 
Molecular weight: 104 
CAS number: [547-64-8] 
Synonyms: methyl hydroxy propionate; Purasolv ML. 
Appearance: methyl lactate occurs as a clear, colorless liquid. 
Boiling point: 143.98C 
Comments: methyl lactate is used as a cellulose acetate solvent. 
18 Comments 
Ethyl lactate is found in food products as a flavoring agent; 
owing to its biodegradability, ethyl lactate is replacing many 
solvents in many household products, including packaging, 
plastics, paints, paint strippers, grease removers, cleansers, 
aerosols, adhesives, and varnishes. 
Ethyl lactate is specified as a flavor chemical in the Food 
Chemicals Codex (FCC).(8) 
The EINECS number for ethyl lactate is 202-598-0. 
19 Specific References 
1 Christensen JM, Suvanakoot U, Ayres JW, Tavipatana W. Ethyl 
lactateethanolwater cosolvent for intravenous theophylline. Res 
Commun Chem Pathol Pharmacol 1985; 50(1): 147150. 
2 Mottu F, Laurent A, Rufenacht DA, Doelker E. Organic solvents 
for pharmaceutical parenterals and embolic liquids: A review of 
toxicity data. PDA J Pharm Sci Tech 2000; 54(6): 456469. 
3 Siew LF, Basit AW, Newton JM. The properties of amylose 
ethylcellulose films cast from organic-based solvents as potential 
coatings for colonic drug delivery. Eur J Pharm Sci 2000; 11(2): 
133139. 
4 George D, Prottery C, Black JG, et al. Ethyl lactate as a treatment 
for acne. Br J Dermatol 1983; 108(2): 228233. 
5 Prottey C, George D, Leech RW, et al. The mode of action of ethyl 
lactate as a treatment for acne. Br J Dermatol 1984; 110(4): 475 
485. 
6 Clary JJ, Feron VJ, van Velthuijsen JA. Safety assessment of lactate 
esters. Regul Toxicol Pharmacol 1998; 27(2): 8897. 
7 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 2197. 
8 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 490491. 
20 General References 

21 Authors 
O AbuBaker. 
22 Date of Revision 
15 August 2005. 
Ethyl Lactate 271

Ethyl Maltol 
1 Nonproprietary Names 
None adopted. 
2 Synonyms 
2-Ethyl pyromeconic acid; 3-hydroxy-2-ethyl-4-pyrone; Veltol 
Plus. 
3 Chemical Name and CAS Registry Number 
2-Ethyl-3-hydroxy-4H-pyran-4-one [4940-11-8] 
4 Empirical Formula and Molecular Weight 
C7H8O3 140.14 
5 Structural Formula 
6 Functional Category 
Flavor enhancer; flavoring agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethyl maltol is used in pharmaceutical formulations and food 
products as a flavoring agent or flavor enhancer in applications 
similar to maltol. It has a flavor and odor 46 times as intense 
as maltol. Ethyl maltol is used in oral syrups at concentrations 
of about 0.004% w/v and also at low levels in perfumery. 
8 Description 
White crystalline solid with characteristic, very sweet, caramellike 
odor and taste. In dilute solution it possesses a sweet, 
fruitlike flavor and odor. 
9 Pharmacopeial Specifications 
See Section 19. 
10 Typical Properties 
Melting point: 89938C 
Solubility: see Table I. 
Table I: Solubility of ethyl maltol. 
Solvent Solubility at 208C 
Chloroform 1 in 5 
Ethanol (95%) 1 in 10 
Glycerin 1 in 500 
Propan-2-ol 1 in 11 
Propylene glycol 1 in 17 
Water 1 in 55 
11 Stability and Storage Conditions 
Solutions may be stored in glass or plastic containers. The bulk 
material should be stored in a well-closed container, protected 
from light, in a cool, dry place. 
12 Incompatibilities 

13 Method of Manufacture 
Unlike maltol, ethyl maltol does not occur naturally. It may be 
prepared by treating a-ethylfurfuryl alcohol with a halogen to 
produce 4-halo-6-hydroxy-2-ethyl-2H-pyran-3(6H)-one, which 
is converted to ethyl maltol by hydrolysis. 
