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PHARMACEUTICAL DOSAGE FORMS Tablets
SECOND EDITION, REVISED AND EXPANDED
In Three Volumes VOLUME 3
EDITED BY Herbert A. Lieberman
Preface 
Tablets are the most commonly prescribed dosage form. The reason for 
this popularity is that tablets offer a convenient form of drug administration, 
provide dosage uniformity from tablet to tablet. are stable over extended 
and diverse storage conditions, and can be produced on high-speed 
compression, labeling, and packaging equipment. As a result, tablet production 
technology is constantly undergoing improvements that enhance 
their ability to deliver, with precision. a desired drug in a dosage form 
intended for immediate or extended therapeutic effect. In addition. the 
growth of the generic industry as well as increased competition from both 
foreign and domestic markets require that a tablet manufacturer have 
greater concern regarding the economics of tablet production by introducing 
less labor-intensive, higher-productivity manufacturing methods for making 
the increasing number of tablet products available today. The changes in 
the science and technology of tablet formulation, production, and quality 
assurance to accomplish the above are reflected in the second edition of 
the three-volume series Pharmaceutical Dosage Forms: Tablets. 
The first volume in this series describes the many types of tablet 
products, giving specific updated examples of typical formulations and 
methods of manufacture. These include single- and multilayered tablets, 
buccal and sublingual tablets, effervescent tablets. and diverse methods 
for manufaeturtng them by wet and dry granulations and by direct 
compression. In addition, medicated candy products are a form of drug 
delivery that has appeared in the marketplace; no complete chapter on 
this technology has been printed in any pharmacy text other than both 
editions of this series on tablets. 
To manufacture tablets a number of unit processes are required, such 
as mixing, drying, size reduction, and compression. The economics of 
tablet production today require an update of the technologies for each of 
these pharmaceutical operations. The granulations and tablets produced 
have particular characteristics that must be analyzed and understood in 
order to produce superior tablets, particularly when new and sometimes 
faster methods of manufacture are introduced. No drug dosage form 
would be meaningful to the patient without the drug being bioavailable. 
The chapter on bioavailability in tablet technology is updated in the second 
edition of Volume 2. Finally, many advances in the specifications and 
care of tablet tooling and problem solving caused by faulty compression 
tools are expertly covered in the second volume. 
Volume 3 in the series on tablets updates the special characteristics 
that should be considered for optimizing tablet production. Particular 
emphasis is given to design methods that should be considered when formuIattng 
a tablet product. Discussions of specialized granule and tablet-coating 
equipment are presented. discussing improvements or presenting new 
equipment developed since the publication of the first edition. Aqueous film 
coating is now firmly established in pharmaceutical coating processes, and 
thus, a shift in emphasis on coating procedures has been made in the revised 
chapter on coating. New coating pans and automation of aqueous 
film- and sugar-coating methods are covered. Fluid-bed processes and 
particle-coating methods, including theoretical considerations, are updated 
to reflect current practices. 
No text on tablet technology eould be considered complete without a 
full theoretical and practical updated description of current methods for 
formulating, manufacturing, and controlling the release of drug from sustained-
release tablet and particle dosage forms. A chapter on sustained 
drug release through coating provides an updated and authoritative discussion 
of this popular form of drug delivery. There is an enhanced emphasis 
on the various polymers and their combinations used to attain sustained 
drug activity. Pilot operations must reflect production methods in order 
to minimize difficulties in transferring a product from preproduction to 
production. Granules prepared by precompression, wet and dry granulation, 
fluidized-bed granulation, and spray drying are compared. A new 
method for preparing a granulation, namely the moisture-activated dry 
granulation (MADG), is also suggested for more widespread pilot evaluation. 
With the increasing emphasis on product uniformity from one tablet to 
another. or from one batch to another, whether the product is made sequentially 
or with long lag periods between batches, or whether the raw 
material source is from several different manufacturers, the concept of 
process validation is essential. An extensive chapter descrfbing the essential 
considerations that should be evaluated in process validation has been 
added to the revised edition of this volume. Although the chapter presents 
a complete detailed description of many validation methods, it also 
shows how less detailed approaches, some of which are commonly used in 
the industry, are useful. Current tablet production methods are described 
with sample control charts to help the readers improve their tablet production 
methods. The importance of the several different functions of production 
departments, their particular skills, and the need for coordinated 
and cooperative work relationships are stressed in the chapter "Tablet 
Production" so that the combined, partnership efforts of all production 
personnel can lead to superior tablet production. Automation of tablet 
compression and coating is also part of the chapter concerned with the 
production of tablets. 
In the discussion of stability, updated stability protocols to comply 
with recent FDA guidelines are presented. A new covariance analysis and
statistical method for expiration date prediction are described. The chapter 
"Quality Assurance" upgrades tablet testing for uniformity. dissolution, 
assay limit, test methods, and compendia! requirements for tablets to comply 
with current USP/NF requirements. Included are instructive figures 
for new schematic sampling plans. an update of the restrictions on the use 
of colors, and a recommended sampling method for raw materials. Thus, 
with this third volume on tablets. all the parameters currently concerned 
with the production of superior tablets are made current and discussed 
extensively. 
An updated and full coverage of the many topics concerned with tablets 
requires highly knowledgeable authors for each of the many areas that must 
be covered. To compile and update the pertinent information needed for 
the various chapters in this book required a multiauthored text of technologists 
with specific expertise and experience in their chosen subject matter. 
Each of the authors was charged with teaching their subject in such a 
fashion that the novice as well as the experienced reader will profit. 
They were to offer basic scientific facts and practical information so that 
all readers can learn theory and apply it toward the knowledge that each 
needs to formulate, produce, and control tablet operations in a scientific 
rather than an empirical manner. 
With this third volume. the editors have finished their task of updating 
the second edition on tablets. The editors are grateful to the authors for 
their fine contributions and. particularly. their patient response to the 
editors' suggestions for changes. The choice of the chapter topics, the 
authors. and the format are the responsibilities of the editors. It is hoped 
that these choices will prove fruitful to our readers by helping them solve 
their tablet technology problems and thereby advance industrial pharmacy's 
contribution toward improving both quality and efficiency in the manufacture 
of tablets. 


I. INTRODUCTION 
The old saying that all progress is change but not all change is progress 
is considered a truism by product manufacturers. Changes that are made 
in the production process of an established product are thoroughly evaluated 
from every point of view before implementation is allowed. The 
very existence of the company depends on its ability to produce products 
for sale. Therefore, any suggested change in the manufacture of an existing 
product must be viewed with suspicion until it can be shown that 
the change will indeed be advantageous to the company and not simply 
represent change for the sake of change. A company's prestige, profitability, 
and compliance with legal requirements are at stake when production 
changes are considered. Therefore, changes in the pharmaceutical 
industry must clearly be warranted before they are implemented. The 
object of this chapter is to introduce to the pharmaceutical scientist how 
changes can be accomplished in a pharmaceutical tablet production facility 
that wID constitute progress for the company. 
A. Unit Operations and Pharmaceutical Processing 
A unit operation can be defined as a process designed to achieve one or 
more changes in the physical and/or chemical properties of the raw material 
( s) being processed. 
Two or more unit operations that are designed to convert the basic 
raw materials into the final product or at least to have significantly 
improved the quality or value of the original raw material(s) describes a 
manufacturing system. In a tablet-manufacturing system, some of the unit 
operations may include (l) particle size reduction, (2) sieving or classification, 
(3) mixing, (4) particle size enlargement, (5) drying, (6) compression, 
(7) sorting, and (8) packaging. 
The literature is well documented with various unit operations involved 
in the manufacture of tableted products which may impact on a number of 
final dosage-form quality features. The features include, but are not 
limited to, such items as content uniformity, hardness, friability drug dissolution 
properties, and bioavailability. The traditional responsibility of 
the development pharmacist has been to identify and control such impacts. 
This includes the establishment of specific operating limits for each unit 
operation to ensure that the production system is under sufficient control 
for the production of safe, effective, and reliable tablets. The scope and 
purpose of this chapter is to examine system design considerations, and as 
a result, the individual unit operations and their potential impact on product 
quality will not be covered. The authors assume that each unit operation 
has been thoroughly investigated and is under sufficient control to 
do what it is purported to do. Specific effects of processing variables on 
product quality are dealt with in the pertinent chapters in this book series. 
B. Batch Versus Continuous Processing 
Most pharmaceutical production operations are batch operations, whereby a 
series of manufacturing steps are used to prepare a single batch or lot of 
a particular product. The same quantity or batch of material, if processed 
en mass through the various production steps to produce the final product, 
will then typically be treated by the manufacturer and the U. S. Food and 
Drug Administration (FDA) as one lot. A relatively few pharmaceutical 
products are prepared by true continuous-processing procedures whereby 
raw materials are continuously fed into and through the production sequence, 
and the finished product is continuously discharged from the final 
processing step(s). In continuous processing, one day's production, the 
production from one work shift, the quantity of a critical raw material from 
a given lot, or a combination thereof may define a single lot of manufactured 
product. Development of continuous-processing procedures requires specially 
designed and interfaced equipment, special plant layouts, and dedicated 
plant space, which reduces plant flexibility. The equipment, special 
plant design requirements, and dedicated space are all factors leading to 
the high costs of setting up and maintaining a continuous-manufacturing 
operation for a product. Unless the volume of product being produced is 
very high, the cost of setting up a product-dedicated, continuous-production 
operation will not usually be justified. Since pharmaceutical products, 
even within a dosage-form class such as compressed tablets, differ materially 
in many important aspects , such as drug dosage, excipients used, critical 
factors, affecting product quality, manufacturing problems, and the 
like, it is usually not feasible or possible to set up a continuous-processing 
operation for one product and then apply it to several others. Thus true 
continuous-processing operations are largely limited in the drug industry 
to large-volume products, which often also have large doses (or high 
weights per tablet), such as Tums, Gelusil, Aldomet, or Alka Seltzer, for 
Which tons of material must be processed each day, on an ongoing basis.

Improved Table Production System Design 
II. BENEFITS OF IMPROVED TABLET 
PRODUCTION SYSTEMS 
In either the batch or the continuous mode of operation, the objective of 
the production function is to produce pharmaceutical tablets for sale. 
Consequently, a production process should always be viewed as a candidate 
for progressive change in an effort to maintain the company's products 
in the marketplace. When looking at a process for possible changes, 
one must be aware of the potential benefits for the company. The major 
benefits that can be obtained, and which constitute the major valid reasons 
for changing or redesigning a pharmaceutical tablet manufacturing 
process, are the following [1- 5] : 
Regulatory compliance 
Current good manufacturing practices (CGMPs) 
Occupational Safety and Health Administration (OSHA) 
Environmental Protection Agency (EPA) 
Increased production capacity and flexibility 
Decreased product throughput time 
Reduced labor costs 
Increased energy savings 
Broadened process control or automation for control, operator interface, 
and reporting 
Enhanced product quality 
Enhanced process reliability 
The benefits that can be derived from the redesign of a process are 
dependent to a large extent on how "good" or "bad" the old process is. 
With perhaps the exception of some CGMP, OSHA, or even EPA requirements, 
the expected benefits to be derived from proposed process design 
changes are generally reduced to a dollar figure in order to compare the 
cost of implementing the change with the expected savings to be generated 
by the change. Proposed changes on a good facility may not be costjustifiable, 
whereas the same proposal on a bad facility can easily be costjustified. 
What can be justified and what cannot is a function of what can 
be referred to as the corporate policy or corporate personality at the time 
the proposal is made. A pharmaceutical company, like any company, is a 
part of the community in which it resides and as such has responsibilities 
to many other societal groups. These include governments, stockholders, 
employees, the community, the competition, and customers. The interaction 
of all these groups with the company results in a corporate personality. 
Therefore, companies have different standards for evaluating different 
financial situations, different production philosophies, varying time 
constraints for design and implementation, and varying technical support 
available for design changes. All of these items will be given consideration 
and will influence the decision-making process when a redesign proposal 
is made. 
III. PRODUCTION PROCESS DESIGN CONSIDERATIONS 
A fact that should be well understood is that the production unit is not an 
independent organization within the company. Any changes made in the 
production unit impact on many other units that come in contact with the 
production unit. However, with the rising costs of materials, labor, inflation, 
and regulations being constantly added to the manufacture of 
pharmaceuticals, the pharmaceutical industry cannot afford to neglect 
change or the modification of existing processes simply because there are 
established standards that may be difficult to change. Increased productivity 
matched with a reduction in direct labor cost will probably be 
the way of the future. This can only be accomplished by a conscious effort 
on the part of those in process development. The development pharmacist 
should therefore be familiar with ways in which the manufacture of 
pharmaceutical products can be increased and labor reduced. Even though 
the development pharmacist will not be thoroughly knowledgeable in all 
areas of process design considerations, he or she should at least be aware 
that those considerations exist and be able to interact with experts in 
those fields to accomplish cost savings. 
Major advances in efficiency have been made in tablet production over 
the last 20-30 years. These advances have come about by the development 
of methods; pieces of equipment, and instrumentation with which tablet production 
systems have been able to (1) improve materials handling. (2) improve 
specific unit operations, (3) eliminate or combine processing steps, 
and (4) incorporate automated process control of unit operations and 
processes. 
A. Materials Handling 
Materials-Handling Risks 
Possibly the single largest contribution to the effectiveness of a manufacturing 
facility is made by the facility's materials-handling capabilities. 
In addition to a lack of efficiency, there are certain risks involved with 
improper or inefficient materials handling. These riaks include increased 
product costs, customer dissatisfaction, and employee safety liabilities. 
Materials that are not handled efficiently can increase the cost of raw materials. 
For example, penalty charges are assessed (demurrage) when 
railroad cars are not loaded or unloaded according to schedule. If raw 
materials are not moved as required by production schedules, delays are 
incurred which can lead to situations in which machine time is wasted, 
personnel time is wasted. in-process inventories are increased, and the entire 
manufacturing process is slowed down. In addition, the improper 
handling and storage of materials can lead to damaged, outdated, and lost 
materials. Improper materials handling can place employees in physical 
danger. An increase in employee frustration generated by constant production 
delays due to poor materials handling can result in reduced morale. 
Materials-Handling Objectives 
A well-designed and efficiently operated materials-handling system should 
impart to the manufacturing facility reduced handling costs, increased manufacturing 
capacity. improved working conditions. and improved raw material 
distribution to the appropriate manufacturing areas. To achieve an 
efficient materials-handling system. as many of the basic general principles 
of efficient materials handling need to be implemented as practical.

Improved Tablet Production System Design 5 
Basic Principles of Materials Handling 
SHORT DISTANCES. Raw materials used in the production process 
should only be moved over the shortest possible distances. Moving materials 
over excessive distances increases production time. wastes energy, 
creates inefficiency, increases the possibilities of delays. and adds to the 
labor costs if the material is moved by hand. 
SHORT TERMINAL TIMES. When material is being transported, the 
means of transportation should not have to spend time waiting On the material 
to be picked up. Material should always be ready when the transportation 
is available. 
TWO-WAY PAYLOADS. The transportation mechanism for raw materials 
should never be moved empty. For example. if tablet-packaging materials 
are being transported from a warehouse to a packaging line by means of a 
fork-lift truck. the return trip could be used, for example, for the removal 
of accumulated scrap material or finished product from the production 
line. 
AVOID PARTIAL LOADS. The movement of quantities of raw materials 
that require only a partial use of the total capacity of the transportation 
system is a waste of time and energy. If the movement of such materials 
cannot be avoided, then the partial loads should be doubled up to make 
efficient use of the transportation system. 
AVOID MANUAL HANDLING. The manual handling of raw materials is 
the most expensive way of moving them. A great deal of direct costs can 
be eliminated by mechanically moving material rather than having it moved 
by the production personnel. 
MOVE SCRAP CHEAPLY. The movement of scrap material is a nonproductive 
function and scrap material should not be a primary work objective 
for a transportation system. Therefore, scrap material should be moved as 
inexpensiVely as possible. One way of achieving this is to handle the removal 
of scrap on return loads after delivering needed materials. 
GRAVITY IS THE CHEAPEST POWER. The movement of material from 
top to bottom through multileveled facilities. if available. is the most efficient 
way of moving material. 
MOVE IN STRAIGHT LINES. A basic theorem of geometry states that 
the shortest distance between two points is a straight line. Therefore, 
the most efficient movement of material is along the straightest and most 
direct path to its destination. 
UNIT LOADS. Raw materials should be delivered to their ultimate 
destination in loads that will be completely consumed by the manufacturing 
process. This will eliminate the need for the excess raw materials to be 
handled at the point of use and to be returned to the storage place. 
LABEL THOROUGHLY. Thoroughly labeled raW materials will eliminate 
or help to eliminate having the improper raw material delivered to a production 
site. Much time and effort is wasted in correcting raw materials 
errors.
Of course. not all of the basic materials-handling principles can be applied 
or applied to the same extent in every situation. How a company designs 
its materials-handling facility and its production process is based on several 
different considerations. The type of process that is being designed, 
batch or continuous; will have a great influence on the type of materialshandling 
system used. The materials-handling system in a batch-ortented , 
multiproduct facility is significantly different from a single-product, continuous-
process. materials-handling system. The type and quantity of 
product as well as the physical characteristics of the raw materials involved 
will also affect the materials-handling system. For example, fluids for 
granulating will have to be pumped, whereas solids will have to be handled 
in another manner, such as with vacuum devices of conveyors. The type 
of building that is available for the manufacturing process may exert the 
single greatest influence on the materials-handling system. The lack of a 
multistoried building will preclude the use of gravity for material flow. 
Like all company decisions. the costs of purchase. installation. operation. 
and maintenance as well as the useful life and the scrap value of the materials-
handling system must be weighed against its advantages. 
Greene 16] quotes an old cliche which best summarizes materials 
handling: 
The best solution to a materials-handling problem is not to move 
the material. If this is possible. then move it by gravity. And if 
this is not possible, usually the next best way is to move it by 
power. If people must move the material, it should be moved by 
the cheapest labor possible. 
Examples of Materials-Handling Improvement 
Improvements in the use of materials-handling techniques have been incorporated 
into the new product facilities of Merck Sharp & Dohme (MSD) and 
Eli Lilly and Company (Lilly). Figure 1 shows a schematic of the granulation 
and tableting area at MSD's new facility for the production of Aldomet. 
There is virtually no human handling of materials during or between 
processing steps. The movement of materials (solids and liquids) through 
the system is accomplished by a sophisticated materials-handling system. 
The system is built in a three-story building Which allows the entire 
process to operate in three operational "eolumns , II The system incorporates 
vertical drops to utilize gravity whenever possible and uses pumps, 
vacuum, and bucket conveyors to move material upward whenever necessary. 
In the fir-st processing column bulk raw materials are loaded into the 
system on the third floor and flow by vertical drop through holding and 
feeding hoppers into mixing equipment and- then into continuous-granulating 
and drying equipment on the first floor. - The dried granulation is 
then transported by vacuum back up to the third floor to start the second 
processing column for milling and sizing. By vertical drop the sized granulatton 
flows down through the lubrication hoppers and mixer and then to 
the tablet compression machines on the first floor. The compressed tablets 
are then transferred by bucket conveyor back up to the third floor and 
the start of the third column. Here. the tablets are collected. batohed , 
and transferred to feed the air suspension film-coating equipment located 
on the second floor. Once coated. the tablets are stored on the second
floor until required for packaging. During packaging operations the tablets 
now by vertical drop from the second floor to the packaging lines 
on the first floor. 
The Aldomet facility was built to meet the need for increased manufacturing 
capacity of Aldomet. The new Aldomet facility requires fewer 
production people, thus keeping direct-labor costs low. Since the facUity 
is continuously monitored by computer throughout each phase of the 
process, Aldomet has a high degree of uniformity and reproducibility. 
The continuous monitoring also bring about a conservation of energy. As 
a result of the numerous and rigid in-process controls in the Aldomet 
process. quality control and the quality assurance costs have been reduced. 
Through the creation of a new building, MSD's compliance with the Good 
Manufacturing Practices regulations was greatly facilitated [71. 
A study of Figure 2. schematically representing Warner-Chilcott's redesigned 
Ge1usil manufacturing system, shows that the dedicated singleprocess 
system makes use of gravity, belts, and pneumatic devices to efficiently 
move material through the process. The old manufacturing operation 
was a semiautomated batch operation with a capacity limit of three 
shifts employing 14 persons. The capacity of the redesigned system for 
manufactur-ing' Ge1usil tablets is three times greater than that of the old 
process. and the unit throughput time for Gelusil manufacture was reduced 
to a third of the old process time. The output of the new extrusion 
process, in one shift with two persons, equals the total daily output from 
the old process. Obviously. another one of the benefits of the new process 
was a reduction in required manpower, Which reduced the direct-labor 
costs involved in producing Gelusil [5.8]. 
While the previous examples involved very large volumes of product 
produced on a continuous basis. batch-oriented production systems have 
also been made more efficient by materials-handling improvements. Figure 
3 shows a schematic of E. R. Squibb IlL Sons Inc.'s (Squibb) production 
process for Theragran M tablets. The vacuum transfer of the granulation 
to the tablet compression machines has been accomplished by a 
vertical drop from storage devices on a mezzanine above the tablet 
machines. 
Lilly's new dry products manufacturing facility (Fig. 4) has increased 
their materials-handling efficiency by the use of (1) a driverless train 
which transports bulk raw materials from the receiving dock to the staging 
area, (2) vacuum powder transfer mechanisms, (3) direct transfer of inprocess 
materials, and (4) the liberal use of vertical drops in the twostory 
operation [9J. 
B. Processing Step Combination or Elimination 
The design of 9. new production facility should attempt to improve the old 
process by eliminating or combining certain processing unit operations. 
This could take the form of simply eliminating tasks that are no longer 
necessary or by the utilization of new pieces of equipment that can perform 
more than one of the unit operations required under the old 
processing system. 
Direct Compression 
Many processing steps have been eliminated in the manufacture of some 
pharmaceutical tablets as a result of the development of directly
A schematic of the Squibb Theragram M tablet production 
(Courtesy of E. R. Squibb, New Brunswick, New Jersey.) 
compressible excipients, wherein powdered drug can be directly mixed 
with the excipient and then immediately compressed into a finiShed tablet. 
Direct compression is the method of choice in tablet manufacture, when 
the process may be employed to produce a high-quality finished product. 
Direct compression offers the most expeditious method of manufacturing 
tablets because it utilizes the least handling of materials, involves no 
drying step, and is thus the most energy-efficient method, and is also the 
fastest, most economical method of tablet production. 
The reformulation of a product from a wet-granulated process to a 
direct-compression process to eliminate several process steps is illustrated 
in Table 1 by the comparison of Lederle Laboratories' (Leaderle) old and 
new tablet-manufacturing processes. If reformulation to direct compression 
cannot be accomplished, purchasing the critical raw material in granular 
form could have the same effect from a processing standpoint. While the 
cost of directly compressible raw material may be higher, the labor, time, 
and energy cost savings realized by eliminating the granulation, drying,