14 Safety 
In animal feeding studies, ethyl maltol has been shown to be 
well tolerated with no adverse toxic, reproductive, or embryogenic 
effects. It has been reported that while the acute toxicity 
of ethyl maltol, in animal studies, is slightly greater than maltol; 
with repeated dosing the opposite is true.(1) Although an 
acceptable daily intake for ethyl maltol has not been set the 
WHO has set an acceptable daily intake for maltol at up to 
1 mg/kg body-weight.(2) 
LD50 (chicken, oral): 1.27 g/kg (3) 
LD50 (rat, oral): 1.15 g/kg 
LD50 (mouse, oral): 0.78 g/kg 
LD50 (mouse, SC): 0.91 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Ethyl maltol should be used 
in a well-ventilated environment. Dust may be irritant and eye 
protection and gloves are recommended. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral syrup). 
17 Related Substances 
Maltol.

18 Comments 
See Maltol for further information. 
Although not included in any pharmacopeias, a specification 
for ethyl maltol is contained in the Food Chemicals Codex 
(FCC), see Table II.(4) 
Table II: Food Chemicals Codex specifications for ethyl maltol. 
Test FCC 1996 
Identification . 
Heavy metals (as lead) 40.002% 
Lead 410 ppm 
Residue on ignition 40.2% 
Water 40.5% 
Assay (dried basis) 599.0% 
19 Specific References 
1 Gralla EJ, Stebbins RB, Coleman GL, Delahunt CS. Toxicity 
studies with ethyl maltol. Toxicol Appl Pharmacol 1969; 15: 604 
613. 
2 FAO/WHO. Evaluation of certain food additives. Twenty-fifth 
report of the joint FAO/WHO expert committee on food additives. 
World Health Organ Tech Rep Ser 1981; No. 669. 
3 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1692. 
4 Food Chemicals Codex, 4th edn. Washington, DC: National 
Academy Press, 1996: 138. 
20 General References 
Allen LV. Featured excipient: flavor enhancing agents. Int J Pharm 
Compound 2003; 7(1): 4850. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
Ethyl Maltol 273

Ethyl Oleate 
1 Nonproprietary Names 
BP: Ethyl oleate 
PhEur: Ethylis oleas 
USPNF: Ethyl oleate 
2 Synonyms 
Ethyl 9-octadecenoate; Kessco EO; oleic acid, ethyl ester. 
3 Chemical Name and CAS Registry Number 
(Z)-9-Octadecenoic acid, ethyl ester [111-62-6] 
4 Empirical Formula and Molecular Weight 
C20H38O2 310.51 
5 Structural Formula 
6 Functional Category 
Oleaginous vehicle; solvent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethyl oleate is primarily used as a vehicle in certain parenteral 
preparations intended for intramuscular administration. It has 
also been used as a solvent for drugs formulated as biodegradable 
capsules for subdermal implantation(1) and in the 
preparation of microemulsions containing cyclosporin.(2) 
Ethyl oleate is a suitable solvent for steroids and other 
lipophilic drugs. Its properties are similar to those of almond oil 
and peanut oil. However, it has the advantage that it is less 
viscous than fixed oils and is more rapidly absorbed by body 
tissues.(3) 
Ethyl oleate has also been evaluated as a vehicle for 
subcutaneous injection.(4) 
8 Description 
Ethyl oleate occurs as a pale yellow to almost colorless, mobile, 
oily liquid with a taste resembling that of olive oil and a slight, 
but not rancid odor. 
Ethyl oleate is described in the USPNF 23 as consisting of 
esters of ethyl alcohol and high molecular weight fatty acids, 
principally oleic acid. A suitable antioxidant may be included. 
9 Pharmacopeial Specifications 
See Table I. 
Table I: Pharmacopeial specifications for ethyl oleate. 
Test PhEur 2005 USPNF 23 
Characters .  
Identification . . 
Specific gravity 0.8660.874 0.8660.874 
Viscosity  55.15 mPa s 
Refractive index  1.4431.450 
Acid value 40.5 40.5 
Iodine value 7590 7585 
Saponification value 177188 177188 
Peroxide value 410  
Oleic acid 560.0%  
Water content 41.0%  
Total ash 40.1%  
10 Typical Properties 
Boiling point: 2052088C (some decomposition) 
Flash point: 175.38C 
Freezing point: 328C 
Moisture content: at 208C and 52% relative humidity, the 
equilibrium moisture content of ethyl oleate is 0.08%. 
Solubility: miscible with chloroform, ethanol (95%), ether, 
fixed oils, liquid paraffin, and most other organic solvents; 
practically insoluble in water. 
Surface tension: 32.3mN/m (32.3 dynes/cm) at 258C(3) 
Viscosity (dynamic): 3.9 mPa s (3.9 cP) at 258C(3) 
Viscosity (kinematic): 0.046mm2/s (4.6 cSt) at 258C(3) 
11 Stability and Storage Conditions 
Ethyl oleate should be stored in a cool, dry place in a small, 
well-filled, well-closed container, protected from light. When a 
partially filled container is used, the air should be replaced by 
nitrogen or another inert gas. Ethyl oleate oxidizes on exposure 
to air, resulting in an increase in the peroxide value. It remains 
clear at 58C, but darkens in color on standing. Antioxidants are 
frequently used to extend the shelf life of ethyl oleate. 
Protection from oxidation for over 2 years has been achieved 
by storage in amber glass bottles with the addition of 
combinations of propyl gallate, butylated hydroxyanisole, 
butylated hydroxytoluene, and citric or ascorbic acid.(5,6) A 
concentration of 0.03% w/v of a mixture of propyl gallate 
(37.5%), butylated hydroxytoluene (37.5%), and butylated 
hydroxyanisole (25%) was found to be the best antioxidant for 
ethyl oleate.(6) 
Ethyl oleate may be sterilized by heating at 1508C for 1 
hour. 
12 Incompatibilities 
Ethyl oleate dissolves certain types of rubber and causes others 
to swell.(7,8) It may also react with oxidizing agents.

13 Method of Manufacture 
Ethyl oleate is prepared by the reaction of ethanol with oleoyl 
chloride in the presence of a suitable hydrogen chloride 
acceptor. 
14 Safety 
Ethyl oleate is generally considered to be of low toxicity but 
ingestion should be avoided. Ethyl oleate has been found to 
cause minimal tissue irritation.(9) No reports of intramuscular 
irritation during use have been recorded. 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection and nitrile 
gloves are recommended. Ethyl oleate is flammable. 
16 Regulatory Status 
Included in the FDA Inactive Ingredients Guide (transdermal 
preparation). Included in parenteral medicines licensed in the 
UK. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Methyl oleate; oleic acid. 
Methyl oleate 
Empirical formula: C19H36O2 
Molecular weight: 296.49 
CAS number: [112-69-9] 
Synonyms: methyl 9-octadecenoate; (Z)-9-octadecenoic acid, 
methyl ester. 
Boiling point: 1681708C 
Density: 0.879 g/cm3 
Iodine number: 85.6 
Refractive index: nD
26 = 1.4510 
Solubility: miscible with ethanol (95%) and ether. 
Comments: prepared by refluxing oleic acid with p-toluenesulfonic 
acid in methanol. 
18 Comments 
The EINECS number for ethyl oleate is 203-889-5. 
19 Specific References 
1 Ory SJ, Hammond CB, Yancy SG, et al. Effect of a biodegradable 
contraceptive capsule (Capronor) containing levonorgestrel on 
gonadotropin, estrogen and progesterone levels. Am J Obstet 
Gynecol 1983; 145: 600605. 
2 Kim C-K, Ryuu S-A, Park K-M. Preparation and physicochemical 
characterisation of phase inverted water/oil microemulsion containing 
cyclosporin A. Int J Pharm 1997; 147: 131134. 
3 Howard JR, Hadgraft J. The clearance of oily vehicles following 
intramuscular and subcutaneous injections in rabbits. Int J Pharm 
1983; 16: 3139. 
4 Radwan M. In vivo screening model for excipients and vehicles 
used in subcutaneous injections. Drug Dev Ind Pharm 1994; 20: 
27532762. 
5 Alemany P, Del Pozo A. Autoxidation of ethyl oleate: protection 
with antioxidants [in Spanish]. Galenica Acta 1963; 16: 335338. 
6 Nikolaeva NM, Gluzman MK. Conditions for stabilizing ethyl 
oleate during storage [in Russian]. Farmatsiya 1977; 26: 2528. 
7 Dexter MB, Shott MJ. The evaluation of the force to expel oily 
injection vehicles from syringes. J Pharm Pharmacol 1979; 31: 
497500. 