Improved Tablet Production System Design 
Table 1 Unit Processing of Solid Dosage Forms, Lederle Laboratories 
11 
Old tablet-manufacturing process 
(wet granulation) 
1. Raw materials 
2. Weighing and measuring 
3. Screening 
4. Manual feeding 
5. Blending (slow-speed planetary 
mixer) 
6. Wetting (hand addition) 
7. Subdivision (comminutor) 
8. Drying (fluid bed dryer) 
9. SUbdivision (comminutor) 
10. Premixing (barrel roller) 
11. Batching and lubrication (ribbon 
blender) 
12. Manual feeding 
13. Compression (Stokes rotary 
press) 
14. Solvent film coating (Wurster 
Column) 
15. Tablet inspection (manual) 
New tablet-manufacturing process 
(direct compression) 
1. Raw materials 
2. Weighing and measuring 
{automatic weigher and recording 
system)a 
3. Gravity feeding 
4. Blending (Littleford blender) 
5. Gravity feeding from the 
storage tanka 
6. Compression (high-speed 
rotary press)a 
7. Aqueous coating (Hi-Coater) 
aIn planning phase. To be installed later. 
Source: Courtesy of Lederle Laboratories, Pearl River, New York. 
and sizing of the raw material may more than justify the increased material 
cost.
Unfortunately, there are many situations in which direct compression 
does not lend itself to tablet production, for example, with low-dose drugs 
or where segregation and content uniformity are a problem, or with highdose 
drugs which are not directly compressible or which have poor flow 
properties, or in the preparation of certain tablets or in many special 
tablet-manufacturing operations. When direct compression is not a feasible 
method of tablet manufacture, wet granulation is usually the method of 
choice. 
Equipment for the Elimination/Combination of 
Processing Steps 
Until relatively recently, wet granulation was a highly labor-intensive and 
time-consuming process. Figure 5 illustrates the various steps involved in 
batch wet-granulation processes in the 1960s and before. Typically, two
separate mixing devices were used for the dry solids blending and for wet 
massing, with a manual transfer step in between. as shown in part A of 
Figure 5. Following wet massing the entire batch was again manually 
granulated by transfer to an appropriate piece of equipment after which 
the granular material was further manually handled by being racked on a 
series of drying trays. After oven drying the entire batch was again 
manually removed from the trays and was dry sized by again being passed 
through a mechanical screening device. Thereafter. the entire batch was 
placed in a dry blender once again for incorporation of the lubricant. 
after which the batch was placed in drums or containers to be held for 
tablet compression. As can be seen in Figure SA. the components of the 
batch or the entire batch was manually handled at least 10 or 11 times.
With the development of specialized high-shear powder and mass mixers 
, and with the further development of fluid-bed dryers, the standard 
wet-granulation batch-processing operation as it is being conducted in the 
1980s is shown in part B of Figure 5. The number of transfer steps has 
been reduced to three or four ~ the manual handling of the batch material 
has been greatly reduced ~ and the time of granulation manufacture has 
been cut from 2 days with an overnight drying step to as little as a few 
hours. This procesaing can be further illustrated by a hypothetical 
processing setup in Figure 6~ and by the process flow chart for the production 
of Lasix in Figure 7. 
New equipment is now being developed and gradually adapted by the 
pharmaceutical industry which handles all of the step s in granulation 
preparation in one piece of equipment. This is depicted in part C of 
Figure 5. It should also be pointed out that not only is handling of materials 
greatly reduced by the newer equipment used in the wet-granulation 
operation, but the new process equipment is also capable of producing 
granulation materials which have unique properties which could not 
previously be routinely produced. Granular particles with a near spherical 
shape can be routinely produced for they may be run under vacuum Conditions 
that reportedly enhance the density and cohesiveness of the granular 
particles. Some of the newer equipment can also be used to apply protective 
coating to the particles during their manufacture. Some of these 
special applications are described in the sections which follow. The reduction 
of materials handling, Which is obvious from Figure 5, as the 
process is currently practiced in the 1980s as compared to earlier times, 
is due in large measure to the development of equipment Which can sequentially 
undertake a series of processing steps which earlier were accomplished 
by separate pieces of equipment. These new, multipurpose pieces 
of equipment, which are capable of combining virtually all of the steps in 
the wet-granulation process, are also described in the following sections.
Improved Tablet Production System Design 1'1 
CONTINUOUS-BATCH POWDER MIXING AND MASSING EQUIPMENT. 
The Littleford Lodige mixer (see Appendix) was one of the first highshear 
powder blenders capable of rapidly blending pharmaceutical powders 
and wet massing within the same equipment. With some formulations the 
equipment may also be capable of producing agglomerated granular particles 
which are ready for fluid-bed or other drying methods without further 
processing. Figure 8 illustrates a conventional Lodige mixer and 
describes the various assemblies of the unit. The unit consists of the 
horizontal cylindrical shell equipped with a series of plow-shaped mixing 
tools and one or more high-speed blending chopper assemblies mounted at 
the rear of the mixer. For the addition of liquids, an injection tube terminating 
in one or more spray nozzles is provided. The nozzle(s) is located 
immediately above the chopper assembly. 
In operation, the plow-shaped mixing tools revolve at variable speeds 
from about 100 to 240 rpm and maintain the contents of the mixer in an 
essentially fluidized condition. The plow device also provides a highvolume 
rate of transfer of material back and forth across the blender. 
When liquid granulating agents are added to dry powders the liquid enters 
the mixer under pressure through the liquid nozzle immediately above the 
chopper assembly or assemblies. Each chopper assembly consists of blades 
mounted in a tulip shape configuration rotating at 3600 rpm. As the liquid 
impinges on the powder in the area of the chopper it is immediately dispersed. 
By controlling the duration of the mixing cycle, the particle size 
of the granulation may be controlled. The choppers perform a secondary 
function in this type of high-shear powder blender. It will be noted on 
examination of part B of Figure 5 that the new processes involved in wet 
granulation may not include a sieving operation. When the chopper blades 
are operated during dry mixing dry lumps of powder are effectively dispersed. 
Consequently, it will often be found that sieving is no longer an 
essential prerequisite of powder blending when this type of equipment is 
employed. 
Using this type of high-shear powder mixing equipment, complete mixing 
may be obtained in as little as 30-60 s, A temperature rise of 10-15 
may be expected if dry blending is continued over a period of 5-10 min. 
When the Littleford Lodige blender is used for wet granulation the work 
which must be done by the mixer will increase as the powder mass becomes 
increasingly wet. This is often reflected in the readings on the 
ammeter of the equipment because the increased work will result in an 
amperage increase. Such readings may be very useful in helping to 
identify the proper end point for the wet-granulation process. 
The equipment illustrated in Figure 8 employs air purge seals. One of 
the major difficulties in the operation of a high-shear powder mixer is 
powder making its way behind the seals and even contaminating the bearing 
assembly. This can lead to two difficulties: contamination of the next 
product with materials previously run in the blender and early failure of 
bearings and seals. A number of pharmaceutical manufacturers have found 
the air purge seal to be a useful device and an effective mechanism for 
overcoming this difficulty with this type of blender. 
The Diosna mixer/granulator is another type of high-shear powder 
mixer and processor (Fig. 9). The mixer utilizes a bowl (1) mounted in 
the vertical position. The bowl is available in seven sizes between 25 and 
100 L. The mixing bowl can be jacketed for temperature control. A highspeed 
mixer blade (2) revolves around the bottom of the bowl. The blade
fits over the pin bar at the bottom of the mixing bowl which powers the 
blade. The blade is specially constructed to discourage material from 
getting under it. The speeds of the mixing blades vary with the size of 
the mixer. The tip speed, however, is kept at 3-4/10 m s-1 on low and 
6-8/10 m s-1 on high. The mixer also contains a chopper blade (3) at 
either 1750 or 3500 rpm. The chopper functions as a lump and agglomerate 
reducer. A pneumatic discharge port (4) may be specially ordered 
for the unit to provide automatic discharge. The unit is provided with a 
lid (5) and the larger units employ a counterweight (6) to assist in raising 
and lowering the lid. The lid has three openings: one to accommodate a 
spray nozzle, a second larger opening for an air exhaust sleeve, and a 
third opening for a viewing port. The units are also equipped with an 
ammeter (7) which may be employed to determine the endpoint of granulation 
operations. Typical time sequences for the use of a Diosna mixer are 
as follows: mixing 2 min or less; granulating, 8 min or less; discharge, 
1 min, with discharge capable of being preset when the pneumatic discharge 
system is in place. 
Vosnek and Forbes [10] reported on the performance features of the 
Diosna. They compared granulations prepared by a traditional method as 
shown in part A of Figure 5 Wherein a pony mixer was used for wet 
massing with granulations with the same product prepared in a Diosna 
mixer followed by fluid-bed drying. Figure 10 shows a comparison of 
particle size distribution of the two granulations. The Diosna equipment 
produced a granulation with a more normal particle size distribution with a 
smaller fraction of the granulation being 200 mesh or below (18 vs. 33%). 
The shape of the particles produced by the Diosna were also more 
Traditional Granulation 
spherical. This is filustrated in Figure 11, where the particles on the 
right side of the figure are from the Diosna, whereas those on the left 
are from the conventional wet granulation process. Physical comparisons 
of tablets prepared from granulations made using a range of granulating 
agents as prepared by the Diosna and by the traditional granulation 
equipment are shown in Table 2. The conclusion to be drawn from the 
table is that the tablets produced with the Diosna equipment using the 
streamlined manufacturing process were as good as and sometimes better 
than tablets made by the traditional wet-granulation process. The Lilly 
study summarized the advantages and disadvantages of the Diosna equipment 
and process as shown in Table 3. The relatively high cost of the 
equipment would be quickly offset by the efficiency and reduced handling 
involved in this streamlined production method. The advantages of the 
equipment obviously were thought to outweigh the disadvantages, since 
Lfily has used this Diosna equipment as their primary powder-mixingI 
processing equipment in their new dry products manufacturing facility 
(see Fig. 4). The available Diosna models with their vessel capacity and 
approximate working capacities are shown in Table 4. 
Figure 12 describes the Littleford MGT mixerI granulator, which has 
been developed by this company to more specifically meet granulation needs.
Since wet granular material may resist transfer by air conveyor systems 
such as the Vacumax, the type of transfer provision shown in Figure 13 
may be especially helpful. The need to raise the equipment to appropriate 
working height in order to discharge directly into a bowl of a fluid-bed 
dryer is not regarded as a major disadvantage, provided powder can be 
conveniently charged into the unit when in a raised position. 
Figure 14 illustrates the Oral mixer/granulator. Available from 
Machines Collette, Inc., this equipment is a modification of the earlier 
Oral industrial planetary mixers. The difference, however. between the 
mixerI granulator and the standard planetary mixer is that the new unit 
contains two mixing devices. A ll:lI'ge mixing arm (1) is shaped to the 
rounded configuration of the bowl (2) and provides the large-scale mixing 
motion in the powder , A smaller chopper blade (3) enters off-center from 
the mixing arm and is located above it. The larger mixing blade and a 
secondary chopper blade system is, therefore. similar to the Lodige and 
Diosna units previously described. The difference, however, is that the 
Gral unit has the configuration of a planetary top-entering mixer. The 
mixing bowl may be loaded at floor level and then raised to the mixing 
position by the hydraulic bowl elevator cradle (7). The bowl is brought

Improved Tablet Production System Design 27 
into contact with a cover (4) providing a tight seal. An advantage of the 
unit is that it may be discharged by its hydraulic port (5), whereas in 
the raised position, offering sufficient space for a container to be placed 
beneath the discharged port. The entire mixer unit does not have to be 
elevated to provide this vertical discharge distance as is the case with the 
previously two mentioned high-shear mixers. As with the other high-shear 
mixers, all parts in contact with the product may be ordered in stainless 
steel. Fluid may be injected into the mixer bowl. The equipment is 
available with timer control (6). The Oral machines can also be supplied 
with explosion-proof as well as standard electrics. The equipment is 
available in five sizes ranging from 10 to 1200 L. 
CONTINUOUS-BATCH MIXING, MASSING, GRANULATION, AND DRYING 
EQUIPMENT. The ideal equipment for the preparation of granulations 
by the wet- granulation process would be one unit which is capable of sequentially 
dry mixing, wet massing. agglomerating. drying, and sizing the 
material being processed. with no materials handling between steps. The 
only interruption 1n such a continuous-batch process might be to stop the 
unit in order to add the lubricant prior to discharging a final product 
ready for compression. This type of approach is indicated in part C of 
Figure 5. A number of equipment manufacturers and pharmaceutical scientists 
have been working toward this goal over the last several decades. 
However. it is only within the last several years that commercial equipment 
has become available for continuous-batch wet granulation in one 
unit.
Fluid-Bed Spray Granulators. The f'll'st equipment reported in the 
pharmaceutical literature to provide continuous-batch wet granulation was 
fluid-bed drying equipment which was modified by the addition of spray 
nozzles or fluid injectors to provide additional liquid-binding and adhesive 
agents to dry-powdered materials which were initially placed in the 
equipment. Scientists working in European pharmaceutical companies were 
the first to report on this approach [11-15]. However. several U. S. 
companies are employing fluid-bed spray granulators (see Appendix). 
Warner-Chilcott utilizes such a process in the manufacture of Pyridium 
tablets. With the active ingredient, phenazopyridine, being a powerful 
dye. the neW process also benefits from the fact that the system is totally 
enclosed during the granulation stage [8]. Figure 15 presents a schematic 
cross section of such a fluid-bed spray granulator. The airflow 
necessary for fluidization of the powders is generated by a suction fan (2) 
mounted in the top portion of the unit which is directly driven by an 
electric motor. The air used for fluidization is heated to the desired temperature 
by an air heater (5). after first being drawn through prefilters 
to remove any impurities (6). The material to be processed is shown in 
the material container just below the spray inlet (1). The liquid granuIating 
agent is pumped from its container (3) and is sprayed as a fine 
mist through a spray head (4) onto the fluidized powder. The wetted 
particles undergo agglomeration through particle-particle contacts. Exhaust 
filters (7) are mounted above the product retainer to retain dust 
and fine particles. After appropriate agglomeration is achieved. the spray 
operation is discontinued and the material is dried and discharged from the 
unit. Figure 16 provides a schematic view of the automatic fluid-bed spraygranulator 
system available from the Aeromatic Corporation, with its integrated 
materials-loading and -handling systems. The unit described in

Figure 15 Schematic cross section of a fluid-bed spray granulator. 
(Courtesy of Aeromatic, Somerville, New Jersey.) 
Motor 
Vacuum 
Convey 
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1 
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Figure 16 Schematic of an automatic fluid-bed spray granulator (Streba 
150) with integrated materials loading and materials handling. (Courtesy 
of Aeromatic, Somerville, New Jersey.)

Improved Tablet Production System Design 29 
Figure 16 is reportedly capable of processing approximately 200 kg per 
batch. The advantages of such rapid wet massing, agglomeration, and drying 
within one unit are obviously attractive. Exclusive of equipment clean-up, 
the process may readily be sequentially completed within 60-90 min or less. 
A number of pharmaceutical companies, both in Europe and in the 
United States, are utilizing fluid-bed processing as a rapid continuousbatch 
approach to wet granulation. However, there are a number of difficulties 
that exist for the process which may account for the fact that 
fluid-bed granulation processing has not been more widely accepted. 
Fluid-bed systems as currently available may not provide adequate mixing 
of powder components. Where potent drugs are employed in a fine state 
of particle size reduction, there will be a tendency of these materials to 
be separated from the powdered bed and collected on the filter of the unit. 
Thus, even if a separate powder-mixing operation is undertaken to produce 
adequate uniformity of drug distribution within the mix, thus demixing 
action must be considered in any attempt to process potent drugs 
in a fluid-bed spray granulator or when there is a considerable disparity 
in the particle size or density of the materials being processed. Unlike 
extrusion, wet screening, and the use of other more conventional mixing 
equipment. the forces of agglomeration which cause the particles to be 
brought together producing the agglomerates are relatively low in the 
fluid-bed spray granulator. Accordingly, not all materials may lend themselves 
to agglomeration in this continuous batch-processing equipment. 
Low-density and hydrophobic materials can be particularly troublesome. 
Another limitation of this type of equipment may be related to particles 
containing granulattng agent on their surfaces which adhere to the filters 
of the equipment. This creates two problems: a reduction in the effective 
area of the filters, which may produce filter failure and a build up 
of pressure within the unit and other difficulties during the granulation 
operation, and problems connected with cleaning the unit following the 
granulation process. 
All production-size fluid-bed dryer equipment should contain explosion 
relief panels. However, special attention should be given to safety precautions 
if organic solvents are used in the fluid-bed spray granulation 
process. A number of fatal accidents have occurred worldwide with the 
use of fluid-bed dryers, as have a number of less serious explosions in 
which only the installation was damaged or destroyed. Dust explosions 
can also occur in a fluid-bed dryer with dry materials. However, when 
working with solvents. especially those with flammable vapors. it might be 
wise to Ill'st check with the supplier of the equipment to review whether 
or not the operation is safe or advisable. 
Other manufacturers of fluidized-bed drying equipment, such as Glatt 
Air Techniques, have developed specialized equipment to provide continuousbatch 
processing fluid-bed granulator capabilities. The number of scientific 
papers which have appeared in this field in recent years attests to 
the interest of the pharmaceutical industry in this continuous-batch 
processing approach. For example, investigators have studied the mixing 
of pharmaceutical raw materials in heterogeneous fluidized beds [11]. the 
physical properties of granulations produced in a fluidized bed [12], the 
effect of fluidization conditions and the amount of liquid binder on properties 
of the granules formed [13], and the various process variables 
influencing the properties of the final granulation [14,15].

Figure 17 A cutaway view of a double-cone mixer/dryer processor. (Courtesy of PaulO. Abbe, Ine , , Little Falls, 
New Jersey.) 
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Figure 21 The Marumerizer, Model QJ-400. 
tion , Process Division.) 
(Courtesy of Luwa Corpora

Improved Tablet Production System Design 39 
Figure 22 The Xtruder , Model EXDCS-I00. (Courtesy of Luwa Corporation, 
Process Division.) 
amount of granulation solution used and the total mixing time. However, 
control of these two variables has proved to be less than satisfactory at 
times. 
The utilization of high-intensity mixers in the wet-granulation process 
dramatically reduces the total time required to reach or exceed a proper 
granulation end point. Therefore. the need of a better understanding and 
control of wet granulation has increased in recent years as the use of 
high-intensity mixers has increased. In recent years. more sophisticated 
techniques for monitoring the granulation process have been investigated. 
Power consumption [3 - 8], torque [9 -l1J. rotation rate [12]. and motor 
load analyzer [13] measurements are indirect methods of monitoring the 
granulation process. Bending moment [4J. beam deflection [14]. and 
probe vibrational analysis [15 -16] techniques directly measure the density 
and frictional changes that occur during wet massing. Most recently. 
conductance [17] and capacitive-sensor [18 - 21] methods have been used 
and found to respond to moisture distribution and granule formation in 
high-intensity mixers.