8 Halsall KG. Calciferol injection and plastic syringes [letter]. Pharm 
J 1985; 235: 99. 
9 Hem SL, Bright DR, Banker GS, Pogue JP. Tissue irritation 
evaluation of potential parenteral vehicles. Drug Dev Commun 
197475; 1(5): 471477. 
20 General References 
Spiegel AJ, Noseworthy MM. Use of nonaqueous solvents in parenteral 
products. J Pharm Sci 1963; 52: 917927. 
21 Authors 
CG Cable. 
22 Date of Revision 
21 August 2005. 
Ethyl Oleate 275

Ethyl Vanillin 
1 Nonproprietary Names 
USPNF: Ethyl vanillin 
2 Synonyms 
Bourbonal; ethylprotal; ethylprotocatechuic aldehyde; 
4-hydroxy-3-ethoxybenzaldehyde; Rhodiarome; vanillal. 
3 Chemical Name and CAS Registry Number 
3-Ethoxy-4-hydroxybenzaldehyde [121-32-4] 
4 Empirical Formula and Molecular Weight 
C9H10O3 166.18 
5 Structural Formula 
6 Functional Category 
Flavoring agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethyl vanillin is used as an alternative to vanillin, i.e., as a 
flavoring agent in foods, beverages, confectionery, and 
pharmaceuticals. It is also used in perfumery. 
Ethyl vanillin possesses a flavor and odor approximately 
three times as intense as vanillin, hence the quantity of material 
necessary to produce an equivalent vanilla flavor may be 
reduced, causing less discoloration to a formulation and 
potential savings in material costs. However, exceeding certain 
concentration limits may impart an unpleasant, slightly bitter 
taste to a product due to the intensity of the ethyl vanillin flavor. 
See Table I. 
Table I: Uses of ethyl vanillin. 
Use Concentration (%) 
Foods and confectionery 0.0020.025 
Oral syrups 0.01 
8 Description 
White or slightly yellowish crystals with a characteristic intense 
vanilla odor and flavor. 
9 Pharmacopeial Specifications 
See Table II. 
Table II: Pharmacopeial specifications for ethyl vanillin. 
Test USPNF 23 
Identification . 
Melting range 76.078.08C 
Loss on drying 41.0% 
Residue on ignition 40.1% 
Organic volatile impurities . 
Assay (dried basis) 98.0101.0% 
10 Typical Properties 
Boiling point: 2858C 
Density (bulk): 1.05 g/cm3 
Flash point: 1278C 
Melting point: 76788C 
Solubility: see Table III. 
Table III: Solubility of ethyl vanillin. 
Solvent Solubility at 208C 
unless otherwise stated 
Alkaline hydroxide solutions Freely soluble 
Chloroform Freely soluble 
Ethanol (95%) 1 in 2 
Ether Freely soluble 
Glycerin Soluble 
Propylene glycol Soluble 
Water 1 in 250 
1 in 100 at 508C 
11 Stability and Storage Conditions 
Store in a well-closed container, protected from light, in a cool, 
dry place. See Vanillin for further information. 
12 Incompatibilities 
Ethyl vanillin is unstable in contact with iron or steel forming a 
red-colored, flavorless compound. In aqueous media with 
neomycin sulfate or succinylsulfathiazole, tablets of ethyl 
vanillin produced a yellow color.(1) See Vanillin for other 
potential incompatibilities.

13 Method of Manufacture 
Unlike vanillin, ethyl vanillin does not occur naturally. It may 
be prepared synthetically by the same methods as vanillin, using 
guethol instead of guaiacol as a starting material; see Vanillin. 
14 Safety 
Ethyl vanillin is generally regarded as an essentially nontoxic 
and nonirritant material. However, cross-sensitization with 
other structurally similar molecules may occur; see Vanillin. 
The WHO has allocated an acceptable daily intake for ethyl 
vanillin of up to 3 mg/kg body-weight.(2) 
LD50 (guinea pig, IP): 1.14 g/kg(3,4) 
LD50 (mouse, IP): 0.75 g/kg 
LD50 (rabbit, oral): 3 g/kg 
LD50 (rabbit, SC): 2.5 g/kg 
LD50 (rat, oral): 1.59 g/kg 
LD50 (rat, SC): 3.54.0 g/kg 
15 Handling Precautions 
Observe normal precautions appropriate to the circumstances 
and quantity of material handled. Eye protection is recommended. 
Heavy airborne concentrations of dust may present an 
explosion hazard. 
16 Regulatory Status 
GRAS listed. Included in the FDA Inactive Ingredients Guide 
(oral capsules, suspensions, and syrups). Included in nonparenteral 
medicines licensed in the UK. 
17 Related Substances 
Vanillin. 
18 Comments 
Ethyl vanillin can be distinguished analytically from vanillin by 
the yellow color developed in the presence of concentrated 
sulfuric acid. The EINECS number for ethyl vanillin is 204- 
464-7. 
19 Specific References 
1 Onur E, Yalcindag ON. Double incompatibility of ethyl vanillin 
(vanillal) in compressed tablets [in French]. Bull Soc Pharm 
Bordeaux 1970; 109(2): 4951. 
2 FAO/WHO. Evaluation of certain food additives and contaminants. 
Forty-fourth report of the joint FAO/WHO expert 
committee on food additives. World Health Organ Tech Rep Ser 
1995; No. 859. 
3 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. 
Cincinnati: US Department of Health, 1987: 721. 
4 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 
11th edn. New York: Wiley, 2004: 1729. 
20 General References 
Rees DI. Determination of vanillin and ethyl vanillin in food products. 
Chem Ind 1965; 1: 1617. 
21 Authors 
PJ Weller. 
22 Date of Revision 
14 August 2005. 
Ethyl Vanillin 277

Ethylcellulose 
1 Nonproprietary Names 
BP: Ethylcellulose 
PhEur: Ethylcellulosum 
USPNF: Ethylcellulose 
2 Synonyms 
Aquacoat ECD; Aqualon; E462; Ethocel; Surelease. 
3 Chemical Name and CAS Registry Number 
Cellulose ethyl ether [9004-57-3] 
4 Empirical Formula and Molecular Weight 
Ethylcellulose with complete ethoxyl substitution (DS = 3) is 
C12H23O6(C12H22O5)nC12H23O5 where n can vary to provide 
a wide variety of molecular weights. Ethylcellulose, an ethyl 
ether of cellulose, is a long-chain polymer of b-anhydroglucose 
units joined together by acetal linkages. 
5 Structural Formula 
6 Functional Category 
Coating agent; flavoring fixative; tablet binder; tablet filler; 
viscosity-increasing agent. 
7 Applications in Pharmaceutical Formulation 
or Technology 
Ethylcellulose is widely used in oral and topical pharmaceutical 
formulations; see Table I. 
The main use of ethylcellulose in oral formulations is as a 
hydrophobic coating agent for tablets and granules.(18) 
Ethylcellulose coatings are used to modify the release of a 
drug,(710) to mask an unpleasant taste, or to improve the 
stability of a formulation; for example, where granules are 
coated with ethylcellulose to inhibit oxidation. Modifiedrelease 
tablet formulations may also be produced using 
ethylcellulose as a matrix former.(1114) 
Ethylcellulose, dissolved in an organic solvent or solvent 
mixture, can be used on its own to produce water-insoluble 
films. Higher-viscosity ethylcellulose grades tend to produce 
stronger and more durable films. Ethylcellulose films may be 
modified to alter their solubility,(15) by the addition of 
hypromellose(16) or a plasticizer;(1719) see Section 18. An 
aqueous polymer dispersion (or latex) of ethylcellulose such as 
Aquacoat ECD (FMC Biopolymer) or Surelease (Colorcon) 
may also be used to produce ethylcellulose films without the 
need for organic solvents. 
Drug release through ethylcellulose-coated dosage forms 
can be controlled by diffusion through the film coating. This 
can be a slow process unless a large surface area (e.g. pellets or 
granules compared with tablets) is utilized. In those instances, 
aqueous ethylcellulose dispersions are generally used to coat 
granules or pellets. Ethylcellulose-coated beads and granules 
have also demonstrated the ability to absorb pressure and hence 
protect the coating from fracture during compression.(19) 
High-viscosity grades of ethylcellulose are used in drug 
microencapsulation.(10,2022) 
Release of a drug from an ethylcellulose microcapsule is a 
function of the microcapsule wall thickness and surface area. 