40 Peck, Anderson, and Banker 
While none of the systems studied have universal unity, all of the 
various approaches have attempted to be responsive to the dynamic 
variables of the process. be applicable to formulation research. and be 
potentially useful in the control of manufacturing processes. The granulation 
monitoring system shows promise as a research tool for gaining insight 
into the granulation process and as a control system for obtaining 
better reproduction of granulations and resultant tablets. The study of 
the wet-granulation process remains an active research area [1- 2, 
22-26]. 
Tableting Improvements 
Pharmaceutical tablet production improvements have also been made by improving 
the performance of a specific unit operation. The development of 
high-speed tableting and capsule-filling machines has allowed many manufacturers 
to increase their tablet and capsule production output by replacing 
their older, much lower-capacity machines. 
Since the introduction of high-speed rotary tablet presses tablet outputs 
are now possible in the range of 8000 -12,000 tablets per minute. 
Because of these high outputs, it has become advantageous. if not necessary, 
to consider automatic control and monitoring of tablet weight. One 
of the early attempts to automatically monitor tablet production with an online 
system for tablet press weight control was the Thomas Tablet Sentinel 
(TTS). This unit utilizes commonly available strain gage technology. 
Strain gages, appropriately placed on a tablet machine, monitor the strain 
that is incurred during the tablet compression step on the machine. 
When a tablet press is in good operating condition, is properly set up, 
and the punch and die tooling has been properly standardized the amount 
of pressure or compressional force developed at each station is dependent 
upon the amount of powder that was contained in each corresponding die. 
Measurement of this compressional force is thus an indirect method of 
monitoring the tablet weights being produced by the machine, and if this 
force could then be used to initiate an automatic weight adjustment, continuous 
monitoring of tablet production would be possible. The TTS system 
shown in Figure 23 is able to do such a task. The schematic of the 
setup of the strain gages and weight adjustment servomotor mechanism is 
shown in Figure 24. Figures 23 and 24 illustrate the latest monitoring 
system which is known as the TTS-II. The TTS-II is a fully automatic, 
on-line. electromechanical tablet weight-control system which is capable of 
continuously monitoring and controlling weights of tablets as they are 
being produced on a single- or double-r-otary press. Figure 24 shows the 
three elements of the TTS- II: (1) the sensing systems, (2) the weight 
control system. and (3) the reject control system. 
The control module may contain meters for monitoring tablets as they 
are being produced within desired quality limits. The latest design also 
includes a tablet-counting system, a defective tablet counter, and a printer 
for recording when weight adjustments are made. The TTS-ll system 
utilizes a sensing system of shield strain gages mounted on appropriate 
pressure points on the machine. An electronic control system feeds power 
to the strain gages and amplifies their output signal. 
The third section of the TTS-II system consists of the weight -control 
system, which functions according to signals received from the electronic 
control portion of the system. Finally. an optional automatic rejectcontrol 
system is available which will reject the tablets that may drift out

Figure 23 Thomas Tablet Sentinel II. (Courtesy of Thomas Bngfneermg , Ine , , Hoffman 
Estates, illinois.) 
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42 
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Improved Tablet Production System Design 49 
programmed, so that the operator may load the coater, set the temperature, 
start the warm airflow, and then start the spray system. Based on 
the requirements of the dosage form being coated (tablets, beads, or 
small particles), the unit is set to coat for an appropriate preselected 
period of time. This technique thus lends itself to the integration with a 
miniprocessor, since all coating procedures are capable of being mechanically 
or electronically controlled. The air-suspension approach may be 
effectively employed with either nonaqueous or aqueous film coating. 
About the same time that air-suspension coating was being perfected, 
another device was being investigated. This was a side-vented or perforated 
coating pan originally developed by Lilly and then sold as the 
Acce1a-Cota by Thomas Engineering (Fig. 29). One of the major advantages 
of this equipment is the one-way flow of air through the tablet bed 
and out the perforations of the pans. This greatly reduces or eliminates 
the "bounce-back" of atomized spray and particle spray drying of the 
spray droplets that occurs, especially with solvent-based coating, with the 
conventional pans. It also benefits coating because the greater air flow 
through the bed facilitates drying. Again, the key to the advance of this 
new coating pan was the availability of suitable spray systems which would 
provide the new spray requirements while allowing for automation and thus 
programmable coating sequences within the coating unit. The side-vented 
coating pan has been successfully used for continuous coating of films and 
sugar systems [24]. It has been reported that by the selection of proper 
viscosity sugar Slurries, a complete sugar coat may be applied over an 
8-h period. This must include such sequencing as spray, pause, and dry 
cycles to allow for adequate sugar slurry spreading prior to drying. It 
should be noted that the Pellegrini pan, which is not side vented, but 
does have the capability of moving large amounts of air through the pan, 
has been adapted to continuous sugar coating, and has also been used 
with programmed control systems. 
Automation and Coating 
For the coating of tablets with sugar systems, it was recognized that it is 
possible to spray, roll out the syrup, and dry. It is also known that this 
sequence can be repeated to produce a suitable coating as long as an 
adequate air supply is available and suitable spray systems can be used. 
With these two elements in place, it is then possible to install timers, 
mechanical or computer controllers, along with suitable solenoid valves, to 
have a completely programmed system. In so doing an operation is developed 
that is capable of being readily validated, since all important 
parameters must first be defined and then precisely controlled by the 
automated system without the variability of human error. Once under 
automated control, a validated process is easy to confirm with appropriate 
printout recording. cf 
Associated with the concept of automation may be the desire to first 
optimize a process, which would then ensure that the controlled process 
is operating at its maximum efficiency. A side-vented. 48-in coating pan 
has been used at Purdue University in the Industrial Pharmacy Laboratory 
(Fig. 30) to study a number of coating variables. This pan is equipped 
with the usual temperature-indicating dials and coating pan pressure differential 
readout. However, it also includes the following features which 
aid in the study of the coating process:

50 Peck, Anderson. and Banker 
Figure 30 An instrumented 48-in Accela-Cota installation. (Courtesy of 
Industrial Pharmacy Laboratory, Purdue University, School of Pharmacy 
and Pharmacal Sciences, West Lafayette, Indiana.) 
1. Variable heat input (1) 
2. Variable air input (2) 
3. Variable exit air control (3) 
4. Measurement of dew point of input (4) or exit air (5) 
5. Temperature detection for input (6) and exit air (7) 
6. Chart 'recording of air velocity, input air temperature, and exit 
air temperature 
7. Associated electronics with future microcomputer attachment 
capacity 
With these measuring capabilities, studies have been conducted on bed 
load, baffling configuration, tablet shape, and spray-pattern configurations. 
The types of coating systems can be evaluated analytically with 
this setup. By measuring and being able to accurately control spray 
rstes and conditions (spray angles, degrees of atomization, etc.), airflow 
rate through the pan, air temperature, and dew point into and from the 
pan it should be possible to optimize not only coat quality features, but 
coating and energy efficiency as well. As energy costs have risen rapidly, 
this latter consideration has become increasingly important. The 
optimization of the parameters involved with aqueous and sugar coating

Improved Tablet Production System Design 51 
are currently being appropriately modeled and simulated, with the projected 
results being verified in the new installation. 
Completely automated coating systems are now available for the control 
of both sugar- and film-coated products. An example of such a system is 
the Compu-Coat II. This is the second generation of a computerized coating 
system based on a new controller. This controller provides real time 
monitoring and control and documentation of the coating pan, air handler, 
and spray system while allowing complete back-up by an independent manual 
system. This system is available for use with the Accela-Cota pans in 
sizes of 24, 48, 60, and 66 in. The spray system is capable of handling 
sugar and film coatings. It is possible to network up to eight coating systems 
with a supervisor interface station, and to expand to 24 pans using a 
production monitoring unit. The software of the Compu-Coat system may 
control the coating formulations to be used, control process parameters, 
and respond to alarm conditions. As indicated earlier, the system is of a 
modular design and is adaptable to multipan use [25,26]. 
D. Increasing Role of Computer Process Control 
Evolution and Growth 
The digital computer control of processes, especially processes in the chemical 
industries, have been studied and used for approximately 25 years. 
By today's standards the original installations were slow and very space 
consuming. However, several successful computer-controlled processes 
were developed. 
The evolution of the computer in process control systems can be seen 
in Figure 31. In the early stages of process control (Fig. 31a) , instrumentation 
monitoring of a process, input (I) devices, such as meters, 
lights, recorders, etc., were mounted on a panel board to provide visual 
and sound input to an operator. The operator could control the process 
by manually activating devices on the panel, output (0) devices, such as 
switches and valves. Process control record keeping was also manually 
performed by the operator(s). 
With the development of the computer. process control configurations 
as shown in Figure 3lb. were used. At this point, computers were very 
large and very expensive. The computers were used to enhance the monitoring 
and alarm functions built into the panel board. Some predictive, 
calculation, and report-writing work was also done by the computer. 
However, the control of the process was still manually done by the operator. 
As computer technology improved, the size and cost of the computer 
decreased and actual computer control of the process was first initiated 
in this configuration by having the computer monitor specific set 
points on the panel board instrumentation. With the computer exerting 
some of the control functions, the inputs required for the operator and 
the manual activation required of the operator were reduced. Computergenerated 
records also increased. 
The initial successes in computer applications to process control did 
not lead to a rapid growth in the computer process control field. Unfortunately, 
a lack of understanding of the necessity of a good project 
design. the size and cost of the first computers. and the lack of adequate 
I/O devices to link the process with the computer caused a great many 
frustrations on the part of both computer customers and computer suppliers. 
As a result, the larger computer companies concentrated their

52 
Manual .. 
Records 
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Peck. Anderson, and Banker 
Ponel 
Boord 
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A .R ~ rp:t = Input/Output - Process :3 
uto ecords lCJ 
Figu re 31 Process control systems.

Improved Tablet Production System Design 53 
efforts in the data-processing field, which requires little I/O equipment. 
and computer process control development was relegated to secondary 
importance. 
At the outset of computer control design the first emphasis was to 
make the process fit the available computer devices. The "force-fit" approach 
resulted in computers being advertised and sold to the management 
function of companies who in turn then gave the computers to the engineering 
function to find an application. The computer purchase was generally 
done without an analysis of work to be done followed by the design 
of the best system. With this type of computerization approach failures 
occurred and the frustration between supplier and customer developed and 
added to the technical hurdles hampering the development of computer control 
of processes [25). 
Interest in computer control of processes began to grow when the system-
engineering approach to control design was used. In developing control 
designs, engineering groups began working with computer companies in 
an effort to design control devices to fit the processes as opposed to 
forcing processes to fit the devices. At the same time, major analog instrument 
manufacturers began to manufacture total I/O packages of computer 
hardware and software systems, enabling their products to be used 
for process control. Companies also began to develop the more powerful 
conversational software packages that enabled the process control engineers 
to use the languages without extensive professional programming aid. 
Another prime factor in the growing interest in computer control is the 
current revolution in microelectronic technology [26]. In the early years 
of process control, the designs called for the use of electromechanical devices 
such as relays, timers, and solenoids in conjunction with analog instruments 
such as temperature- and pressure-monitoring devices. All of 
these components were mounted on large panel boards. The systems were 
rarely fUlly automatic and significant operator interaction was required. 
especially if the process went "out-of-spec." 
At times, adding on to the control of a process was difficult simply because 
there was no more room on the panel board. As with any electromechanical 
system, wear and tear, dirt, and heat can take their toll if the 
devices are not carefully and frequently maintained [25). 
Figure 31 illustrates the improved configuration for computer process 
control utilizing the increased capability of computers, their reduced size 
and cost, and the increased availability of I/O control devices. Because of 
the increased amount of control the computer was able to do. the amount of 
reports generated by the computer also increased. The panel board was 
essentially kept for visual display only; the operator received very little 
input, was required to take very little manual action, and made few written 
reports. 
The development of solid-state electronic devices at first improved the 
reliabUity of process control by eliminating mechanical devices. As development 
continued, extensive flexibility in the process control could be developed 
into the controlling devices. In addition, since 1960 the cost of a 
computer divided by its computing power has dropped by a factor of more 
than 100 [27]. 
As computer technology developed, the devices for interfacing the operator 
and the computer developed to the point of eliminating the panel 
board (Fig. 3lD). The televisionlike cathode ray tube (CRT) monitoring 
console expands the visual displays available to the operator, and what

54 Peck, Anderson, and Banker 
Figure 32 Basic devices required for a process control system. 
little process control action is required by the operator can be made at the 
CRT monitoring console. The manual action and report writing by the operator 
are eliminated. 
Basic Process Control Devices 
The hardware required in computer process control can be divided into 
five basic components, and is illustrated schematically in Figure 32. 
SENSORS, First of all. there must be devices to measure the variables 
of the process which must be considered in making control decisions. 
These devices are called sensors and are needed because a process computer 
cannot deal directly with the variables. For example. a computer 
cannot measure temperature directly. Therefore. a sensor must measure 
the temperature and convert (transduce) that information into an electrical 
signal for electronic use [28, 29]  
I/O DEVICES. The second basic device for computer process control 
is an I/O device. This device transforms the signals from the sensors 
into signals that are usable by the computer. In other words, the I/O 
device enables the computer to interface with the outside world. The I/O 
device must also be used to take signals from the computer and convert 
them into action via devices and instruments controlling the process. 
COMPUTER. Programmable Controller, The third device is the computer 
itself. If the process to be controlled consists of numerous sequential 
(logical) steps, then the controlling device can be a first level 
computer device called a logic controller. A logic controller can replace 
the older relay-type control. As long as the process is purely logical J 
the controller will monitor the process step-by-step to the end and then 
go back and run the process over again in the exact same way. The programmable 
controller is the modern logic controller, making the purchase 
of relay logic systems nonadvantageous. Even though relay controllers 
are reliable, every change in the process has to be wired into the system 
by hand. With the modern controllers. a programming change in the controller 
itself can handle a process change [30].

Improved Tablet Production System Design 55 
Microcomputer. Unlike the logic control. which is a simple onloff type 
of control, the next level of control requires that measurements be taken 
during the process, such as pressures and temperatures, that an algorithm 
take those measurements and make some sort of decision, and that 
corrective action be implemented. This type of control is referred to as 
feedback control and is normally the system used in computer control systems. 
The computer device that can first be used in this type of situation 
is the microcomputer. The capacity of a microcomputer is such that a 
device can handle six to 12 feedback loops per process cycle. 
Microcomputer systems are not very flexible unless the design engineers 
learn the particular machine language. Very few microcomputers 
operate in the higher level languages, such as FORTRAN, and microcomputers 
generally do not operate with a universal computer language. 
The basic language of each machine must be learned. 
The flexibility of microcomputers is limited. If 10 processes require 
control, then 10 microcomputers in the plant could control them. However, 
the reality is that with time there could be four or five different microcomputer 
systems controlling the 10 processes, and therefore four or five 
different computer languages in use. The different languages add to the 
confusion When a process change takes place because consideration must 
now also be given to the compatibility of the languages in use. 
The cost of the actual programmable controller and microcomputer devices 
is similar, but the microcomputer will cost more in terms of time to 
program. 
Minicomputer. The number of feedback loops and the speed of the response 
times required in the loops determine the size of the computing 
machine needed. These factors determine when a control system design 
will require the minicomputer. Short response times and numerous loops 
require a minicomputer. 
The distinction between microcomputers and minicomputers is very difficult. 
There are microcomputers that can outperform a minicomputer. 
ACTIVATORS. The fourth basic component of a computer process control 
system is a set of process activators. Activator devices, such as electric 
solenoids. electric motors, and hydraulic valves, take the command 
signals from the computer via the I/O device and turn them into action in 
the process [28]. 
PERIPHERALS. The last basic set of process control components allows 
reports to be printed and information stored, information to be added to 
the control process or the process changed, and the system to be visually 
monitored. These devices are called peripherals, and the term comprises 
such items as disk storage devices, typewriters, printers, card readers, 
keyboards. and CRT screens. 
Distributed Process Control Systems 
DEVELOPMENT. The development of the microcomputer has made it 
possible to place the 110 monitoring and controlling device close to the 
point of use, which has allowed for a basic redesign of process control 
systems (see Fig. 3lE). The control system can now be more sophisticated. 
Plant optimization and management information can be handled by a "host"

56 Peck, Anderson, and Banker 
microcomputer while simultaneously monitoring the process-controlling microcomputers 
distributed throughout the entire process. This type of design 
of computer process control is called distributed control. 
Distributed control systems reduce installation costs by reducing the 
amount of field wiring that must be done in the panel systems. The shorter 
cable runs of the distributed systems also help eliminate the electrical 
interferences that often distort low-voltage electrical signals. The distributed 
system replaces the large panel board in favor of the much smaller 
CRT display. Because of the low cost of microcomputers, each remote unit 
can have an on-line backup unit which will continue the control function 
should the first microcomputer fail, thus increasing the reliability of the 
distributed system over the older systems. The repair of a distributed 
microcomputer is relatively easy. In many cases, a device can be repaired 
by the simple replacement of a printed circuit board [25,31]. 
To change to distributed systems has not come without criticism. Many 
people feel that the distributed systems reduce the number of personnel 
needed to monitor a control system below a safe limit and that in a situation 
of plant upset, several operators working simultaneously on a panel 
board are better able to correct the situation than one person on a single 
CRT  In addition, many people feel that it is a necessity that a panel 
board showing the schematic of the process be used in the monitoring of 
that process [31]. 
CONFIGURATIONS. There are two basic approaches to designing a 
distributed control system: (1) the loop approach, and (2) the unit operation 
approach. In the loop approach, the individual computer is programmed 
to control a specific number of selected functions within the 
process. Similarly. a single computer could be placed in control of a 
single function in several process loops. With the unit operation approach, 
the computer is in control of a single unit operation. The unit operation 
approach has the advantage of being inherently modular and the control of 
a process can be instituted in a stepwise manner. In other words, the 
most critical operation of a process could possibly be controlled by computer 
first and the rest of the process added to the control system as 
time and money allow. 
The host minicomputer and the microcomputers it is monitoring can be 
arranged in anyone of a number of operational configurations. Figure 33 
illustrates some of the configurations used in distributed process control. 
In each configuration. if the host computer fails, the microcomputers can 
continue their control functions. If any of the microcomputers fail, the 
others can continue to communicate to the host computer and continue 
their control functions [31]. 
The major obstacles to computer process control today are 
1. The continued need for smaller computer devices with high 
capabilities 
2. Better I/O interfacing devices 
3. Better operator Imachine interfacing devices 
Process Control Organizations 
Along with the development of computer process control design. hardware, 
and software has come the development of several important related organizations 
that have enhanced. and can continue to enhance, its development:

Improved Tablet Production System Design 
(1) the control engineering functions in manufacturing companies, (2) 
major instrument- and equipment-manufacturing companies able to supply 
both equipment and related control devices, (3) process control groups 
within the major computer manufacturers, and (4) large engineering contractors 
specializing in the design and installation of computer control 
systems (Table 5) [26]. 
Application to Pharmaceutical Processing 
Pharmaceutical manufacturing generally operates in a batch configuration 
with a series or sequence of steps. Most batch operations have a large 
number of simple steps that require the assistance of manufacturing personnel, 
and that assistance is not generally overly challenging. The 
automatic control of the sequential operation can in many situations improve 
the following areas: 
1. Product throughput time 
2. Consistency of acceptable product batch-to-batch 
3. Compliance with OSHA and EPA regulations 
4. Conservation of energy 
(a] Point to Point 
(bl Multiple Drop or Data Bus 
Ie) Hierarchical 
57 
(dl 
[e] Star 
Figure 33 Distributed process control configurations.

58 Peck. Anderson, and Banker 
Table 5 Suppliers of Computer Systems for Process Control 
Bailey Controls 
29801 Euclid Avenue 
Wickliffe; OH 44092 
Fisher Controls Co. 
205 South Center 
Marshalltown, IA 50158 
Foxboro Company 
120 Norfolk Street 
Foxboro, MA 02035 
Honeywell, Inc. 
Process Management Systems Div. 
2222 W. Peoria Avenue 
Phoenix, AZ 85029 
Kaye Instruments 
15 DeAngelo Drive 
Bedford; MA 01730 
Reliance Electric Company 
Control Systems Division 
350 West Wilson Bridge Road 
Worthington, OH 43085 
Taylor Instrument Company 
P.O. Box 110 
Rochester. NY 14692 
5. Reduction of labor 
6. Flexibility to change the batch process control as the process 
changes 
7. Stable plant operation with reduced operational errors and rejected 
product 
8. Reliable control of the process 
From the above list of advantages of automatic control it is obvious 
that the control system must (1) provide good performance characteristics, 
(2) maintain that performance over a long period of time. and (3) be easy 
to install, maintain, troublashoot , and repair [30,32]. 
With the development of the microcromputer and distributed control 
design, several manufacturers of equipment that are used in the pharmaceutical 
industry are supplying microcomputers and controllers with their 
equipment. Not only does some of the equipment increase the efficiency 
of a process as described earlier, but the automatic controller increases 
the reliability of the operative control of the equipment and increases the 
ability of the machine to be interfaced into a computer controlled process. 
The individual control of a specific piece of equipment also offers the 
ability of automating a single-unit operation without automating the entire 
process. Table 6 gives a list of suppliers and their equipment that are 
so controlled. 
Implementation of Computer Control 
NATURE OF THE COMPUTER CONTROL PROJECT. Reducing the frustrations 
in implementing computer process control that were pointed out 
earlier in this section requires a high level of cooperation and communication 
between the various groups involved, especially between the function 
that wants the control and the group charged with designing and installing 
the control.