In tablet formulations, ethylcellulose may additionally be 
employed as a binder, the ethylcellulose being blended dry or 
wet-granulated with a solvent such as ethanol (95%). 
Ethylcellulose produces hard tablets with low friability, 
although they may demonstrate poor dissolution. 
Ethylcellulose has also been used as an agent for delivering 
therapeutic agents from oral (e.g. dental) appliances.(23) 
In topical formulations, ethylcellulose is used as a thickening 
agent in creams, lotions, or gels, provided an appropriate 
solvent is used.(24) Ethylcellulose has been studied as a stabilizer 
for emulsions.(25) 
Ethylcellulose is additionally used in cosmetics and food 
products. 
Table I: Uses of ethylcellulose. 
Use Concentration (%) 
Microencapsulation 10.020.0 
Sustained-release tablet coating 3.020.0 
Tablet coating 1.03.0 
Tablet granulation 1.03.0 
8 Description 
Ethylcellulose is a tasteless, free-flowing, white to light tancolored 
powder. 
9 Pharmacopeial Specifications 
See Tables II and III. 
10 Typical Properties 
Density (bulk): 0.4 g/cm3 
Glass transition temperature: 1291338C(26) 
Moisture content: ethylcellulose absorbs very little water 
from humid air or during immersion, and that small 
amount evaporates readily.(27,28) See also Figure 1.

Table II: Pharmacopeial specifications for ethylcellulose. 
Test PhEur 2005 USPNF 23 
Identification . . 
Characters .  
Acidity or alkalinity .  
Viscosity See Table III See Table III 
Loss on drying 43.0% 43.0% 
Residue on ignition  40.4% 
Sulfated ash 40.5%  
Lead  410 ppm 
Heavy metals 420 ppm 420 mg/g 
Acetaldehyde 4100 ppm  
Chlorides 40.1%  
Organic volatile impurities  . 
Assay (of ethoxyl groups) 44.051.0% 44.051.0% 
Table III: Pharmacopeial specifications for ethylcellulose viscosity. 
Test PhEur 2005 USPNF 23 
Nominal viscosity 
>6 mPa s 75140% of that stated 
for its nominal 
viscosity 
75140% of that stated 
for its nominal 
viscosity 
610 mPa s 80120% of that stated 
for its nominal 
viscosity 
80120% of that stated 
for its nominal 
viscosity 
410 mPa s 80120% of that stated 
for its nominal 
viscosity 
90110% of that stated 
for its nominal 
viscosity 
Particle size distribution: see Table IV; see also Figures 2 and 3. 
Solubility: ethylcellulose is practically insoluble in glycerin, 
propylene glycol, and water. Ethylcellulose that contains less 
than 46.5% of ethoxyl groups is freely soluble in chloroform, 
methyl acetate, and tetrahydrofuran, and in mixtures 
of aromatic hydrocarbons with ethanol (95%). Ethylcellulose 
that contains not less than 46.5% of ethoxyl groups is 
freely soluble in chloroform, ethanol (95%), ethyl acetate, 
methanol, and toluene. 
Specific gravity: 1.121.15 g/cm3 
Viscosity: the viscosity of ethylcellulose is measured typically at 
258C using 5% w/v ethylcellulose dissolved in a solvent 
blend of 80% toluene :20% ethanol (w/w). Grades of 
ethylcellulose with various viscosities are commercially 
available; see Table IV. They may be used to produce 5% 
w/v solutions in organic solvent blends with viscosities 
nominally ranging from 7 to 100 mPa s (7100 cP). Specific 
ethylcellulose grades, or blends of different grades, may be 
used to obtain solutions of a desired viscosity. Solutions of 
higher viscosity tend to be composed of longer polymer 
chains and produce strong and durable films. 
The viscosity of an ethylcellulose solution increases with 
an increase in ethylcellulose concentration; e.g. the viscosity 
of a 5% w/v solution of Ethocel Standard 4 Premium is 
4 mPa s (4 cP) and of a 25% w/v solution of the same 
ethylcellulose grade is 850 mPa s (850 cP). Solutions with a 
lower viscosity may be obtained by incorporating a higher 
percentage (3040%) of a low-molecular-weight aliphatic 
alcohol such as ethanol, butanol, propan-2-ol, or n-butanol 
with toluene. The viscosity of such solutions depends almost 
entirely on the alcohol content and is independent of 
toluene. 