Improved Tablet Production System Design 
Table 6 Computer-Controlled Pharmaceutical Processing Equipment 
59 
Processing equipment 
Automatic particle inspection for ampuls and 
vials 
Automatic tablet checker 
Automatic tablet-coating system 
Automatic tablet sugar-coating module 
Compu - Coat II coating system 
Dataplus 2000 control system 
Fette tableting presses 
Fitzaire fluid-bed dryer 
Flo-Coater fluid-bed spray granulator 
Fluidaire fluid air dryer 
Hata Rotary tableting presses 
Hi-Coater tablet-coating system 
Pharmakontroll rotary press monitor 
Thomas tablet sentinel 
Developing company 
Eisai USA, Inc. 
Fuji Electric Co., Ltd. 
Graco, Inc. 
Vector Corp. 
Thomas Engineering 
Glatt Air Techniques 
Raymond Automation 
Fitpatrick Co. 
Vector Corp. 
Fluidaire 
Elizabeth-Hata 
Vector Corp. 
Emil Korsch oHG. Berlin 
Thomas Engineering 
The initial request or interest for some level of automatic process control 
will probably come from a research and development, production, or 
production support function within a company which thinks that a product 
can be produced better and/or quicker if computer control of the process 
were instituted. 
Some engineering function of the company will then have the responsibility 
for putting the desires of the production request into operation. 
The engineering function responsibility is to work with the process 
group to supply the mechanics of accomplishing the task required by the 
process group. The responsibility of the process group is to supply the 
engineering function with enough information about the process and the 
influences of the process on the quality of the product so that the engineering 
function can make the best decisions in securing the appropriate 
mechanics to accomplish the task. 
THE IMPORTANCE OF COMMUNICATION. At the very outset of the 
control project design it is essential that communications be definite and 
clear. The first thing to realize is that in most companies the production 
and engineering functions speak different "languages ;" 
The language problem stems from the fact that both the processing 
group and the engineering group use terms unique to their functions. 
The language probem can become worse when the topic of computers and 
the associated technologies are discussed. The vocabulary of data 
processing and process control is developing as fast as the technology it

60 Peck, Anderson. and Banker 
describes. The processing group should be aware of the engineering 
group1s understanding of processing terminology. Likewise, the engineering 
group should be sensitive to a possible lack of understanding of engineering 
terminology within the processing group. Differences in termin010gy 
familiarity between groups should be minimized by education or communication 
style so that the communication between groups during the 
project can take place on a common level of understanding and be fully 
productive. 
A short glossary of computer terms [33] has been included (Table 7) 
to exemplify the language problem that can exist and perhaps initiate a 
familiarization of "computerese. If 
The process group must first specify. in detail, how the process requiring 
change is now being run. The engineering function wID reqgire 
such information as the equipment presently being used, the number of 
persons involved in the process, the exact details of each process step. 
and the effects of process steps on the final product quality. 
The next information required is how the process needs to be 
changed. The process group does not need to indicate how the change 
wID be accomplished, but should spell out in detail what changes are required 
in the old process. 
Because of the data-processing capabilities of a computer, reports 
can be generated during the process that can be used to tell the process 
operator what is going on in the process. Data from such reports can be 
used for quality control records and other data could be used to make decisions. 
To eliminate the frustrations of future reprogramming, project 
cost overruns, specifying a computer with inadequate memory capacity, 
creating unhappy groups that cannot get the reports they want, the specifics 
of the reports to be generated during the process must be decided 
before the engineering group can specify the mechanics of the process 
control system. Such things as the type, number. frequency, and mode 
(pictures, listings, hard copy, black and white CRT. color CRT) of the 
reports need to be considered in deta:il and specified. 
The report that deta:ils all of the process control objectives and requirements 
is sometimes referred to as the functional specification (funet 
spec). To reinforce the need for detail in writing this document. a good 
rule-of-thumb is to ask for every statement made: Can anyone assume 
anything in what has just been written? If assumptions can be made, 
then the statement is not detailed enough. If assumptions can be made, 
then the engineering function is forced to make decisions about a process 
that they probably know very little about, especially as it pertains to 
final product quality. Therefore, the people charged with writing the 
funct spec must take great pains to detail the process so that engineering 
does not make an erroneous assumption and jeopardize the quality of the 
final product. 
With the funct spec in hand the engineering function can gain an understanding 
of the process and what is wanted, and can proceed to determine 
what equipment and technology is available or has to be invented 
to accomplish the goal established. The engineering function will also 
place a price tag on the project. If the cost of the control project is too 
great, the funct spec may be rewritten to scale down the size of the 
project and, hopefully, the cost. 
The communication of the "needs" and the costs of satisfying those 
needs are often continued until the exact needs of the process group are

Improved Tablet Production System Design 
Table 7 Glossary of Computer Terms 
61 
Access time 
Address 
Architecture 
Batch processing 
Binary 
Bit 
Byte: 
Core memory 
CPU 
CRT display 
Data 
Diagnostics 
Digital circuits 
Disk memory 
Downtime 
EDP 
Floppy disk 
The time needed to retrieve information from the 
computer. 
The number indicating where specific information 
is stored in the computer's memory 
A purely conceptual term signifying the fundamental 
design aspects of a computer system. 
Literally, a batch of programs or data which has 
been accumulated in advance and is processed 
during a later computer run. 
A number system based solely on ones and zeros 
(base 2). 
The smallest information unit that a computer can 
recognize; 1 or O. 
A byte is an arrangement of 8 bits. 
Using small magnetic doughnuts, or cores, as its 
storage element, core memory preceded semiconductor 
memory in the evolution of computer technology 
and is now largely obsolete. 
(Central processing unit) The part of the computer 
that controls the interpretation and execution 
of the processing instructions. 
(Cathode ray tube) A televisionlike screen which 
may be used for viewing data while they are being 
entered into or retrieved from a computer. 
The raw information within a computer system. 
Programs for detecting and isolating a malfunction 
or mistake in the computer system; features that 
allow systems or equipment to self-test for flaws. 
Electronic circuits providing only two values as 
an output, one or zero, and nothing else. 
Memory using rotating plates on which to store 
data and programs. 
The time during which a computer is not operating 
because of malfunctions, as opposed to the 
time during which it is functionally available but 
idle. 
(Electronic data processing) The transformation 
of raw data into useful data by electronic equipment; 
sometimes referred to as ADP, or automatic 
data processing. 
A component similar to a 45 rpm record made of 
flexible material and used for storing computer 
data.

Table 7 (Continued) 
GIGO (Garbage in, garbage out) A shorthand expression 
meaning that if you put in incorrect or 
sloppy data, you will get incorrect or sloppy 
answers; originally contrived to establish that 
errors are always the user's fault, never the 
computer's. 
Hard copy Computer output recorded in permanent form, 
such as the paper copy produced by a printer. 
Hardware The physical components of the computerprocessing 
system, for example, mechanical, 
magnetic, electrical, or electronic devices. 
Ie (Integrated circuit) A digital electronic circuit 
or combination of circuits deposited on Semiconductor 
material; the physical basis of a computer's 
intelligence and the key to the microelectronic 
revolution in computers. 
Input The data that is entered into the computer; the 
act of entering data. 
Instruction A group of bits that designates a specific computer 
operation. 
Intelligent terminal 
Interface 
K
Language 
Language, BASIC 
Language, COBOL 
Language, FORTRAN 
Language, Machine 
Mainframe 

Memory 
A typewriter with a television screen attached to 
it that can remember things, do calculations. type 
letters, communicate with other intelligent terminals. 
draw pictures. and even make decisions. 
The juncture at which two computer entities meet 
and interact with each other; the process of 
causing two computer entities to intersect. 
Equals 1024 bytes. 
A set of words and the rules for their use that 
is understood by the computer and operator alike 
for programming use. 
An easy-to-use high-level programming language 
that is popular with the personal computer systems 
(Beginners All-Purpose Symbolic Instruction 
Code)  
A high-level programming language widely used 
in business applications (Common Business 
Oriented Language). 
A high -level programming language designed to 
facnitate scientific and engineering problem 
solving (Formula Translation). 
The language. patterns of ones and zeros. directly 
intelligible to a computer. 
A large computer. as compared to minicomputers 
and microcomputers. 
The selection of the computer Where instructions 
and data are stored; synonymous with storage.

Improved Tablet Production System Design 
Table 7 (Continued) 
63 
Memory cap acity 
Microcomputer 
Minicomputer 
Nibble 
Output 
Peripheral 
Program 
Realtime 
Semiconductor 
Software 
Storage 
System 
Terminal 
Throughput 
Timesharing 
Turnaround time 
Word 
Word length 
Word processor 
The maximum number of storage positions (bytes) 
in a computer memory. 
A small computer in which the CPU is an integrated 
circuit deposited on a silicon chip. 
A computer that is usually larger, more powerful, 
and costlier than a microcomputer but is not 
comparable to a mainframe in terms of productivity 
and range of functions. 
A nibble is an arrangement of 4 bits. 
The information generated by the computer. 
A device, for example, a CRT or printer, used 
for storing data. entering it into or retrieving it 
from the computer system. 
A set of coded instructions directing a computer 
to perform a particular function. 
The fmmedlate processing of data as it is entered 
into the oomputer-, 
A material having an electrical conductivity between 
that of a metal and an insulator; it is used 
in the manufacture of solid state devices such as 
diodes. transistors, and the complex integrated 
circuits that make up computer digital circuits. 
A general term for computer programs, procedural 
rules and, sometimes, the documentation 
involved in the operation of a computer. 
See Memory. 
The computer and all its related components. 
A peripheral device through which information is 
entered into or extracted from the computer. 
A measure of the amount of work that can be accomplished 
by a computer during a given period 
of time. 
The method that allows for many operators using 
separate terminals to use a computer simultaneously. 
The time between the initiation of a computer job 
and its completion. 
A group of bits that the computer treats as a 
single unit. 
The number of bits in a computer word. 
An automatic typewriter, often equipped with a 
video display screen. on which it is possible to 
edit and rearrange text before having it printed.

64 Peck, Anderson. and Banker 
refined to within budget constraints. The costs of the new control system 
must be justified by the improvements brought about by the new 
process. 
At this point in the project, the hardest and the most time-consuming 
part has been completed. The remainder of the project, including specifying 
and ordering the actual control devices, writing and checking the 
computer control programs, and installing and checking the system, becomes, 
in comparison. a minor part of the project providing the initial 
background work has been done properly [31,32]. 
ROLE OF THE INDUSTRIAL PHARMACIST. In the introduction to this 
chapter reference was made to the industrial pharmacist/scientist being 
aware of certain areas from which process efficiencies could be developed 
and, with such an awareness, being able to function with the engineering 
group within a pharmaceutical firm to help improve the manufacturing 
processes. As the development of computer process control grows and is 
applied to pharmaceutical processes. the role of the pharmacist grows even 
larger. The unique awareness of the impact and influence of a manufacturing 
process on the safety and efficacy of a final drug dosage form is 
the sole reponsibility of the industrial pharmacist. In the age of computer 
control the industrial pharmacist will have to know in detail how each unit 
operation in the manufacture of a drug product can influence the final 
drug product and what parameters within a unit operation are important 
and should be monitored and controlled to produce reliable drugs. The 
indu strial pharmacist will play an important role in helping to develop the 
increasing role of computer process control in the pharmaceutical industry. 
IV. VALIDATiON 
Validation as a concept and a system of procedures came into being in the 
pharmaceutical industry to ensure the sternity of parenteral and other 
atezile products. Basically, the system involved placing sensors and 
measuring devices in all the critical locations or recording sites within 
sterilizers to accurately record temperature (or other conditions impacting 
on the attainment of sterility) so that following a sterilization cycle with a 
particular product. in a particular container, under full production conditions, 
examination of the records of the sterilization conditions would provide 
absolute assurance that sternization was achieved in every product 
unit so processed. Validation requires previously establishing, in such 
sterilization applications. the permutations and combinations of conditions 
(time, temperature, steam pressure, cycle conditions. ete .) which will 
produce sternity with a very high degree of certainty. Thereafter. recorded 
data from each production sternization run provide the documentation 
that all units within all regions of the sterilizer were exposed to conditions 
that have clearly been established and documented by careful previous 
experimentation to produce sterility. 
Currently. validation concepts are being recognized for their value in 
helping to assure the quality features of classes of drug products other 
than sterile products. Validation procedures are being applied to solid 
oral dosage forms and especially to compressed tablets. Validation is 
most important in tablet products in which manufacturing process conditions 
are known to have the potential to affect important product quality

Improved Tablet ProducUon System Design 65 
features, such as bioavailability. Thus, in the design of a new tablet 
product and its method of manufacture, or as the design of process for 
the manufacture of tablets is improved and evaluated, it will be necessary 
to consider the concept of validation. It is increasingly recognized that 
an adequate process for the pharmaceutical product is a validated process. 
A definition currently in use by the Food and Drug Administration is: 
"A validated manufacturing process is one which has been proved to do 
what it is purported or represented to do. The proof of validation is obtained 
through the collection or evaluation of data preferably from the 
process and the developmental phase and continuing through into the production 
phase" [34]. While the FDA definition is for a validated manufacturing 
process, it suggests by reference to a developmental phase that 
validation involves more than the actual production process. Indeed this 
would be so for most tablet products. 
Inherent in any discussion of validation is the assumption that the 
product involved is well understood and that the essential design parameters 
are under control. Validation, therefore, is not indep endent of product 
formulation. It is not enough to start thinking about validation when 
a formulation is turned over to a pilot plant or production group. It is 
essential that the development pharmacist or pharmaceutical scientist be 
knowledgeable not only in formulation and physical pharmacy, but also in 
pharmaceutical processing and manufacturing operations. Otherwise an 
experimental formula may be developed whereby the qualrty features of the 
product are very sensitive to the manufacturing conditions and variables 
routinely and normally encountered in practice, or involves such a large 
number of variables impacting on assorted quality features that validation 
becomes difficult or impossible. 
There are pharmaceutical products currently being marketed that cannot 
be Validated based on their design. Included in this group are some 
sustained-release products, which involve a sequence of steps whereby 
powdered drug is dusted on sugar beads with other mixed hydrophilic and 
hydrophobic powders, employing a "binder" of polymers, fats, waxes, and 
possibly shellac in a mixed solvent (sometimes including water plus organic 
solvents), followed by addition of a retard coating, again using fats, 
waxes, and polymers in varying stages of solution and dispersion. In 
such systems, simply controlling rates of powder addition, Iiquid binder, 
addition, spray-gun conditions, and geometry in the coating pan, or 
other processing conditions will not lead to validation. When the binder 
and retard dispersions vary as to extent of polymer, fat, wax hydration! 
solvation in each batch, and are not and cannot be controlled (a formulation 
factor), no degree of process manufacturing control can produce a 
controlled product. Furthermore, as the number of variables which can 
influence product quality increase (both process and formulation variables), 
the number of interaction effects capable of producing further (and often 
less predictable) effects increase in an exponential manner. Validation of 
such systems becomes a true nightmare. 
Another design parameter that must be studied in development is the 
establishment of raw materials specifications. If raw materials specifications 
are inadequate, no amount of process validation can ensure a satisfactory 
product. Thus, an important responsibility of the development 
group is to determine that the physical and chemical specifications for all 
active and excipient materials have been adequately set. For example, 
where polymers are employed, have molecular weight, degree of SUbstitution

66 Peck, Anderson, and Banker 
of chemical groups, and polymer grade, including purity, been adequately 
defined? Does the nature of the product or method of manufacture require 
special specifications for the drug or excipients (such as a particular 
particle size or particle size distribution for drugs Which are to be 
directly compressed or which have dissolution or bioavailability problems)? 
Are special precautions required for a drug having chemical instability or 
reactivity potential (such as lower moisture content limits for excipients to 
be combined with a hydrolyzable drug)? Unless such formulation or drugrelated 
variables, which can by themselves influence product quality features 
or do so by interacting with processing variables, are identified and 
appropriate specification limits set in place, no level of subsequent process 
control and validation can lead to a reproducible product. 
Two approaches may be taken to determine the specifications that are 
adequate for raw materials after the need for such critical specifications 
has been identified. The first approach is to set the most rigid specification 
far that property that could reasonably be achieved. The advantage 
of this approach is that it is direct, reasonably simple. and requires minimal 
experimentation. The disadvantage is that this approach may represent 
overkill, and unnecessary costs or undue limitation of suppliers. The 
second approach involves conducting well-designed experiments to determine 
where the critical specification(s) should be set. Vary the specification 
in question for the raw material, employing the most rigid value that 
could reasonably be achieved as one specification, relax that specification 
for another sample of the material to a value that might be expected to be 
borderline. and use an intermediate specification for perhaps a third 
sample of the material. Make product of each raw material, employing 
manufacturing conditions in each case that would be expected to impact 
least favorably with the critical product quality features being examined. 
Review the data from the experiments and determine whether the most 
rigid specification is actually necessary, or whether the intermediate specification 
will suffice, or whether the least rigid specification is adequate. 
This approach is most useful when the development pharmacist has an accurate 
understanding of the product system in question and its ultimate, 
exact method of manufacture, and can project the range of processing 
variables the product may be subjected to and the effect of the direction 
of such process variations on the quality feature in question. Ideally, 
raw materials specifications will be appropriately set before a product is 
placed in production for process validation. When appropriate standards 
have not been established for raw materials specifications, and where such 
variation in raw materials is significantly impacting on product quality features, 
attempts to achieve process validation through control of the manufacturing 
operation can become an exercise in futility. 
Experienced development and production personnel of most companies 
can recite case studies in which a new product could be made on a small 
scale in the laboratory but could not be reliably reproduced in production. 
A different type of frustration is expressed, depending on whether the account 
is told by the development person or by the production person. 
Production personnel have a powerful argument at their disposal against 
accepting any product and/or manufacturing procedure that defies or does 
not reasonably lend itself to Validation. It is imperative that R&D and 
production groups work together to see that validation can be and is 
achieved.

Improved Tablet Production System Design 67 
As the validation concept is applied to pharmaceutical products of increasing 
complexity of design and manufacture. it is very clear that validation 
must be initiated at a very early stage in the design of any product. 
not only from the traditional "process" orientation, but also from a "product" 
orientation. Based on this philosophy. validation may be defined as a 
systematic approach to ensuring product quality, by identifying process 
variables that influence product qualtty features. in order to establish 
processing methods and the necessary control of these methods, which 
when followed will assure meeting all product quality specifications after assuming 
that the formulation is reasonable and that the raw material specifications 
are adequate. 
A. Validation Priorities 
Perhaps the initial step in validation is to consider which product most requires 
a full validation treatment and which least. Validation efforts could 
be centered on processes that involve a company's largest selling and most 
commercially important products. Products containing drug(s) with a very 
low dose. chemical instability. low solubility or poor wetting properties. 
which can lead to content uniformity, stability. or bioavailability problems; 
products with a history of production problems. often bordering on being 
unacceptable. or which unaccountably produce occasional lots that are unacceptable 
or borderline; sustained or controlled release products whose 
processes are not under control should have a high validation priority. In 
other words, the initial validation effort could be focused to provide the 
greatest beneficial effect. 
Another approach to validation priority setting is to review the documentation 
and data currently available on present products and start validating 
those products which can be done the quickest and easiest. For 
example. a product that has a moderate dose (perhaps 25 to 150 or 200 
mg) of a very soluble. stable drug. which is readily compressible and has 
no bioavailability or other problems. and which has been made for years 
by direct compression. with no history of a defective batch. while readily 
meeting all product specifications. might be easily validated with historic 
data. This approach can be advantageous in that validation concepts are 
learned with the easier projects before more complex validations are 
undertaken. 
B. Steps in Validation 
Step 1 
Identify all the quality features and specifications which will or do define 
product quanty and acceptability. final product as well as in-process 
specifications (see Table 8 for examples of in-process product specifications 
as well as process control parameters). 
The first step in validation is thus to be certain that specifications 
have been appropriately set to define the primary product quality features 
and to establish their limitS of acceptability. Specifications may be set on 
intermediate materials as well as on the finished product. For example. a 
variety of specifications may be placed on the powder mixture or granulation. 
in addition to the specifications which are placed on the final tablet

68 Peck. Anderson. and Banker 
Table 8 Unit Operations and Possible Control Tests Associated with the 
Manufacture of a Wet-Granulated Compressed Tablet 
Process variable 
Screening 
Mixing 
Granulating 
Drying (oven) 
Size reduction 
Compression 
Purpose 
Ensure a set particle 
size of raw material 
Homogeneous mixture 
Convert powders to 
granules having 
suitable flow and 
compressive properties 
Reduce moisture content 
to proper level for compression 
Size reduction 
Manufacture of 
compressed tablet 
Test parameters 
1- Mesh analysis 
2. Bulk volume 
1. Mesh analysis 
2. Chemical content 
uniformity analysis 
3. Yield reconciliations 
1- Weight per subpart 
2. Amount of granulating 
agent per subpart 
3. Endpoint of batch 
4. Mixing time 
5. Granule size (wet) 
1- Weight per tray 
2. Thickness per tray 
3. Relative humidity of 
air 
4. Velocity of air 
5. Time 
6. Loss on drying 
7. Yield reconciliation 
1. Bulk volume 
2. Flow 
3. Mesh analysis 
4. Yield reconciliation 
5. Loss on drying 
1- Weight/10 tablets 
2. Hardness 
3. Thickness 
4. Appearance 
5. Disintegration 
6. Dissolution 
7. Weight variation 
8. Content uniformity 
9. Friability 
10. Compressional force 
II. Tablets per minute 
12. Yield reconciliation 
13. I\arl Fischer/loss on 
dr-ying

Improved Tablet Production System Design 69 
product. It is important that the list of specifications be sufficiently full 
and complete to assure full eompendial , new drug application (NDA), or 
company standards. Not all product specifications come under validation 
treatment. Some product specifications bear on purity and generally are 
not influenced by processing; they bear on raw material quality and 
specifications. Other quality features may not be sensitive to processing 
condition variations and thus may not be included in the validation treatment 
or are of minor concern in such treatment. An example might be a 
tablet which is formulated such that compressional force. under any projected 
range of compressive loads, has no significant influence on tablet 
disintegration or drug dissolution rate. 
Quality features for tablets have been addressed throughout the chapters 
in this series of books and will not be repeated here, other than to 
note that they should usually include, as a minimum for an oral uncoated 
tablet, weight variation, content uniformity. hardness, friability, disintegration-
dissolution specifications, and size uniformity. 
Identification of critical product quality features for tablet products 
must be treated as a separate undertaking for each and every product. 
No standard or master approach exists. For example, not all tablet products 
have fr.ability problems. In fact. the great majority do not, and 
friability may then be discounted as a feature in the Validation program. 
Rate of drug dissolution. as it relates to the rate and completeness of bioavailability, 
and assurance of consistency of bioavailability from lot to lot 
may be of great concern for some tablet products and of little or minor 
concern for others. 
Dissolution might reasonably be expected to be of great concern in situations 
of potential bioavailability. such as with a very slightly soluble 
acidic drug moiety which has an intermediate to large dose and is only well 
absorbed in the upper gastrointestinal tract. In such a case, great attention 
must be paid to such factors as methods of wet massing. how binders 
are incorporated in the product, wet massing times. or the granulation 
method employed. rate of compression, consistency of feeding granulation 
to the dies, compressive force, particle size and particle size control, 
methods of incorporating disintegrants, and other factors depending on the 
method of tablet manufacture. On the other hand. the assured achievement 
of content uniformity in such a large-dose product, through an extensive 
validation program. might be totally unnecessary or of minimal 
concern. 
The concerns of product qualtty might be just the reverse with a low 
dose of a highly soluble amine drug which is well absorbed along the 
gastrointestinal tract. Bioavailability assurance through validation might 
be completely unnecessary and pointless. but in comparison to the acidic 
high-dose drug previously described, content uniformity may now become 
the primary concern and focus of the validation efforts. In other situations. 
validation of both bioavailability and content uniformity goals might 
be warranted and in some situations neither of these quality features is 
of major concern because they are readily achieved under all conceivable 
permutations and combinations of processing conditions that could be imagined 
for the product. 
The situations given above are intended to point out that the critical 
quality features are matters to be identified for each and every product. 
These critical quality features may depend on the pharmacokinetic properties 
of the drug (including but not limited to where and how the drug

70 Peck, Anderson, and Banker 
is absorbed). physical chemical properties of the drug, drug dose, and 
chemical stability of the drug. 
Step 2 
Review product performance against the proposed specifications. After describing 
the quality features which must be achieved in the product and 
the minimum acceptable values for each such feature, the specifications 
developed for that product should be reviewed and agreed upon as being 
appropriate and reasonable by knowledgeable people in research and development. 
production. and quality assurance. 
Another point that might be reviewed in this step is whether or not 
the product in question has sets of specifications which constitute possibly 
critical ncompeting objectives. n NelU'ly all tablet products do have competing 
objectives. For example, if during the manufacture of a hard, nonfriable, 
nondusting uncoated tablet these quality features arc enhanced. 
then the rapid tablet disintegration and drug dissolution release rate quality 
features would be expected to degrade and even become unacceptable. 
Another type of competing objectives circumstance is encountered with 
insoluble antacids. Most insoluble antacids exist as very fine powders 
which have very poor compressibility. Their effectiveness is related to 
their fine particle size and large surface. which is directly related to their 
ability to neutralize gastric acid. Any steps which are taken to facilitate 
compression by enhancing particle consolidation may be expected to reduce 
the activity of such antacids. 
Thus, processing procedures such as precompression, increased punch 
dwell time, increased pressure, or procedures used to increase granule 
bonding cannot benefit both sets of quality features simultaneously because 
these processing effects will produce competing effects on the two sets of 
quality features, no matter how the processing effects are controlled. 
Fortunately. through proper formulation such competing objectives are not 
difficult to handle for most drugs. However. when the occasional drug 
comes along with such traits as a large dose, low solubility, poor wetting, 
borderline bioavailability, and poor compression properties, the fact that 
one is dealing with competing objectives cannot be ignored, and should be 
carefully considered in the design of the validation protocol. 
Step 3 
Identify the methodology, processes. and pieces of equipment that are or 
will be used in the manufacture of the product(s). 
Once the product quality and acceptability standards have been established 
in steps 1 and 2, the process that manufactures the product must 
be thoroughly identified. If a tablet is made by direct compression, the 
process wUl differ significantly in the unit operations involved as compared 
with wet granulation. Not only must the processes that impact directly on 
the manufacture of the product be identified but those systems that support 
the process and thereby have an indirect impact on the process must 
be identified. Table 9 lists some of the associated systems that support 
tablet production and could have an impact on tablet validation considerations.