SEM: 1 
Excipient: Ethylcellulose 
Manufacturer: Hercules Ltd. 
Lot No.: 57911 
Magnfication: 60 Voltage: 10 kV 
SEM: 2 
Excipient: Ethylcellulose 10 mPa s (10 cP) fine powder 
Manufacturer: Dow Chemical Co. 
Magnification: 600 Voltage: 5kV 
Ethylcellulose 279

SEM: 3 
Excipient: Ethylcellulose 100 mPa s (100 cP) fine powder 
Manufacturer: Dow Chemical Co. 
Magnification: 600 Voltage: 5kV 
SEM: 4 
Excipient: Ethylcellulose 
Manufacturer: Hercules Ltd. 
Lot No.: 57911 
Magnfication: 600 Voltage: 10 kV 
In addition, nonpharmaceutical grades of ethylcellulose 
that differ in their ethoxyl content and degree of polymerization 
are available. 
Table IV: Summary of ethylcellulose grades, suppliers, viscosity, and 
particle size. 
Grade Supplier Solution 
viscosity 
(mPa s) 
Mean 
particle 
size (mm) 
Ethocel Std 4 Premium Dow Chemical 3.05.5  
N-7 Aqualon 5.68.0  
Ethocel Std 7FP Premium Dow Chemical 6.08.0 5.015.0 
Ethocel Std 7 Premium Dow Chemical 6.08.0 310.0 
T-10 Aqualon 8.011.0  
N-10 Aqualon 8.011.0  
Ethocel Std 10FP Premium Dow Chemical 9.011.0 3.015.0 
Ethocel Std 10P Premium Dow Chemical 9.011.0 375.0 
N-14 Aqualon 12.016.0  
Ethocel Std 20P Premium Dow Chemical 18.022.0  
N-22 Aqualon 18.024.0  
Ethocel Std 45P Premium Dow Chemical 41.049.0  
N-50 Aqualon 40.052.0  
N-100 Aqualon 80.0105.0  
Ethocel Std 100FP Premium Dow Chemical 90.0110.0 30.060.0 
Ethocel Std 100P Premium Dow Chemical 90.0110.0 465.0 (
11 Stability and Storage Conditions 
Ethylcellulose is a stable, slightly hygroscopic material. It is 
chemically resistant to alkalis, both dilute and concentrated, 
and to salt solutions, although it is more sensitive to acidic 
materials than are cellulose esters. 
Ethylcellulose is subject to oxidative degradation in the 
presence of sunlight or UV light at elevated temperatures. This 
may be prevented by the use of antioxidant and chemical 
additives that absorb light in the 230340nm range. 
Ethylcellulose should be stored at a temperature not 
exceeding 328C (908F) in a dry area away from all sources of 
heat. It should not be stored next to peroxides or other 
oxidizing agents. 
12 Incompatibilities 
Incompatible with paraffin wax and microcrystalline wax. 
13 Method of Manufacture 
Ethylcellulose is prepared by treating purified cellulose (sourced 
from chemical-grade cotton linters and wood pulp) with an 
alkaline solution, followed by ethylation of the alkali cellulose 
with chloroethane as shown below, where R represents the 
cellulose radical: 
RONa . C2H5Cl ! ROC2H5 . NaCl 
The manner in which the ethyl group is added to cellulose can 
be described by the degree of substitution (DS). The DS 
designates the average number of hydroxyl positions on the 
anhydroglucose unit that have been reacted with ethyl chloride. 
Since each anhydroglucose unit of the cellulose molecule has 
three hydroxyl groups, the maximum value for DS is three. 
280 Ethylcellulose

Figure 1: Equilibrium moisture content of ethylcellulose. 
Figure 2: Particle size distribution of ethylcellulose. 
14 Safety 
Ethylcellulose is widely used in oral and topical pharmaceutical 
formulations. It is also used in food products. Ethylcellulose is 
not metabolized following oral consumption and is therefore a 
noncalorific substance. Because ethylcellulose is not metabolized 
it is not recommended for parenteral products; parenteral 
use may be harmful to the kidneys. 
Figure 3: Particle size distribution of ethylcellulose (Ethocel). 
Ethylcellulose is generally regarded as a nontoxic, nonallergenic, 
and nonirritating material. 