Improved Tablet Production System Design 
Table 9 Support Systems Associated with 
the Manufacture of Pharmaceutical Solid 
Dosage Forms 
Heating, ventilation, air conditioning (HVAC) 
Periodic maintenance systems 
Water systems 
Compressed gas systems (air) 
Cleaning systems 
Vacuum systems 
Electrical 
Drainage 
Dispensing of raw material 
Paperwork systems 
Personnel training 
Computer process control 
Special environmental protection systems 
71 
Step 4 
Identify the potentially relevant and critical process variables. The information 
base for this step in the total product validation is the list of 
specifications and limits for the quality features which have been placed on 
the product. together with the basic manufacturing process. formulation, 
and raw materials specifications which were previously set. A knowledgeable 
development pharmacist can usually look at the product specifications 
and manufacturing method, and predict the process variables and process 
steps which will have the greatest potential for impacting on the particular 
specifications for the product. The processing steps and control of these 
steps which are expected to impact most directly on primary product objectives. 
such as bioavailability or drug dissolution rate, should receive 
the closest attention. Examples of the types of processing variables which 
should be considered for particular product specifications are binder concentration, 
granule density, optimal mixing time, mill settings, and others. . 
Step 5 
Conduct the process validation experiments. Before validation experiments 
can be performed. the various pieces of equipment used in the different 
unit operations of the process must be certified to operate as they were 
designed to. In addition, any auxiliary equipment operation-monitoring

72 Peck, Anderson, and Banker 
instruments such as ammeters, wattmeters, rpm indicators, chart recorders, 
and temperature indicators must be in working condition and calibrated. 
While equipment certification should be a responsibility of a company's engineering 
function, those involved in the validation project must be sure 
that the certification is performed to ensure that the equipment used in the 
validation studies will function reliably. 
The next step is to undertake well-designed and controlled experiments 
to establish the influence of the processing variables and combinations of 
variables on the quality features of the product. A variety of approaches 
can be taken, from full mathematical/statistical optimization, with the system 
actually being modeled, to a relatively few determinations for a drug 
having no bioavailability or manufacturing problems. Validation in the 
latter case may simply involve the documentation of current process controls 
and a historic review of the product's acceptance test records. 
When the validation project becomes more complex. such as where competing 
objectives exist, or where cause and effect relationships are not 
obvious. the following general approach is suggested in order to develop a 
validation protocol. 
1. Establish preliminary limits on each processing procedure, above 
and below which you never expect to go in practice. In some cases it will 
be possible to set an exact single specification for a processing procedure. 
such as a given mixing time. In other cases a range will be required and 
it should be set as noted above. A range should be used when an exact 
condition cannot be achieved, as in the volumes of granulating agent used. 
wet-massing times, tablet machine and coating pan speeds, coating weights. 
temperatures. or airflow rates. When such processing conditions are expected 
to impact on quality features. and where exact control is not feasible. 
project or determine the maximum range that might be reasonably expected 
to be encountered in practice (remember, future production runs must be 
inside these ranges or the product will be "outside validation II)  
2. Examine the listing of limits from the preceding step in light of the 
most critical product quality features you are to achieve. Select the 
processing variables and combination of variables along with their respective 
limits which you would expect to impact least favorably on these quality 
features and make the product under those conditions. Examine to see if 
any extremes of the above processing conditions or combination of extremes 
of processing conditions place the product outside the acceptance specifications 
for any parameter. 
Step 6 
Review. monitor, and revalidate as needed. Once a process has been validated 
it is necessary to continuously monitor the parameters controlling the 
process. If instruments are used they must be calibrated on a routine 
basis. Equipment must receive periodic maintenance so that performance 
does not change. Care must also be taken that no part of the process is 
changed. A process change. improvement or otherwise, must be revalidated. 
Constant review of all specifications, product and process, is also 
necessary to enable the specifications to be "tightened1I or "broadened" to 
enhance the total validated system.

Improved Tablet Production System Design 
ACKNOWLEDCMENT 
Special acknowledgment to Mr. Ken Main t P.E . t Division Electrical Bngineer, 
Aluminum Company of America, Alcoa, Tennessee, for his help and 
insight in the development of the computer process control section. 
APPENDIX: LIST OF MANUFACTURERS 
73 
Mixer/G ranulator 
Drydispenser 
Jaygo, Inc. 
199 Seventh Avenue 
Hawthorne, NJ 07506 
Diosna 
Dierks and Sohne 
45 Osnabruck 
Sandbachstrasse 1 
West Germany 
Lodige Mixer/Granulator 
MGT Vertical Mixer/Granulator 
Littleford Brothers, Inc. 
15 Empire Drive 
Florence, Kentucky 41042 
Fielder Mixer/Granulator 
Raymond Automation Co. 
508 Westport Avenue 
Norwalk, Connecticut 06856 
Gral Mixer /Granulator 
Maines Collette, Inc. 
P.O. Box 818 
Wheeling, IL 60090 
Fluid-Bed Cranulator/Dryer 
Aeromatic 
198 Route 206 South 
Somerville, NJ 08876 
Glatt
Glatt Air Techniques, Inc. 
260 West Broadway 
New York. NY 10013 
Freund 
Vector Corp. 
675 44th Street 
Marion, Iowa 52302 
DOUble-Cone and Twin-Shell 
Blenders with liquid feed and 
vacuum drying capabilities 
Double Cone Rota-Cone 
Paul D, Abbe 
146 Center Avenue 
Little Falls, NJ 07424 
Twin Shell Processor 
The Patterson-Kelley ce., Inc. 
Process Equipment Division 
East Stroudsburg, PA 18301 
Nauta Mixer 
Day Mixing Co. 
Cincinnati, Ohio 45212 
L/D Series Blender 
Gemco, Inc. 
301 Smalley Avenue 
Middlesex t NJ 08846 
Specialized Granulation Equipment 
Roto Granulator 
Key International , Inc. 
480 Route 9 
Englishtown, NJ 07726 
Marumerizer 
Luwa Corporation 
4433 Chesapeake Drive 
P.O. Box 16348 
Charlotte, NC 28216

74 
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Peck, Anderson, and Banker 
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3. Schuesaler, O. P., Pharmaceutical Plant Design in Today's Regulatory 
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9. Kamman. J. P., Pharmaceutical Plant Design for GMP and Process 
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10. Vosnek, K. J. and Forbes, R. A., Diosna-Granulating with Wet 
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19. Kristensen, H. G. and Schaefer. T., Drug Dev; Ind. Phar., 13(4,5): 
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20. Hunter, B. M. and Ganderton, D. J. Pharm. Pharmacol., 25(Suppl.): 
71P - 78P (1983). 
21. Lindberg, N. 0., Leander. L., Wenngren. L., Heigesen, H and 
Reenstierna, B., Acta Pharm. Suecica, 11:603-620 (1974).

Improved Tablet Production System Design 75 
22. Leuenberger, H., Bier, H. P., and Sucker, H. B., Pharm. Technol., 
3( 6) :61- 68 (1979). 
23. Leuenberger, Hot Pnarm, Acta Helv., 57:72-82 (1982). 
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28. Travers, D. N., Rogerson, A. G and Jones, T. M., J. Pharm. 
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29. Lindberg, N. 0., Leander, L., and Reenstierna, B., Drug Dev; Ind. 
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35. Staniforth, J. Nq Walker, S., and Flanders, P q Int. J. Pharm., 
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73: 420 - 421 (1984). 
38. Fry, W. C., Stanger, W. C., Wu, P. P., and Wichman, K. C., 
Computer-Interfaced Capacitive Sensor for Monitoring the Granulation 
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Lafayette, Indiana, September 13-15. 1978.

2
Coating of Pharmaceutical 
Solid-Dosage Forms 
Stuart C. Porter and Charles H. Bruno 
Coloreon, West Point, Pennsylvania 
I. INTRODUCTION 
The application of coatings to the surface of pharmaceutical solid-dosage 
forms. especially tablets. has been practiced for over 150 years. 
Although such a process is often applied to a dosage form that is 
functionally complete I and thus may cause US to reflect on the need for 
incurring the additional expense. it is evident that the continued use of 
coating processes in pharmaceutical production remains very popular. 
Such popularity relates to the many benefits obtained when a dosage form 
is coated, which include: 
Improved esthetic qualities of the product 
Masking of unpleasant taste and odor 
Enabling the product to be more easily swallowed by the patient 
Facilitating handling. particularly in high-speed filling Ipackaging 
lines 
Improving product stability 
Modifying drug-release characteristics 
Over the course of time. coating processes have developed from the 
art of earlier years to those that are more technologically advanced and 
controlled such that compliance with good manufacturing practices (GMPs) 
is facilitated. The design of new equipment, the development of new 
coating materials. and the recognition of the impact of applied coatings 
on subsequent release of drug from the dosage form have all contributed 
to improved products. 
77

78 Porter and Bruno 
Changes that have occurred in coating processes reflect a desire to; 
Consistently obtain a finished product of high and reproducible 
quality 
Achieve processes in which the economics are maximized, particularly 
with respect to process times and equipment utilization 
While the methods for applying coatings to solid-dosage forms are 
varied. and some are described elsewhere in this book, this chapter will 
focus on the processes of sugar coating and film coating. and will discuss 
these processes with respect to; 
Raw materials 
Application techniques 
Potential problems 
Available coating equipment 
II. SUCAR COATINC 
A. Introduction 
The process of su gar coating, which has its origms in the confectionery 
industry. is perhaps one of the oldest pharmaceutical processes still in 
existence. 
Although in recent years modernization of the process with respect to 
panning equipment and automation has taken place, sugar coating is still 
considered to be more of an art rather than a science. 
While methods (and materials) for coatings date back over 1000 years 
(early Islam makes reference to pill coatings based on mucillage of 
psyllium seeds), the current pharmaceutical process of sugar coating 
originated in the middle of the nineteenth century when sugar as a raw 
material became plentiful, and the forerunner of modern panning equipment 
was invented. 
Although the tendency is to produce pharmaceutical coating pans from 
stainless steel, early pans were made from copper because drying was effected 
by means of an externally applied heat source. Current thinking, 
even with conventional pans, is to dry the coated tablets with a supply 
of heated air and to extract the moisture and dust-laden air from the 
vicinity of the pan. 
Although the sugar-coating process has experienced declining popUlarity 
in the United States, it is still retained by many companies worldwide, 
since many advantages can be realized, including: 
Raw materials are inexpensive and readily available 
Raw materials are widely accepted with few regulatory problems (with 
the exception of perhaps colors) 
Inexpensive, simple equipment can be used 
Sugar-coated products are esthetically pleasing and have wide consumer 
acceptability 
The process is generally not as critical (as film coating) and recovery 
(or rework) procedures are more readily accomplished

Coating of Pharmaceutical Solid-Dosage Forms 
However, in spite of the relative simplicity of the sugar-coating 
process, it does have some potential shortcomings, for example: 
79 
The size and weight of the finished product results in increased packaging 
and shipping costs 
The brittleness of the coatings renders the coated tablets susceptible 
to potential damage if mishandled 
The achievement of high esthetic quality often requires the services of 
highly skilled coating operators 
The final gloss is achieved by a polishing step which can make imprinting 
difficult 
The inherent complexity (from the standpoint of the variety of procedures 
and formulations used) of the process makes automation 
more difficult 
In spite of these difficulties, many companies have made excellent use 
of modern process technology (including automation), so that the requirements 
of current GMPs, including documentation, are readily achieved with 
a high degree of reproducibility in the quality and performance of the 
finished product. 
B. Raw Materials Used in Sugar Coating 
As expected, the major ingredient used is sugar (sucrose), although this 
may be substituted by other materials (such as sorbitol) for low caloriel 
diabetic products (typically in the candy industry). Sugar-coating formulations 
are for the most part aqueous. 
The sugar-coating process consists of various steps, each designed to 
achieve a particular function. Consequently, a variety of additives may 
be incorporated into each type of formulation. Examples of such additives 
are: 
Fillers (calcium carbonate, talc, titanium dioxide) 
Colorants (dyes, aluminum lakes, iron oxides, titanium dioxide) 
Film formers (acacia, gelatin, cellulose derivatives) 
Antiadhesives (talc) 
Flavors 
Surfactants (as wetting agents and dispersion aids) 
Although most of the coating formulations used in the sugar-coating 
process are applied as liquids, some (e.g., dusting powders) are applied 
dry.
A typical sugar-coating process encompasses five stages: 
1. Sealing 
2. Subeoatdng 
3. Grossing 
4. Color coating 
5. Polishing 
While each of these stages is varied, the common feature throughout 
is that the process requires repeated applications of coating liquid, each

80 Porter and Bruno 
application followed by a period during which the tablets are allowed to 
tumble freely to allow complete distribution of the coating materials. and 
finally. a drying period when moisture is removed from the coating prior 
to the next application. 
Sealing 
Most of the coating formulations used in the sugar-coating process are 
aqueous. whereas tablet cores are typically porous. highly absorbent. and 
formulated to disintegrate rapidly when they make contact with water. 
Consequently. if these cores are not appropriately protected at the outset. 
ultimate product stability (both physical and chemical) can be seriously 
compromised. The purpose of sealing is to offer this initial protection. 
and to prevent some tablet core ingredients from migrating into the coating. 
and ultimately spoiling the appearance of the final product. 
Sealing is accomplished by the application of a polymer-based coating 
(either by ladle or spray techniques) to the surfaces of the tablet cores. 
Examples of polymers that might be used include shellac, zein. hydroxypropyl 
methylcellulose (HPMC), polyvinyl acetate phthalate (PVAP), and 
cellulose acetate phthalate (CAP). These are typically dissolved (at a 
15-30% w/w concentration) in an appropriate organic solvent, preferably 
one of the denatured ethanol products. 
While use of shellac has been universal, this polymer can cause problems. 
One problem results from the fact that shellac can polymerize on 
storage. causing the solUbility characteristics of the coating to change. 
This problem can either be minimized by incorporating PVP into the shellac 
formulation [1] or by using one of the other. more stable polymers (such 
as PVAP). 
When using any of the water-insolUble polymers as the basis for a sealcoat 
formulation. it is important to apply only the minimum quantity of coating 
needed to give the appropriate protection; otherwise drug-release 
characteristics may well be affected. 
When the seal coat is applied by a ladle technique, detackifiers, such 
as talc, are often used to minimize the risk of "twinning" or clumping. 
Overzealous use of talc should be avoided. however, otherwise it might be 
difficult for the subsequent sugar coat to bond to the surface of the seal 
coat.
Finally. if the final product is to have enteric properties, this result 
is usually achieved by using one of the enteric polymers (such as PVAP 
or CAP) as the basis for the seal coat and ensuring that sufficient coating 
material is applied. 
Subcoating 
SUbcoating is the first major step of the sugar-coating process and provides 
the means for rounding off the tablet edges and building up the 
core weight. It also provides the foundation for the remainder of the 
sugar-coating process. with any weakness in the final sugar coat often 
being attributable to weaknesses in the subcoat. 
In order to facilitate this buildup. subcoating formulations almost always 
contain high levels of fillers such as talc. calcium carbonate. calcium 
sulfate, kaolin, and titanium dioxide. In addition, auxiliary film 
formers such as acacia, gelatin, or one of the cellulose derivatives may

Coating of Pharmaceutical Solid-Dosage Forms 81 
- 
Coat~ng 
Coating 
II' 
Figure 1 Schematic of examples of acceptable tablet-core shapes for 
sugar coating. 
also be included in order to improve the structural integrity of the 
coating. 
It is important during subcoattng to get effective coverage of the 
coating material over the tablet corners and on the edges if a quality result 
is to be achieved. To this end. selection of appropriate tablet 
shapes is important. Certainly. tablet shapes which minimize the corners 
(such as tablets compacted on deep concave punches or dual radius 
punches). as shown in Figure 1, can aid in effective coverage. Additionally, 
it is necessary to minimize tablet edge thickness. otherwise 
twinning will be more prevalent and incomplete edge coverage (by the 
coating) is likely to occur (Fig. 2). 
Core 
can causeJ!} 
Incomplete 
Edge Coverage 
~ can cause 
Twinning 
Figure 2 Schematic example of poor tablet core shape for sugar coating. 
(The twinning problem illustrated is more prevalent when using capsuleshaped 
tablets .)

82 Porter and Bruno 
Table 1 Examples of Formulations Used in the Lamination Subeoating 
Process 
Binder solutions 
Dusting powders 
Gelatin 
Gum acacia 
Sucrose 
Distilled water 
Calcium carbonate 
Titanium dioxide 
Talc (asbestos free) 
Sucrose (powdered) 
Gum acacia 
I 
3.3% w/w 
8.7 
55.3 
32.7 
40.0% w/w 
5.0 
25.0 
28.0 
2.0 
II 
6.0% w/w 
8.0 
45.0 
41.0 
1.0 
61.0 
38.0 
Two main approaches to the process of subcoating are often practiced, 
depending on whether a lamination technique or a suspension subcoat 
formulation is used. Each has its distinct features and advantages. 
LAMINATION PROCESS. The lamination process is perhaps the older 
of the two techniques used, and involves alternate applications of binder 
solutions and dusting powder until the required level of coating is achieved. 
While materials and formulations for binder solutions and dusting powders 
are varied. some typical formulations are shown in Table 1. 
When using the lamination technique it is important to ensure that a 
careful balance is achieved between the relative amounts of binder solution 
and dusting powders used. Underutilization of dusting powders increases 
the risk of sticking and twinning, whereas overdusting can create tablets 
that have brittle coatings. 
While achievement of quality results with the lamination process typically 
requires employment of skilled operators. there is no doubt that this 
type of process can permit rapid buildup of the coating. 
On the downside, the lamination process can be messy, more difficult 
to use by less-skilled operators, and more difficult to automate. 
SUSPENSION SUBCOAT INC PROCESS. In simple terms, suspension 
subcoating formulations result from combining the binder and powder 
formulations used in the more traditional lamination process. Examples of 
a typical formulation are shown in Table 2. 
Use of the suspension subcoatfng approach reduces the complexity of 
the process, allowing it to be used effectively by less-experienced operators. 
and ultimately facilitates automation of the process.

Coating of Pharmaceutical Solid-Dosage Forms 
Table 2 Examples of Suspension Subcoating Formulations 
I II 
Sucrose 40.0% w/w 58.25% w/w 
Calcium carbonate 20.0 18.45 
Talc (asbestos free) 12.0 
Titanium dioxide 1.0 1.00 
Gum acacia 2.0 
Gelatin (120 bloom) 0.01 
Distilled water 25.0 22.29 
83 
Grossing (or Smoothing) 
In order to manufacture a quality sugar-coated product, it is imperative 
that the surface of the coating be smooth and free from irregularities 
prior to application of the color coat. 
While the requisite smoothness may be achieved during the application 
of the subeoat , it is not unusual to find that further smoothing (prior to 
color coating) is necessary. Depending on the degree of smoothing required, 
the smoothing coating may simply consist of a 70% sucrose syrup, 
often containing titanium dioxide as an opacifier/whitening agent, and possibly 
tinted with other colorants to provide a good base for subsequent 
application of the color coat. 
If a substantial amount of smoothing is required, as in the case in 
which the subcoat tablets have a pitted surface, other additives (such as 
talc, calcium carbonate, corn starch) may be used in low concentrations to 
hasten the smoothing process. 
Color Coating 
Many would agree that color coating is one of the most important steps in 
the sugar-coating process because of the immediate visual impact that is 
associated with overall quantv , 
Use of appropriate colorants, which are dissolved or dispersed in the 
coating syrup, allows the desired color to be achieved. Two basic approaches 
to coloring sugar-coating syrups exist, each giving rise to differing 
coating techniques. These two approaches involve the use of 
either water-soluble dyes or water-insoluble pigments. 
Prior to the 1950s, soluble dyes were used extensively to achieve the 
desired color. This technique was handled by an experienced eoater , 
Who had acquired his skill over many years of work experience. Much of 
the color coating required 2 or 3 days, and unless handled properly. resulted 
in tablets that were nonuniform in color or mottled, since the soluble 
dye can migrate to the surface during drying. Additionally, color

84 Porter and Bruno 
reproducibility from batch-to-batch was not predictable. and light sensitivity 
with subsequent fading was also a problem when using dyes. 
The use of insoluble, certified lakes has virtually replaced the soluble 
dye in pharmaceutical tablet coating. Lakes have several advantages; 
namely. color migration on drying is eliminated. since lakes are insoluble. 
light stability is improved, mottled tablets are a rare occurrence. and coating 
time is SUbstantially shortened. While lakes are insoluble. they are 
not totally opaque. Consequently, coloring properties can be optimized by 
combining lakes with opacifiers such as titanium dioxide. The most efficient 
process for color coating involves the use of predtspersed , opacified 
lake suspensions. By varying the ratios of lake and opacifier , various 
shades can be produced. 
DYE-COATING PROCESS. The features of a typical sugar-coating 
process that utilizes water-soluble dyes as colorants include: 
Sequential application of coating syrups containing specific dye concentrations 
(typically, as coating progresses, dye concentrations in 
the syrup may be increased until the target color is achieved) 
Addition of a quantity of colored syrup (at each stage) that is sufficient 
to just wet the total tablet surface, followed by gentle drying 
to achieve requisite smoothness and prevent color migration 
Employment of relatively low concentrations of colorant (necessary to 
achieve final color uniformity). resulting in a requirement to make 
anywhere up to 50 separate color syrup applications (particularly 
for dark colors) 
There is no doubt that in the hands of a skilled operator the quality 
of sugar-coated tablets that employ the dye-coating method are difficult to 
match (this is particularly true from the standpoint of "cleanliness." depth. 
and "brflltance" of the final color). 
However. such a process is not without its difficulties, namely: 
Color migration problems (resulting from either underdrying or too 
rapid a drying) are commonplace. 
Color variability. across the surface of individual tablets, Which occurs 
as the result of unevenness of the subeoat layer and transparency 
of the color coat. 
Tablet-to-tablet color variability which may result because the transparent 
coloring system has not been uniformly distributed. 
Batch-to-batch color variation which is likely to occur because of 
variability in the total quantity of color applications made, or as a 
result of small differences in amount of colorant weighed out for 
each batch (water-soluble dyes produce very intense colors and a 
little goes a long way). 
The process is time consuming (because of the slow drying required 
and the need to make so many individual color applications). 
PIGMENT-COATING PROCESS. Pigments have demonstrable advantages 
over water-soluble dyes. two important ones being: 
1. Lack of solubility in aqueous media (which eliminates color migration 
on drying) 
2. Superior light stability

Coating of Pharmaceutical Solid-Dosage Forms 85 
However, because pigments are discrete, insoluble particles, careful 
attention must be paid to the pigment-dispersion process. Hence, the popularity 
of commercially available pigment-dispersion concentrates. 
Some of the major characteristics of sugar-coating formulations and 
processes when pigment colorant systems are used include: 
Use of a single-color concentration throughout the color-coating 
process, thus making it easier to achieve the target end color (in 
order to obtain a different color, it is necessary to vary the ratios 
of the lake pigments with respect to the opacifier, titanium 
dioxide) 
Achievement of batch color uniformity after only a few applications of 
colored syrup (often color development is complete after eight to 
10 applications, and the remaining five to seven applications are 
simply used to smooth off the tablet surface) 
Reduced drying times resulting from the fact that the insoluble colorants 
do not migrate on drying, and thus can be dried more 
rapidly 
Overall shortened color-coating process as a result of reduced number 
of color applications and shortened drying times 
One should, however, be aware of what some might construe to be disadvantages 
with pigment coloring systems and the associated coating 
process: 
Colorants derived from pigments (especially when lakes are used in 
combination with titanium dioxide) are generally not as bright or 
clean-looking as those obtained with soluble colorants. 
If the pigment color-coating process is rushed, it is relatively easy to 
produce rough tablets that are difficult to polish. 
There is a need to ensure that pigments are effectively dispersed in 
the coating syrup (certainly, pigm ent color concentrates eliminate 
this problem), otherwise color "specking" might be a problem. 
Since most pigment coloring systems contain lakes (which are typically 
acidic), it is inadvisable to keep coating systems hot for any 
length of time once the color has been added; otherwise excessive 
amounts of invert sugar will be formed. 
With the exception of the first of these problems, all the others can 
easily be avoided, and thus advantages of the pigment coating process 
tend to prevail, making it the process of choice. 
Summarizing these advantages I they are: 
Greater ability to get a uniform color on the surface of each tablet 
Greater batch-to-batch color uniformity 
Significant reduction in thickness of the color coat 
Significant reduction in processing time 
Polishing (Glossing) 
Since freshly color-coated tablets are typically dull (i.e. I they have a 
matte surface finish). it is necessary to polish them in some way to 
achieve the gloss that is typical of finished sugar-coated tablets.

86 Porter and Bruno 
While methods to achieve a desirable gloss tend to vary considerably. 
it is generally recommended that tablets should be trayed overnight (prior 
to polishing) to ensure that they are sufficiently dry. Excessively high 
moisture levels in tablets submitted for polishing will: 
Make achievement of a good gloss difficult 
Increase the risk of "blooming" and "sweating" over longer periods of 
time 
Glossing or polishing can be carried out in various types of equipment 
(e. g.. canvas- or wax-lined pans), including that used for applying the 
sugar coating itself (which is more typical in automated processes). 
Polishing systems that may be used include: 
Organic-solvent-based solutions of waxes (beeswax, carnauba wax, 
candelilla wax) 
Aleoholic slurries of waxes 
Finely powdered mixtures of dry waxes 
Pharmaceutical glazes (typically alcohol solutions of various forms of 
shellac, often containing additional waxes) 
Printing 
If sugar-coated tablets are to be further identified with a product name, 
dosage strength, or company name or logo, this has to be accomplished by 
means of a printing process. 
Typically, such printing involves the application of a pharmaceutical 
branding ink to the coated tablet surface by means of a printing process 
known as offset rotogravure. 
Sugar-coated tablets may be printed either before or after polishing. 
with each approach having its advantages and disadvantages. Printing 
prior to polishing enables the ink to adhere more strongly to the tablet 
surface, but any legend may subsequently be removed by either friction or 
as a result of contact with organic solvents during the polishing process. 
Printing after polishing avoids the problem of print rub-off during polishing, 
but branding inks do not always adhere well to the waxed tablet surface. 
Adhesion of printing inks can be enhanced by application (prior to 
printing) of a modified shellac, preprint base solution. 
c. Application Techniques 
Application of sugar coatings to pharmaceutical tablets has long been considered 
one that requires a significant amount of skill on the part of the 
operator. While this philosophy has a lot of truth in it, and While it is 
certainly difficult for untrained operators to achieve qUality results, the 
employment of special techniques (such as the use of suspension subcoat 
formulations and coatings colored with proprietary pigment dispersions) 
makes quality results achievable even for less-skilled operators. 
While many different types of coating formulation (Sec. II.B) will be 
applied during the coating process, similarities in application exist for each 
of them. 
The basic application procedure in each case involves three steps in 
sequence:

Coating of Pharmaceutical Solid-Dosage Forms 
1. Application of an appropriate volume (sufficient to completely 
cover the surface of every tablet in the batch) of coating liquid 
to a cascading bed of tablets 
2. Distribution of the coating liquid uniformly across the surface of 
each tablet in the batch 
3. Drying of the coating liquid once uniform distribution is achieved 
87 
Specific details of actual procedures adopted may vary from companyto-
company. However, the ultimate goal in each case is to ensure that 
the coating is uniformly distributed throughout the batch. Although this 
goal may be facilitated by the manner in which the coating liquid is applied, 
and by manual stirring of the wet tablets to help eliminate "dead 
spots" (regions in the tablet bed that are difficult to reach with the coating 
liquid), the main mechanism for distribution of the coating liquid relates 
to the shearing action that occurs as tablets cascade over one 
another. 
For the greatest period of time, sugar-coating liquids were applied 
manually by allowing premeasured quantities of coating liquid to be poured 
across the moving tablet bed. In recent times, there has been a greater 
reliance on mechanical dosing techniques, involving the use of spray guns 
or dosing "spaeges" (Fig. 3). 
One of the major misconceptions concerning the use of mechanical 
dosing techniques, particularly spray guns, is that they can exert a 
major influence on uniformity of distribution of the sugar-coating liquid. 
Again, it is important to emphasize that the main factor controlling distribution 
of the coating liquid relates to contact between the cascading tablets, 
and transfer of liquid from one tablet to another as the result of this contact. 
ThUS, particularly When using spray guns, it is not necessary to 
finely atomize the coating liquid in order to ensure effective distribution 
of that liquid. Indeed, excessive atomization can cause "fogging!! where 
much of the coating liquid can end up on the walls of the pan rather than 
on the tablets. Consequently, many advocates for the use of spray guns 
simply allow the liquid to stream from the nozzle. For this reason, use 
of a device similar to that shown in Figure 3 can be equally effective and 
less expensive than using spray guns. 
Summarizing, since coating uniformity is achieved as the result of 
tablet-to-tablet transfer of liquid coating material, it is not necessary for 
each tablet to pass through the zone of application (which is a necessity 
in the film-coating process). Factors which influence coating uniformity in 
the sugar-coating process are that: 
The coating material remains fluid until it is spread across the surface 
of every tablet in the batch. 
Sufficient volume of coating liquid is applied to ensure that every 
tablet in the batch is capable of being wetted (thus liquid volumes 
may have to be changed as the process progresses in order to 
reflect changes in tablet size and drying conditions). 
The coating pan exhibits good mixing characteristics, particularly so 
that dead spots are avoided (many coating pans of conventional 
design, i.e., the traditional pear-shaped design, may have to be 
modified by inclusion of mixing baffles, otherwise mixing may have 
to be augmented by manual stirring of the tablets by the operator).

88 Porter and Bruno 
Figure 3 Figure showing a dosing sparge for sugar coating.

Coating of Pharmaceutical Solid-Dosage Forms 
D. Problems in Sugar Coating 
89 
In any coating process, a variety of problems may arise. Often such problems 
may be related to formulation issues that have been compounded by 
those associated with processing. 
Problems with Tablet Core Robustness 
The attritional effects of any coating process on tablet cores is well 
understood. Consequently. tablet cores must be sufficiently robust to 
resist the stress to which they will be exposed during coating. 
With this in mind; particular attention must be paid to important tablet 
physical properties such as hardness (diametral crushing strength), friability, 
and lamination tendency. Failure to address these issues is likely 
to result in a situation in which tablet fragmentation occurs during the 
coating process. 
Tablet fragmentation is not only a problem from the standpoint that 
the broken tablets will obviously not be saleable (and thus would have to 
be inspected out). but additionally. the broken fragments may typically become 
"glued" (because of the adhesive nature of the coating fluids) to the 
surface of undamaged tablets (Fig. 4); thus spoiling a significant portion 
of the batch. 
Quality Problems with Finished Tablets 
CHIPPING OF COATINGS. Sugar coatings are inherently brittle and 
thus prone to chipping if mishandled. Addition of small quantities of 
polymers (such as cellulosics, polyvinyl pyrrolidone, acacia, or gelatin) to 
one or more of the various coating formulations often helps to improve 
structural integrity. and thus reduces chipping problems. 
Excessive use of insoluble f'lllers and pigments tends to increase the 
brittleness of sugar coatings, and thus should be avoided where possible. 
CRACKING OF THE COATING. Tablet cores that expand, either during 
or after coating, are likely to cause the coating to crack (Fig. 5). 
Such expansion may result from moisture absorption by the tablet core. 
or may be caused by stress-relaxation of the core after compaction (a 
phenomenon Which is known to occur, for example, with ibuprofen). 
Moisture sorption can be minimized by appropriate use of a seal coat, 
whereas expansion due to postcompaction stress relaxation can be resolved 
by extending the time between the compaction event and commencement of 
sugar coating. 
NONDRYING COATINGS. Inability to dry sugar coatings properly, 
especially those based on sucrose, is often an indicator that excessive 
levels (greater than 5%) of invert sugar is present. Inversion of sucrose 
is exacerbated by keeping sucrose syrups at elevated temperatures under 
acidic conditions for extended periods of time. Such conditions occur 
when sugar-coating solutions containing aluminum lakes are kept hot for 
too long; or such sugar-coating formulations are constantly being reheated 
to redissolve sugar that is beginning to crystallize out. 
TWINNING (OR BUILDUP OF MULTIPLES). By their very nature, 
sugar-coating formulations are very sticky, particularly as they begin to

90 Porter and Bruno 
Figure 4 Figure showing how broken tablets can ruin a whole batch of 
product in sugar coating.

Coating of Pharmaceutical Solid-Dosage Forms 
Figure 5 Sugar-coated tablets with cracked coating. 
91 
dry, and allow adjacent tablets to stick together. Buildup of multiples 
really becomes a problem when the tablets being coated have flat surfaces 
(as shown in Fig. 2) which can easily come into contact with one another. 
This can be particularly troublesome with high-dose, capsule-shaped 
tablets that have high edge walls. Appropriate choice in tablet punch design 
can be effectively used to minimize the problem. 
UNEVEN COLOR. Because it has a major impact on final tablet appearance, 
the color-coating stage of the sugar-coating process is critical 
to ultimate tablet quality. 
Uneven distribution of color. particularly with the darker colors, is 
often viaually apparent. and thus a major cause of batch rejection. Many 
factors may contribute to this type of problem, including: 
Poor distribution of coating liquids during application. This may be 
caused by poor mixing of tablets in the coating process, or failure 
to add sufficient liquid to coat completely the surface of every 
tablet in the batch. 
Color migration of water-soluble dyes while the coating is drying. 
Unevenness of the surface of the subcoat when using dye-colored 
coatings. This unevenness causes a variation in thickness of the 
transparent color layer that is perceived as different color 
intensities. 
"Washing back" of pigment-colored color coatings. While pigments do 
not migrate on drying, if excessive quantities of coating liquid are 
applied during the coloring process, there is a tendency for the 
previously applied (and dried) color layers to be redissolved and 
distributed nonuniformly; thus giving rise to nonuniform appearance. 
This problem is. particularly noticeable for formulations predominantly 
colored with aluminum lakes where the level of opacifying 
pigments (such as titanium dioxide) is low (La . dark colors). 
Excessive drying between color applications. This can cause erosion 
of the color layer and contributes to unevenness in the color coat.

92 Porter and Bruno 
"BLOOMING" AND llSWEATING." Residual moisture (in f"mished sugar-. 
coated tablets) can often be a problem. Over a period of time ~ this 
moisture can diffuse out and affect the qUality of the product. Moderate 
levels of is reached, below which there is a critical 
cessation of molecular motion on the local scale. Under these temperature 
conditions, the polymer exhibits many of the properties of inorganic 
glasses, including toughness, hardness, stiffness, and brittleness. For 
this reason, the glass-transition temperature is often described as one below 
which a polymer is brittle, and above which it is flexible. This definition 
is, at times, a little simplistic, and so a better definition of glasstransition 
temperature is that temperature above which there is an increase 
in the temperature coefficient of expansion [201. 
Because the glass-transition temperatures of many of the polymers used 
in film coating are in excess of the temperature conditions experienced in 
the typical coating process, it is often necessary to modify the properties 
of the polymer. This modification allows the final coating to better withstand 
the conditions to which it will be subjected in the typical coating 
process. An appropriate modification involves the process of plasticization. 
Plasticizers reduce the glass-transition temperature of amorphous 
polymers and impart flexibility. The basic requirements to be met by a 
plasticizer are permanence and compatibility. Permanence dictates that the 
plasticizer has a low vapor pressure and low diffusion rate within the 
polymeric film, a requirement that favors high molecular weight plasticizers. 
Compatibility, on the other hand, demands that the plasticizer be miscible

104 Porter and Bruno 
with the polymer and exhibit similar intermolecular forces to those present 
within the polymer. 
It is not uncommon to see reference made to two types of plasticization. 
The first is internal plasticization, and refers to the situation in which 
chemical changes are made within the structure of the polymer itself, as 
with copolymers (exemplified by many of the acrylic polymers systems used 
in film coating). The second, termed external plasticization, occurs when 
an external additive (the plasticizer) is combined in admixture with the 
polymer. 
Effective plasticization is critical when using aqueous polymeric dispersions 
in order to ensure that sufficient free volume exists at normal 
processing temperatures to facilitate coalescence of the polymeric particles 
into a continuous film. 
Since the plasticizer by its interaction with the polymer affects the 
intermolecular bonding between polymer chains, it is only to be expected 
that this additive will change the properties of the coating (Table 8). In 
these cases, although well-defined quantitative effects can be demonstrated, 
the magnitude of the effect is very much dependent on the compatibility, 
or degree of interaction, of the plasticizer with the polymer. Methods for 
determining the interaction between film-coating polymers and appropriate 
plasticizers have been described by Sakellariou et ale [29] and Entwistle 
and Rowe [22]. Plasticizers. by their very nature. are not universal, 
since selection is very much determined by which polymer is being used. 
COLORANTS. Colorants are included in many film-coating formulations 
to improve the appearance and visual identification of the coated product. 
Certain types of colorant (as will be discussed later in this section) can 
provide other physical benefits. 
As described under sugar coating (Sec. II). various types of approved 
colorants exist that can be used in film coating. While a detailed review 
of colorants that can be used in pharmaceutical dosage forms has been 
Table 8 Effects of Plasticizers on the Properties of Film Coatings 
Property Effect of increasing plasticizer concentration 
l. Tensile strength 
2. Elastic modulu s 
3. Film adhesion 
4. Solution viscosity 
5. Film permeability 
6. Glass-transition 
temperature 
Decreased [27] 
Decreased 
May be increased, but results often variable 
[ 27] 
Increased. and magnitude of effect dependent 
on molecular weight of plasticizer [11] 
Can be increased [27] or decreased [28], depending 
on chemical nature of plasticizer 
Decreased. but magnitude of effect dependent 
on compatibility with polymer [29]

Coating of Pharmaceutical Solid-Dosage Forms 105 
given elsewhere [30]. it is appropriate to briefly review here those types 
that may be used in film coating. Such colorants include: 
Water-soluble dyes (e.g FD&C Yellow #5 and FD&C Blue #2) 
Aluminum lakes (of FD&C water-soluble dyes) 
Other lakes (e.g D&C Red #6) 
Inorganic pigments (e.g  titanium dioxide, iron oxides. calcium sulfate, 
calcium carbonate) 
"Natural" colorants (e. g  riboflavin, tumeric oleoresin. carmine 40) 
Unlike sugar coating. film coating had its origins as a nonaqueous 
process. Consequently, with few exceptions. most formulators preferred 
to use pigments as colorants in their film-coating formulations. While the 
more recent introduction of aqueous technology has opened the door to 
using water-soluble colorants, use of pigments has persisted owing to the 
advantages shown by this form of colorant. including: 
Ability to increase solids content of coating solution without dramatically 
affecting viscosity [11] (particularly advantageous in aqueous 
film coating) 
Ability to improve the moisture barrier properties of film coatings [27] 
Pigments consist. however. of discrete particles, and thus a substantial 
effort is required to ensure that they are well dispersed in the coating 
liquid. Such dispersion will be inadequate if dry pigment is simply added 
to the coating liquid with the aid of a low-shear stirrer (e. g  a Lightnin' 
mixer). Inadequate pigment dispersion leads to coating defects. as discussed 
by Porter [31] and Rowe [32J. Particle size of the pigment within 
the film (a parameter often related to efficiency in the dispersion process) 
will also affect perceived color [32] and may influence the surface roughness 
of the coating [33]. 
Since colorants are mostly added to a film-coating formulation for their 
visual effects. it is important to understand the physical behavior of 
colorants in a polymer film. As pigments are used almost exclusively as 
colorants in film coatings. further reference in this section to colorants 
will be restricted to pigments. 
When coloring a film coating not only is it important to create a given 
visual effect. but also to ensure that the appearance is as uniform as possible 
throughout the particular batch of coated product. and consistent 
from batch-to-batch. 
Such uniformity is facilitated when the colorant chosen is able to effectively 
mask the appearance of the substrate without requiring the use 
of excessive quantities of colorant (which could increase the risk of 
physical defects in the coated product) or applying excessive quantities of 
coating (which impacts total cost of the process). This ability to mask 
the substrate is often described in terms of hiding power or opacity of the 
colored coating. These characteristics of the coating are often related to 
contrast ratio. a term defined as the ratio of the Y tristmulus value for a 
111m measured over a black background (i.e  Yb) to the similar value 
measured over a white background (Yw). Thus 
Yb 
Contrast ratio =Yw x 100