As ethylcellulose is not considered to be a health hazard, the 
WHO has not specified an acceptable daily intake.(29) 
LD50 (rabbit, skin): >5 g/kg(30) 
LD50 (rat, oral): >5 g/kg 
15 Handling Precautions 
It is important to prevent fine dust clouds of ethylcellulose from 
reaching potentially explosive levels in the air. Ethylcellulose is 
combustible. Ethylcellulose powder may be an irritant to the 
eyes and eye protection should be worn. 
16 Regulatory Status 
GRAS listed. Accepted for use as a food additive in Europe. 
Included in the FDA Inactive Ingredients Guide (oral capsules, 
suspensions and tablets; topical emulsions and vaginal preparations). 
Included in nonparenteral medicines licensed in 
Europe. Included in the Canadian List of Acceptable Nonmedicinal 
Ingredients. 
17 Related Substances 
Hydroxyethyl cellulose; hydroxyethylmethyl cellulose; methylcellulose. 
18 Comments 
Ethylcellulose is compatible with the following plasticizers: 
dibutyl phthalate; diethyl phthalate; dibutyl sebacate; triethyl 
citrate; tributyl citrate; acetylated monoglyceride; acetyl tributyl 
citrate; triacetin; dimethyl phthalate; benzyl benzoate; butyl 
and glycol esters of fatty acids; refined mineral oils; oleic acid; 
stearic acid; ethyl alcohol; stearyl alcohol; castor oil; corn oil; 
and camphor. 
Ethylcellulose has also been used as a backing membrane on 
mucoadhesive patches intended for buccal administration. The 
Ethylcellulose 281

membrane had high tensile strength, and provided excellent 
unidirectional drug flow.(31) Studies have also suggested 
ethylcellulose for use in floating microparticles based on lowdensity 
foam powder, for gastroretentive drug delivery 
systems.(32) 
A specification for ethylcellulose is contained in the Food 
Chemicals Codex (FCC). 
19 Specific References 
1 Ozturk AG, Ozturk SS, Palsson BO, et al. Mechanism of release 
from pellets coated with an ethyl cellulose-based film. J Control 
Release 1990; 14(3): 203213. 
2 Narisawa S, Yoshino H, Hirakawa Y, Noda K. Porosity-controlled 
ethyl cellulose film coating. IV. Evaluation of mechanical strength 
of porous ethyl cellulose film. Chem Pharm Bull 1994; 42(7): 
14911495. 
3 Bodmeier R, Paeratakul O. The effect of curing on drug release and 
morphological properties of ethylcellulose pseudolatex-coated 
beads. Drug Dev Ind Pharm 1994; 20(9): 15171533. 
4 Dressman JB, Derbin GM, Ismailos G, et al. Circumvention of pHdependent 
release from ethyl cellulose-coated pellets. J Control 
Release 1995; 36(3): 251260. 
5 Iyer U, Hong WH, Das N, Ghebre-Sellassie I. Comparative 
evaluation of three organic solvent and dispersion-based ethyl 
cellulose coating formulations. Pharm Technol 1990; 14(9): 68 
86. 
6 Sarisuta N, Sirithunyalug J. Release rate of indomethacin from 
coated granules. Drug Dev Ind Pharm 1988; 14(5): 683687. 
7 Porter SC. Controlled-release film coatings based on ethylcellulose. 
Drug Dev Ind Pharm 1989; 15(10): 14951521. 
8 Sadeghi F, Ford JL, Rubinstein MH, Rajabi-Siahboomi AR. Study 
of drug release from pellets coated with surelease containing 
hydroxypropylmethylcellulose. Drug Dev Ind Pharm 2001; 27(5): 
419430. 
9 Goracinova K, Klisarova L, Simov A, et al. Preparation, physical 
characterization, mechanisms of drug/polymer interactions, and 
stability studies of controlled-release solid dispersion granules 
containing weak base as active substance. Drug Dev Ind Pharm 
1996; 22(3): 255262. 
10 Lin S. Studies on microencapsulation. 14. Theophylline bioavailability 
after single oral-administration of sustained-release microcapsules. 
Curr Ther Res Clin Exp 1987; 41(4): 564573. 
11 Pollock D, Sheskey P. Micronized ethylcellulose: opportunities in 
direct-compression controlled-release tablets. Pharm Technol 
199