106 Porter and Bruno 
Colored films having contrast ratios close to 100 exhibit excellent 
hiding power, whereas those having values close to zero are almost transparent 
(and thus have poor hiding power). Since contrast ratio is also 
affected by film thickness, determinations (and comparisons) must always 
be made on films of equal thickness. 
Rowe [35] has listed the contrast ratios for coatings containing 
various colorants. From his comparison, it is evident that the better results 
are obtained for films containing certain inorganic pigments (e. g. , 
titanium dioxide and iron oxides). or those that absorb the higher wavelengths 
of visible light (e. g., FDIC Blue #2). These results can be explained 
by the theories of light, which predict that hiding power will be 
influenced by: 
Light reflected at the polymer/pigment interface, which is influenced 
by differences in the respective refractive indices of the polymer 
and pigment [35] 
Quantity (and wavelength) of light absorbed by the colorant 
Understanding these basic principles may help the formulator optimize 
a particular coating formulation, especially with respect to the concentration 
of colorant required, and the quantity of coating needed to develop a 
uniform appearance. Some optimal results in this respect have been described 
by Porter and Saraceni [15]. 
While it is important to understand the physical behavior of colorants, 
one should not lose sight of the impact that pigments can have on other 
physical characteristics of the coating. Some of these effects are listed in 
Table 9. 
SOLVENTS. While choice of an appropriate solvent deserves careful 
attention, the rise in importance of aqueous film coating has virtually eliminated 
solvent selection from the formulation process. Nonetheless, certain 
types of film coatings and film-coating processes require that SOme organic 
Table 9 Effects of Pigments on the Properties of Film Coatings 
Property Effect of increasing pigment concentration 
Decreased (effect may be minimized by effective 
pigment dispersion) 
Increased [36] 
Little effect [27] 
Increased I but not substantially [11] 
Decreased [27], unless critical pigment volume 
concentration is exceeded 
Increased, but magnitude of effect dependent 
on refractive index of pigment, and Ught 
absorbed by pigment [34] 
1. Tensile strength 
2. Elastic modulus 
3. Film adhesion 
4. Solution viscosity 
5. Film permeability 
6. Hiding power

Coating of Pharmaceutical Solid-Dosage Forms 107 
Table 10 Common Solvents Used in Film Coating 
Class Examples 
1. Water 
2. Alcohols Methanol 
Ethanol 
Isopropanol 
3. Esters Ethyl acetate 
Ethyl lactate 
4. Ketones Acetone 
5. Chlorinated hydrocarbons Methylene chloride 
1: 1: 1 Trichloroethane 
solvents still be used. Thus, to a limited extent, selection of an appropriate 
solvent may still be necessary. 
A list of some of the more common solvents that have been used in 
film coating is shown in Table 10. 
When selecting a particular solvent or solvent blend there are several 
factors that must be considered. The first prerequisite is the ability to 
form a solution with the polymer of choice. In this respect, it is often 
difficult to determine whether true solutions are formed or whether they 
are mainly macromolecular "dispersions." Banker [37] stated that optimal 
polymer solution will yield the maximum polymer chain extension, producing 
films having the greatest cohesive strength and thus the best mechanical 
properties. 
One method for determining interactions between the polymer and solvent. 
and aiding in selecting the most suitable solvent for a given polymer, 
is to use the solubility parameter approach. This approach is based on 
the theoretical treatment of the familiar free energy equation as proposed 
by Hildebrand and Scott [38] and is expressed in this way: 
L\H = V m m
= overall heat of mixing 
=total volume of the mixture 
= energy of vaporization of either component 1 or 2 
ep = volume fraction of either component 1 or 2 
L\H
m 
V
m 
L\E 
where

108 Porter and Bruno 
The expression (~E)IV is often termed the cohesive energy density, 
written 02} where 0 is the solubility parameter and is equivalent to 
([flE]/V)1 2 in the above equation. If 0 1 = O2, then flHm = O. Thus, in 
the free-energy equation 
flF =~H - T~S 
m 
where ~F is the free-energy change, T is absolute temperature, and ~S is 
the entropy of mixing. The free energy is now dependent on the mixing 
entropy. As there is a large increase in the entropy when a polymer dissolves, 
the set of circumstances thus far described ensures that there will 
be miscibility between the solvent and polymer. 
Kent and Rowe [39} used the solubility parameter approach in evaluating 
the solubility of ethylcellulose in various solvents for film coating. 
They determined the intrinsic viscosities of several grades of ethylcellulose 
in a range of solvents of known solubility parameters utilizing the equations 
derived by Rubin and Wagner [40}. They graphically evaluated the 
effect of solvent solu bility parameter on intrinsic viscosity for a range of 
sol vents classified either as (1) poorly hydrogen bonded. (2) moderately 
hydrogen bonded, or (3) strongly hydrogen bonded, and determined both 
the best class of solvent to use and the optimum solvent solubility parameter. 
ThUS, this approach can be used to determine the best solvent for 
the polymer from a thermodynamic standpoint. The technique can also be 
used for optimizing solvent blends, the individual components of which may 
or may not themselves be thermodynamically good solvents. 
Before dtssolution can take place the solvent must penetrate the 
polymer mass. Once this has occurred, a swollen gel will form which rapidly 
disintegrates to form a solution. The rate of solution is facilitated by 
small solvent molecules which diffuse rapidly into the polymer mass. Unfortunately. 
thermodynamically good solvents are not always kinetically 
good. ones. and vice versa; thus, a compromise may be necessary. 
An additional function of the solvent system is to ensure a controlled 
deposition of the polymer onto the surface of the substrate. If a good coherent 
and adherent film coat is to be obtained, the volatility of the solvent 
system is an important factor. In the final formulation, the selected 
solvent system usually represents a compromise between thermodynamic, 
kinetic, and volatility factors and results in a solvent blend being used. 
After all formulation factors have been resolved, attention must be 
paid to the changes in solvent ratios that can occur during the application 
process. This will cause no problem if all components of the blend, or the 
least volatile component, are good solvents for the polymer. However, if 
this is not the case, the solvent -polymer thermodynamic balance changes 
as evaporation progresses. The polymer can thus be precipitated before a 
cohesive film is formed. Alternatively, the solubility of the polymer in the 
remaining solvent may not be sufficient to ensure that the optimum film 
properties will be obtained. In this situation, it is essential to use a 
constant-boiling or azeotropic solvent mixture whose composition does not 
change on evaporation. 
B. Conventional Film Coatings 
The greatest area of application for film coatings is that where the coating 
is mainly designed to improve product appearance, perhaps improve

Coating of Pharmaceutical Solid-Dosage Forms 109 
stability and ease of ingestion of the dosage form, but not alter drugrelease 
characteristics from that dosage form. 
From this description, it is apparent that esthetics are of paramount 
importance, and consequently are likely to influence selection of the raw 
materials to be used in the formulation. This selection is often based on 
factors that affect the mechanical properties (such as tensile strength, 
elasticity, and adhesion) of the coating, allow the smoothest, glossiest 
coatings to be obtained, and produce coatings that readily dissolve in the 
human gastrointestinal tract. 
Conventional film coating is also the area where aqueous technology 
has gained the highest acceptance. Thus, with few exceptions, most ingredients 
are selected for their solubility in water (this is especially true 
for polymers). 
Polymers 
Common polymers used in conventional film coating are listed in Table 11. 
The most popular class of polymers used in conventional film coating 
are cellulosics, many of which have good organic-solvent and aqueous 
solubility, thus facilitating the transition to aqueous film coating. Of 
these cellulosics, ethylcellulose is not water soluble, and was originally 
used as a film modifier in admixtures with hydroxypropyl methylcellulose 
(HPMC) in organic-solvent-based formulations. To a limited extent, this 
blending process has continued in aqueous film coating. In this case, 
aqueous solutions of HPMC are mixed with aqueous dispersions of ethyIcellulose. 
However, except when one needs to produce special barrier 
Table 11 Polymers Used in Conventional Film-Coating 
Formulations 
Class 
1. Cellulosics 
2. Vinyls 
3. Glycols 
4. Acrylics 
Examples 
Hydroxypropyl methylcellulose 
Hydroxypropylcellulose 
Hydroxyethylcellulose 
Methylhydroxyethylcellulose 
Methylcellulose 
Ethylcellulose 
Sodium carboxymethylcellulose 
Polyvinyl pyrrolidone 
Polyethylene glycols 
Dimethylaminoethyl methacrylatemethylacrylate 
acid ester copolymer 
Ethylacrylate-methylmethacrylate 
copolymer

110
20 
Porter and Bruno 
O+-----.---,---,.----r----, 
o 10 20 30 40 50 
% (w/w) of EthylcelluJose in Polymer Mix 
(a)
1.0 
,,-.. 
o a. 
o 0.8 ........ 
..J o
~
c
c:J 
::> 
a: 
Cl 
Iz
woa: 
w
c, 
TIME (hours) 
Figure 28 Effect of scale of coating process (Wurster) on release of chlorpheniramine 
from nonpareils coated with aqueous ethyl cellulose dispersion 
(Burelease 10% by weight of coating applied). 
Inlet air humidity 
Nozzle location 
Atomizing air pressure/volume 
Spray rate 
Coating liquid solids content 
Metha [59] has described in detail the importance of many of these 
variables and how they relate to the scale-up process. As a word of caution. 
careful consideration (in the optimization process) should be given 
to the scale on Which the scale-up process is based. Many times, initial 
studies are conducted on small (0.5-1.0 kg) laboratory scales; unfortunately 
this may not be an appropriate basis for predicting scale-up 
factors. By way of example, the data shown in Figure 28 are indicative 
of how feasibRity studies conducted in a 1-kg capacity Wurster may not 
be entirely predictive of what is likely to happen on scale-up. In this 
example, a more appropriate starting point is likely to be the 5-kg pilot 
scale. where results obtained more closely match those obtained on the 
50-kg scale. 
Commercial Equipment 
As discussed earlier, most fluid-bed equipment used for fHm coating was 
based on the Wurster design, with many pharmaceutical companies using 
custom-built equipment under a licensing agreement with WARF. However, 
in the last 10- 15 years, several manu facturers of commercial fluidbed 
equipment have adapted their designs to fuliill the needs of the

Coating of Pharmaceutical Solid-Dosage Forms 145 
film-coating process. The trend has been to provide equipment designed 
on the modular concept, where a basic processing unit is intended to 
accommodate a variety of processing inserts. These inserts can facilitate 
the use of fluid-bed processes for drying, granulating, spheronizing, and 
coating. 
While many similarities exist for equipment supplied by the various 
vendors, opportunities for differentiation exists with: 
Clamping systems (i.e., the mechanism for clamping the various removable 
sections together). which are typically either compressed 
air or hydraulic 
Explosion protection, where some manufacturers use 2-bar construction 
plus explosion-relief venting, whereas others rely on 10-bar 
construction 
Filter-bag assemblies, which can be based on either a split-filter 
shaking or pulsed-air blow-back systems 
Heating units, Where typically either conventional steam or electric 
can be provided. but where there is a growing preference for 
"face and by-pass" systems that permit more precise control over 
processing temperatures while facilitating rapid changes (in temperature) 
to be made When required 
The trend is to provide standard equipment with appropriate options 
so that designs can be more easily customized to meet end-user requirements. 
Specialized designs, with taller expansion chambers that facilitate 
appropriate deceleration when coating small particles, are becoming common. 
As with other types of coating equipment, opportunities for providing completely 
automated processes now exist. 
GLATT FLUID-BED COATING EQUIPMENT. Originally, the Glatt Air 
Techniques' designs were based on the WSG processing unit. which is 
capable of accepting a variety of inserts. More recently. however, in 
order to better address the situation in which the material to be coated 
is of small particle size (ranging from approximately 100 um- 2 mm), the 
emphasis has shifted toward the GPCG processing unit. Inserts can be 
provided to permit drying. granulating (or top-spray coating), Wurster 
coating (bottom spray). and rotor granulationllayering/coating (tangential 
spray). 
An example of a 5- to lO-kg pilot GPCG unit is shown in Figure 29. 
Other common features of the Glatt equipment are: 
Filter systems based on the split filter. shaking principle 
2-Bar construction with explosion relief (although 10-bar construction, 
at an added cost. may be available) 
Microprocessor-based control panels when non-explosion-proof operating 
environments are permissible 
Hydraulic clamping systems 
AEROMATIC FLUID-BED COATING EQUIPMENT. Aeromatic fluid-bed 
coating equipment is again designed to accommodate a variety of modular 
inserts. A typical laboratory scale unit, capable of processing up to 
3- 5 kg of material. is shown in Figure 30. 
Inserts that can be utilized with this manufacturer's equipment 
include:

146 Porter and Bruno 
Figure 29 Figure of a Glatt GPCG-5 fluid-bed coating unit. (Courtesy 
of Glatt Air Techniquest Ramsey, New Jersey.) 
Dryer (with options for batch or continuous processing) 
Spray granulator (and top-spray coating) 
Aero-coater (Wurster, bottom-spray coating) 
Ultra coater (bottom/tangential spray for tablet coating) 
Some additional features of Aeromatic equipment are: 
Sequential blow-back filter system 
Clamping system based on compressed air 
Standard 10-bar construction , 
Unlike some of the competitive equipment , the Wurster process (Aerocoater) 
does not require a completely separate unit, but rather is created 
by adding the inner Wurster chamber (insert) to the product bowl of 
the batch granulator unit. This obviously provides some opportunity 
for economizing on cost.

Porter and Bruno 
Figure 30 Figure of an Aeromatic multi fluid-bed coating unit. 
eCourtesy of Aeromatic. Inc., Columbia, New Jersey.) 
147 
VECTOR-FREUND FLU ID-BED COATING EQUIPMENT. The design of 
the Vector-Freund fluid-bed coating equipment was originally based on 
that of the Floweoater , which features spray nozzles located (and angled 
downward) in the sidewalls of the product container. This design permits 
the same equipment to be used for fluid-bed drying, coating, and 
granulating.

148 Porter and Bruno 
Figure 31 Figure of a Vector-Freund Flowcoater multi fluid-bed coating 
unit. (Courtesy of Vector Corporation. Marion. Iowa.)

Coating of Pharmaceutical Solid-Dosage Forms 
More recently, the Flowcoater multi unit (Fig. 31) has been introduced, 
which features separate inserts for: 
Drying 
Granulating (and top-spray coating) 
Wurster coating 
Spheronizing/layering/coating (a tangential spray, rotor unit that is 
based on the operating principle of the CF granulator) 
149 
HUTTLIN KUGELCOATER. In terms of fluid-bed fllm coating, the 
Kugelcoater is rather unique, both in basic design and for the fact that 
it does not consist of a central processor that accepts multiple inserts. 
A simplified schematic of the Kugelcoater is represented in Figure 32, 
whereas a photograph of the equipment is shown in Figure 33. 
The product container of the Kugelcoater is spherical. Inlet fluidizing 
air is introduced via a tube that passes down the center of the product 
container. The design permits this air to enter the product container at 
the bottom. A series of spray nozzles are also located at the bottom of 
the product container in such a way that fluidizing air creates a "balloon" 
effect to keep the product being coated away from the spray nozzles. 
Exhaust 
Al.r 
Product 
Redirectl.on 
Screen 
Inlet Al.r 
Static Coarse Fl.lter 
.---__ Product Contal.ner 
"Balloon" Al.r Pocket 
Spray Gun 
;{} 
\lPneumatlc Product Loadl.nq 
and Unloadl.nq 
Figure 32 Schematic diagram of a Kugelcoater.

150 Porter and Bruno 
Figure 33 Fig'Ure of a Hiittlin Kugeleoater , 
national, Englishtown, New Jersey.) 
(Courtesy of Key Inter- 
The product fluidization pattern is constrained by a product redirection 
screen that restricts product entry into the filter system. 
This unique design. encompassing the inclusion of multiple spray nozzles 
intended to maximize uniformity of distribution of the coating, also 
permits pneumatic loading and unloading of product. 
Various sizes of the Kugelcoater are available, ranging from lab models 
with product container capacities of 2 L to those having capacities of 
700 L. 
c. Application Equipment 
In most modern pan-coating operations, one major emphasis is to provide a 
means of mechanically applying coating liquids, and thus avoid manual 
techniques such as ladling. 
While there are similarities in requirements (for mechanical application 
of coating liquids) between the sugar-coating and film-coating processes,

Coating of Pharmaceutical Solid-Dosage Forms 151 
certain differences exist that almost certainly influence selection of appropriate 
equipment. 
Sugar-coating liquids typically have solids contents in excess of 70% 
(w/w), and consequently can be extremely viscous. Contrast this with 
the fact that film-coating liquids rarely contain greater than 20% nonvolatile 
materials (Which typically fall in the range of 5 -15%). 
Uniform distribution of sugar-coating liquids is achieved by the cascading 
action (of the product being coated) that takes place within the pan 
and causes transfer of liquid from one piece to another. This transfer 
should occur before any substantial drying occurs. Thus, the application 
equipment needs only to be very simple in design and allow the coating 
liquid to stream onto the surface of the cascading product. 
Conversely, film-coating liquids (almost without exception) need to be 
applied in a finely atomized state and uniformly distributed across the surface 
of the product being coated. 
In the context of this chapter. mechanical application refers to any 
method of introducing a coating liquid across the surface in an appropriate 
manner other than hand ladling. 
Application Sparges 
Application sparges were discussed earlier in this chapter (and illustrated 
in Fig. 3) and refer to simple equipment that allow the coating liquid to 
stream across and onto the surface of the cascading bed of the product 
being coated. 
The simplicity of this type of equipment makes it extremely suitable 
for use in the sugar-coating process. 
Airless Spray Equipment 
Airless spray equipment generally consists of a particular design of spray 
gun that contains a nozzle with an extremely small orifice (typically 
200-400 um or 0.009-0.015"). The coating liquid is delivered under significant 
pressure (often in the range of 3.5 - 20.0 MPa or 500 - 3000 psi) 
and velocity, and literally explodes into tiny droplets as it emerges from 
the nozzle. Because of the high shear generated at the nozzle, a nozzle 
insert or tip made of tungsten carbide is used. Nozzle tips are available 
in a wide range of configurations that permit cone spray or flat (or ovalized) 
spray patterns to be generated. 
Liquid flow rates through airless spray equipment are typically high. 
Stearn [62] described how such liquid flow rates. based on examination of 
fundamental flow theories, are: 
Directly proportional to the cross-sectional area of the nozzle orifice 
Directly proportional to the square root of hydraulic pressure (of 
coating liquid) 
Inversely proportional to density of the coating liquid 
Since a minimum hydraulic pressure is required for optimal atomization 
of the coating liquid. and there is a practical lower limit on orifice size 
(before clogging becomes a serious problem), airless spray equipment is 
mainly restricted to applications where high-volume delivery of coating 
liquids is required. Such applications include production scale. organicsol 
vent-based film coating or similar scale sugar coating.

152 Porter and Bruno 
Air-Spray Equipment 
Air-spray application equipment is generally less expensive than the corresponding 
airless equipment, and is capable of delivering coating liquids at 
low to relatively high application rates. The functional components of an 
air-spray gun are the fluid cap (through which the liquid emerges) and 
the air cap (through which compressed air is delivered to create the 
driving force for atomization). Typically, the air cap fits over the fluid 
cap (or nozzle) and forms an annulus that allows compressed air to impinge 
on the stream of coating liquid emerging from the fluid nozzle. This impingement 
causes the coating liquid to be broken up into tiny droplets. 
Droplet size and size distribution are typically controlled by atomizing 
air pressure and volume. In most pan-coating operations, in order to 
allow the coating liquid to be spread out, the air cap also has "wing tips" 
that permit compressed air to be directed laterally onto the atomized spray 
so that the spray pattern is ovalfzed, In order to avoid increased risk of 
spray drying and turbulence. care should be taken not to try and ovalize 
excessively the spray patterns. For this reason, air-spray guns typically 
are unable to cover as much of the surface of the product bed as airless 
guns, and thus more air-spray guns must be used for a particular application 
(e.g., in a typical 48" Accela-Cota setup, whereas two airless guns 
may provide adequate coverage, three or more air-spray guns may be 
required to provide equivalent coverage). 
Air-spray equipment is typically suited to small-scale coating operations 
and all those involving the use of aqueous formulations (where the 
atomizing air effectively augments the drying capabilities of the airhandling 
system). Air-spray equipment should be used with great care 
for organic-solvent-based film coating processes, since the atomizing air 
can cause excessive spray drying. 
Ultrasonic-Spray Equipment 
Recently, attempts have been made to utilize ultrasonic nozzles as a means 
of effectively atomizing and applying coating liquids. Such nozzles are 
commonly used in oil burners and as part of the lithophotographic process 
used in the semiconductor industry. and to apply specialized coatings onto 
the surfaces of medical devices. 
The major advantages of such nozzles are that they are economical to 
operate (although initial capital cost can be high). produce atomized 
liquids with uniform size distributions and low velocities, and eliminate 
many of the problems associated with overspray and fogging. 
While various designs of ultrasonic nozzles are available, those used 
for coatings typically have relatively large orifices and conical tips. The 
operating principle of an ultrasonic nozzle is similar to that of a speaker 
in audio equipment. In this case, ceramic piezoelectric transducers convert 
electrical energy into mechanical energy, which is transmitted to a 
titanium horn that forms the atomizing tip. Coating liquid that is introduced 
onto the atomizing surface absorbs some of the vibrational energy. 
causing a wave motion to be set up in the liquid. If the vibrational 
amplitude is carefully controlled, the liquid wID break free from the surface 
of the nozzle as a fine mist (with median droplet sizes in the range 
of 20-50 um) . 
So far, the use of ultrasonic nozzles with pharmaceutical coating 
liquids has met with t.ery limited success. Most polymeric-coating

Coatin.g of Pharmaceutical Solid-Dosage Forms 153 
solutions appear to present a problem with respect to achieving effective 
and-controllable atomization. This limitation seems to reflect the complex 
rheological and cohesive properties of these solutions. Such nozzles might 
be used more effectively where the coating liquid is a dispersion (e. g. , 
many of the formulations used in sugar coating or the aqueous latex systems 
used in film coating). 
Berger [63] has given a more complete description of ultrasonic nozzles, 
their applications, and limitations. 
D. Metering/Delivery Equipment 
This discussion of metering/delivery equipment refers to that equipment 
Which enables coating liquid to be delivered from a bulk holding tank to 
the application equipment described in the previous section (Sec. IV.C). 
Pressurized Con.tainers 
Pressurized containers (or pressure pots, as they are commonly called) 
were once commonly used with many organic-solvent-based film-coating 
systems and have recently been reintroduced as components of some 
specialized automated delivery systems. 
Basically, such a system consists of a special liquid holding tank that 
can be pressurized by compressed air. Once pressurized, the liquid is 
forced from the tank through feed lines to the spray nozzle. Fluid delivery 
rates with such equipment will be dependent on air pressure. 
liquid viscosity and density, length and internal diameter of the feed lines, 
and design of the spray nozzles used. 
All other things being equal (for a given system and coating liquid), 
flow rate is controlled via a pressure regulator that determines pressure 
within the tank. 
Precision with such a system may be inadequate when attempting to 
deliver low-viscosity aqueous-coating liquids (such as latex dispersions). 
Peristaltic Pumps 
Peristaltic pumps (or "tubing" pumps) are commonly used in many coating 
operations. The operating principle of these pumps is based on the ability 
to create liquid flow in a tube by squeezing and stretching that tube. 
Most common peristaltic pumps have a pump head that allows a piece of 
tubing to be clamped in a U - shaped fashion against a rotating mechanical 
device (such as "fingers" or rollers) that squeezes the tube and creates 
motion of the liquid within the tube. To function effectively, the material 
from which the tubing is made should have sufficient resiliency that it 
quickly recovers its original shape after squeezing. For this reason. preferred 
tubing is made from silicone rubber. 
Peristaltic pumps have two major advantages: 
1. They are simple and inexpensive (to purchase and operate). 
2. They are sanitary (since the liquid being transferred does not 
come in direct contact with the mechanical pump head). and cleanup 
is easUy accomplished by passing a cleaning liquid through the 
tubing, and tubing that is difficult to clean can be replaced at 
little cost.

154 Porter and Bruno 
There are some major drawbacks with such equipment, including: 
They are not positive displacement pumps. 
Linearity, and often accuracy, decreases as the pump speed is increased 
(particularly at the high end of the speed range). 
Accuracy decreases as the tubing wears and fatigues. 
Their effectiveness is limited by liquid viscosity. 
Gear Pumps 
Gear pumps are becoming extremely popular in aqueous film coating. They 
are positive displacement pumps that rely on two counterrotating gears to 
draw liquid into and through the pump housing. Because the gears come 
into contact with the coating liquid, they must be made of noncorrodible 
materials. Gear pumps can transfer liquids with a wide range of viscosities, 
but rely on the inherent "lubrdctty" of the coating liquid to minimize wear 
in the gear mechanism. 
Some limitations of gear pumps are: 
Cost 
Requirement for more complicated clean-up procedures 
Likelihood of excessive wear of mechanism when pumping highly pigmented. 
low-viscosity coating liquids 
Likelihood of inducing coagulation of latex-coating systems as a result 
of shear developed as liquid passes through pump head 
While many gear pump s rely on a direct mechanical drive. some recent 
models have an indirect magnetic drive. 
Piston Pumps 
Piston pumps. which are also positive displacement pumps, rely on a reciprocating 
piston (typically powered by a compressed air motor) to transfer 
the coating liquid. Such a pump can easily handle very viscous liquids 
and so is well suited to sugar-coating and most film-coating operations. 
Those piston pumps driven by air motors usually have a particular 
pressure ratio rating (such as 30; 1, 10; 1, or 5: 1). This rating refers to 
amount by Which pressure supplied by the air operating the pumps is increased 
when transferred to the liquid being pumped. For example J 10 
psi air pressure applied to a 30:1 ratio pump will generate 300 psi of liquid 
line pressure. For this reason, such pumps are commonly used as the delivery 
mechanism in airless spray systems. 
More recently, electrically driven piston pumps, which have variable 
speeds and stroke lengths and generate very little line pressure, have 
been introduced as components of air-spray systems used in aqueous film 
coating. An example of such a pumping system is the VOlumetric pump 
PD 1000/S supplied with the Pellegrini-OS coating system. 
Piston pumps, like gear pumps, are relatively expensive and not as 
easy to clean as tubing pumps. In addition, the shearing action as the 
pump reciprocates may induce coagulation of latex-coating systems. This 
is particularly true when any significant line pressure is generated.

Coating of Pharmaceutical Solid-Dosage Forms 
V. AUTOMATED COATING PROCEDURES 
A. Jntroduction 
155 
In the early days of tablet coating, the addition of coating liquids, determination 
of distribution/mixing times. and application of drying and 
exhaust air were all manual operations. Decisions as to when heated air 
should be applied, coating liquid should be added, and how long to allow 
for uniform distribution of the coating liquid were all judgmental factors on 
the part of the operator. 
In order to achieve a high level of reproducibility in the process and 
simplify the documentation process, it is apparent that the above situation 
has many limitations. 
To effectively automate a process, it is necessary to remove the requirements 
for direct (and repeated) involvement by the operator. The 
process must be well developed and precisely defined (when a poorly defined 
process is automated it will simply produce consistently unacceptable 
results time after time). In particular, it is imperative to avoid using any 
critical steps that can only be achieved on such a limited basis as to 
render the whole process impractical. 
The benefits to be derived from a well-automated process are; 
Independence from operator judgment 
Achievement of consistent product quality 
Achievement of a fully optimized process with greater potential for 
minimizing processing times 
Production of hard-copy documentation 
It is critical, however, that an automated process possesses a fail-safe 
mechanism so that process shutdown takes place in the event of process 
failure. Such a procedure will reduce the liklihood that a batch of product 
is ruined. 
The automation of a coating process typically involves two basic 
activities: 
1. Timing and sequencing (more appropriate for sugar coating where 
a sequence of events must occur at specific time intervals) 
2. Measuring and controlling appropriate processing parameters 
The second of these two activities can be the more difficult, particularly 
since appropriate precision in measuring devices may be difficult to 
achieve. Measuring and control devices may be classified as; 
Electromechanical 
Pneumatic 
Electronic 
There is no doubt that electronic devices are preferred in order to 
deal with the complexities of today's coating processes. Electronic devices, 
however, are subject to drift, and thus must constantly be zecalibrated 
to ensure accuracy and precision.

156 Porter and Bruno 
Figure 3lJ. Figure of a totally automated film-coating process. (Courtesy 
of Meltech. East Hanover. New Jersey.) 
A description of some pan-coating control systems has been given by 
Thomas [64], and an example of a modern fully automated tablet coating 
process is shown in Figure 34. 
B. Automation of Sugar Coating 
In basic terms, sugar coating can be considered. from the automation 
standpoint. to be a complex. noncritical process. Complexity stems from 
the significant number of timing and sequencing functions that are required. 
Noncriticality (from a relative standpoint) occurs because many of the coating 
parameters need not be controlled to extreme accuracies. For example, 
accurate control of airflow and temperature is not critical as long as specific 
objectives (such as achieving a particular state of product dryness 
before the next addition of coating liquid occurs) are met. 
Early attempts at automation of the sugar-coating process involved 
achieving the appropriate sequencing and timing by means of timers. 
Such an approach is very simple but has limitations. namely: 
If constant, predictable drying conditions are not achieved (such as 
use of temperature and humidity-controlled drying air). then seasonal 
variations in conditions may result in predetermined sequencing 
and timing to be totally inappropriate for a specific set 
of conditions. 
As coating build-up occurs, there may be a need to adjust the volumes 
of coating liquid applied.

Coating of Pharmaceutical Solid-Dosage Forms 157 
Over the last 25 years, various descriptions of automated procedures 
have appeared in the pharmaceutical literature [65 - 67]  
An early commercially available system, the Drdamat , has been described 
by Rose [68]. 
A more recently introduced commercial, fully-automated, sugar-coating 
process is the Sandomatic system, which was first described by Melliger 
and Goss [69]. 
The important independent process variables that need to be monitored 
and controlled in a typical sugar-coating process are: 
Drying air volume (or flow) 
Drying air temperature 
Drying air humidity 
Pan speed 
Quantity of coating liquid applied (at each step) 
C. Automation of Film Coating 
In comparison to sugar coating, film coating is a simpler, but more critical 
process to automate. Little sequencing is required, but important process 
conditions must be monitored and controlled to a high degree of accuracy. 
Important independent variables that need to be measured and controlled 
in a film -coating process inc1u de: 
Drying air volume 
Drying air temperature 
Drying air humidity 
Pan speed 
Spray rate (more precisely, the delivery rate from each spray gun in 
a multiple-gun setup) 
Atomizing air pressure/volume 
Pattern air pressure/volume 
In addition, it may be necessary to control various dependent variables, 
particularly in the aqueous process where the margin for error can be 
much less than in other types of coating process. Some of the important 
dependent variables that need to be monitored are: 
Tablet bed temperature 
Exhaust air temperature 
Exhaust air humidity 
Tablet bed moisture 
Since these variables cannot be controlled directly, it will be necessary 
to control the interaction between those independent variables that influence 
a particular dependent variable. For example, exhaust air temperature 
may be kept under control by maintaining an appropriate balance between: 
Inlet air volum e 
Inlet air temperature 
Inlet air humidity 
Spray rate

158 Porter and Bruno 
In the aqueous film-coating process, the importance of taking into account 
the moisture content of the inlet drying air cannot be overemphasized. 
The simplest way of dealing with this issue is to keep inlet air 
humidity constant by use of a dehumidificat .on process. Such an approach 
can, however. prove to be extremely expensive, since the volumes of air 
that need to be conditioned are typically very large (in an aqueous filmcoating 
process, e.g a typical 48" Accela-Cota coating a batch of tablets 
in 90 min wID require approximately 5000 m3 of conditioned air). 
An alternative is to compensate for variation in humidity of inlet air 
by adju sting one or more of: 
Air volume 
Inlet air temperature 
Spray rate 
Lachman and Cooper [70] have described an early attempt to automate 
the film-coating process. More recently, the automation principles of the 
Sandomatlc process have been applied to film coating. Also, virtually 
every supplier of pan-coating equipment can provide automated equipment, 
and selection may well depend on the preferences, and individual needs, 
of the pharmaceutical manufacturer. 
REFERENCES 
1. Signorino, C. A., U.S. Patent 3,738,952 (1973). 
2. Rowe. R. C . Int. J. Pharm., 43:155 (1988). 
3. McGinlty, J. W., Aqueous Polymeric Coatings for Pharmaceutical 
Dosage Forms. Marcel Dekker, New York, 1988. 
4. Skultety, P. F., Rivera, D., Dunleavy, J., and Lin, C. T. Drug 
Dev. Ind. Pharm., 14(5):617 (1988). 
5. Reiland, T. L. and Eber, A. C  Drug Dev; Ind. Pharm., 13(3): 
231 (1986). 
6. Thoennes, C. J. and McCurdy, V. E., contributed paper at PT 
Section of 3rd Annual Meeting of AAPS, Orlando, Florida, Oct. 1988. 
7. Ebey, G. C.. Pharm. Tech.. 11( 4) : 40 (1987). 
8. Rowe, R. C., J. Pharm. Pharmacal., 29: 723 (1977). 
9. Fisher, D. G. and Rowe, R. C., J. Pharm, Pharmacol., 28:886 
(1976)  
10. Rowe, R. C., J. Pharm. Pharmacal., 30:669 (1978). 
11. Aulton, M. E., Twitchell, A. M., and Hogan, J. E.. Proceedings of 
AGPI Conference, Paris (1986). 
12. Rowe, R. C., J. Pharm. Pharmacal., 32:851 (1980). 
13. Rowe, R. C. and Forse, S. F., Acta Pharm. Tech., 28( 3) : 207 
(1982)  
14. Twitchel, A. M Hogan, J. E., and Aulton, M. E., J. Pharm. 
Pharmacal., 398: 128P (1987). 
15. Porter, S. C. and Saraceni, K., Pharm. Tech., 12(9):78 (1988). 
16. Kara, M. A. K., Leaver, T. M and Rowe, R. C., J. Pharm. 
Pharmacal., 34:469 (1982). 
17. Rowe, R. C., Pharm, Int., 6(9):225 (1985).

Coating of Pharmaceutical Solid-Dosage Forms 159 
18. Wicks, Z. W., Jr., FUm Formation. Series on Coatings Technology, 
Federation of Societies for Coating Technology, Philadelphia (1986). 
19. Burrett , H., Offic. Dig., 34(445):131 (1962). 
20. Williams, M. L., Landel, R. F., and Ferry, J. D., J. Am. Chem. 
Soc., 77:3701 (1955). 
21. Wicks, Z. W., Jr., J. Coatings Technol., 58(743):23 (1986). 
22. Entwistle, C. A. and Rowe, R. C., J. Pharm  Pharmacol., 31: 269 
(1979)  
23. Rowe, R. C., J. Pharm. Pharmacal., 33: 423 (1981). 
24. Bindschaedler, C., Gurney, R., and Doelker, E., Labo-PharmaProbl. 
Tech., 31(331):389 (1983). 
25. Bradford, E. B. and Vanderhoff, J. W., J. Macromol. Chem., 1(2): 
335 (1966). 
26. Gross, H. M. and Endicott, C. J., D&CI, 86( 2) : 170 (1960). 
27. Porter, S. C., Pharm  Tech., 4( 3) : 66 (1980). 
28. Crawford, R. R. and Esmerian, O. K., J. Pharm. set., 60(2):312 
(1971) . 
29. Sakellariou, P., Rowe, R. C., and White, E. F. To, Int. J. Pharm., 
31: 55 (1986). 
30. Woznicki, E. J. and Schoneker, D. R., Coloring agents, In Encyclopedia 
of Pharmaceutical Technology. Marcel Dekker, New York, in press. 
31. Porter, S. C., Int. J. Pharm, Tech. Prod. Mfr., 3( 1) : 21 (1982). 
32. Rowe, R. C., Pharm. Acta. Helv . 60(5/6):157 (1985). 
33. Rowe, R. C., J. Pharm. Pharmacol., 33;51 (1980). 
34. Rowe, R. C., J. Pharm. Pharmacol., 36: 569 (1983). 
35. Rowe, R. C. and Forse, S. F., J. Piuirm, Pharmacal., 35:205 
(1983)  
36. Rowe, R. C., Int. J. Pharm., 14:355 (1983). 
37. Banker, G. S., J. Pharm, Sci., 55;81 (1966). 
38. HUdebrand, J. and Scott, R., The Solubility of Non-Electrolytes, 
3rd Ed. Reinhold, New York, 1949. 
39. Kent, D. J. and Rowe, R. C., J. Pharm. Pharmacal., 31(5):269 
(1979)  
40. Rudin, A. and Wagner, R. A., J. Appl. Polym. Sc , 19:3361 
(1975)  
41. Johnson, K., Hathaway, R. D., and Franz, R. M., Presented at the 
Contributed Paper Session of the 3rd Annual Meeting of AAPS, 
Orlando, Florida, 1988. 
42. Porter, S. C., In Aqueous Polymeric Coatings for Pharmaceutical 
Dosage Forms (J. W. McGinity, ed.), Marcel Dekker, New York, 
1988, p , 317. 
43. Ozturk, S. S., Palsson, B. 0., Donohoe, B., and Dressman, J. B., 
Pharm. se, 5( 9) : 550 (1988). 
44. Edgar, B., Bogentaft, C., and Lagerstrom, P. 0., Biopharm Drug 
Disp., 5:251 (1984). 
45. Theeuwes, F., J. Pharm. sa., 64(12):1987 (1975). 
46. Lindholm, T. and JuIsin, M., Pharm. tna., 44(9):937 (1982). 
47. Jarnbhekar, S. S., Breen, P. J., and Rojanasakul , Y., Drug Dev. 
Ind. Pharm., 13( 15) : 2789 (1987). 
48. Rowe, R. C., J. Pharm. Pharmacal., 35:112 (1983). 
49. Rowe, R. C., J. Pharm. Pharmacol., 32: 851 (1980).

160 Porter and Bruno 
50. Breech. J. A., Lucisano, L. J., and Franz, R. M., J. Pharm. 
Pharmacol.. 40: 282 (1988). 
51. Rowe. R. C. and Forse, S. F., Acta. Pharm. Technol.. 28(3):207 
(1982). 
52. Kim. S., Mankad. A  and Sheen, P. Drug Dev. Ind. Pharm., 12(6): 
801 (1986). 
53. Down. G. R. B., J. Pharm. Pharmacal., 34(4):281 (1982). 
54. Shah, B. B., Contractor, A. M.. and Auslander. D. E., Pharm. 
Res., 5(10):S-253 (1988). 
55. Wurster. D. E., U.S. Patent 2.648,609 (1953). 
56. Hall. H. S. and Hinkes, T. M., Presented at the Symposium on 
Microencapsulation: Processes and Applications. American Chemical 
Society. Chicago, Aug. 27-31, 1973. 
57. Glatt Technically Speaking, 2( 1) : 1 (1989). 
58. Jones. D. M., Pharm. Technol., 9(4):50 (1985). 
59. Mehta, A. M., Pharm. Technol., 12( 2) : 46 (1988). 
60. Olsen. K. W. and Mehta. A. M., Int. J. Pharm. Tech. Prod. Mfr 
6( 4) : 18 (1985). 
61. Johansson, M. E., Ringberg, A., and Nicklasson, M., J. Microencapsul 
4(3):217 (1987). 
62. Stern. P. W., J. Pharm; Sci 63(7):1171 (1974). 
63. Berger, H. L., Machine Design, July 1988. 
64. Thomas. R., Pharmaceut. Eng., 16:Aug. -Oct. (1981). 
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66. Heyd, A. and Kanig, J. L., J. Pharm. sa., 59(8):1171 (1970). 
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Presented at A.I.Ch.E. Meeting, New York, Nov. 17, 1977. 
68. Rose, F., D&C.I 44:Nov. (1971). 
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70. Lachman. L. and Cooper. J., J. Pharm. Sci; , 52( 5) : 490 (1963).

3
Particle-Coating Methods 
Dale E. Wurster 
University of Iowa. Iowa City, Iowa 
I. INTRODUCTiON 
There are many important pharmaceutical reasons for applying coatings to 
both pure chemicals used as medicinal agents and to physical -chemical 
systems employed as dosage forms [l-4J. Similar coatings are also widely 
used in other industries to coat particulate solids. One of the most widespread 
pharmaceutical uses today is for the control of drug release from 
various types of oral or parenteral dosage forms designed to have either 
an enteric, a timed, or a sustained-release effect. Thus, particle coatings 
can be formulated so that the escape of the drug from the dosage 
form occurs primarily via a diffusional process. The various physical 
parameters influencing diffusion can then be modified in order to control 
the rate of drug release. In other systems, the dissolution kinetics of 
the applied coat serve to control the availability of the contained drug. 
In still other cases, drug release can be controlled by chemical reactions 
involving the coating material or by simple attritional effects on the coat. 
No matter what mechanism of controlled drug release one wishes to use, it 
is apparent that this can usually be achieved by the proper formulation of 
coating materials and the manner in which they are applied. 
A second type of effect achieved by coating procedures is the enhancement 
of the chemical stability of drugs. It is possible to formulate 
coating materials to guard against the penetration of substances which will 
cause specific degradation reactions. Thus, coatings can be designed to 
resist the penetration of water vapor when the product contains drugs 
which are susceptible to hydrolytic decomposition. For those drugs which 
degrade by oxidative reactions, coatings can be used which inhibit the 
transport of oxygen to the lab:ile compound. In cases where detrimental
161

162 Wurster 
interactions result from materials contained within the physical system rather 
than from external influences, the incompatible materials can be separated 
by suitable coatings. 
Of course, coating procedures have long been used to occlude drugs 
with an unpleasant taste from the taste receptors, or to impart pleasing 
colors to a product to make it more attractive visually. Certain other 
physical parameters, such as particle density, surface characteristics, or 
geometry, can also be altered by the use of coatings to obtain processing 
advantages. For example, coatings can sufficiently change the geometry 
and surface of small particles so that the flow properties of a powder are 
enhanced. 
It is the primary intent of this chapter to present a discussion of 
those processes which are useful in particle coating to meet the above 
needs. While the theoretical mechanisms involved in controlling such factors 
as drug release and chemical stability are of great interest to all who 
work with these systems, a discussion of these mechanisms is not within 
the scope of this chapter. Primary emphasis is, therefore, directed toward 
the processes which are useful for the coating of solid particles. However, 
methods which are mainly useful for the microencapsulation of liquids are 
also briefly discussed. This is because these processes can usually be 
modified so that, in some manner, particulate solids can also be coated. 
II. WURSTER PROCESS 
A. Introduction 
The commonly called air-suspension particle-coating method, also known as 
the Wurster process,* has been utilized for many years by the pharmaceutical, 
chemical, food, agricultural, and other industries. The rapidity 
of the operation, the ability to control variables, the uniformity of the coat 
produced, and the fact that it can be used to coat particles varying greatly 
in size. shape, and density are some of the main advantages of the 
process. Further, the process does not restrict either the kind of coating 
materials used or the solvents employed in the coating fluids. Even chemical 
reactions designed to produce polymer coatings from applied monomer 
solutions can be easily conducted in the column. 
Because it is possible to control the variables of the process the method 
is sufficiently flexible to make it extremely versatile. Thus, the 
process can be utilized to coat medicinal tablets [5 -13] or other large particles, 
to microencapsulate fine particles [14], to control drug release from 
coated particles [15,16], and to prepare compressed tablet granulations 
[17,18] or the like. By the proper adjustment of process conditions, it is 
possible to either coat solid particles Or to cause particles to aggregate. 
It is also possible to control the density, geometry, friability, and other 
physical parameters. of the treated particles. 
There is little doubt that the Wurster process provides the most rapid, 
efficient, and cost-effective method of producing film-coated compressed 
"'Wisconsin Alumni Research Foundation, Madison. Wisconsin.

Particle-Coating Methods 
tablets. Similar advantages are gained in microencapsulation and compressed-
tablet granulation procedures. 
B. General Description 
163 
The Wurster process* can be appropriately be described as an upwardmoving, 
highly-expanded pneumatically transported bed of particles coupled 
with a downward-moving, more condensed, fluidized bed of particles on the 
periphery of a vertical column. The two beds are separated by the tubular 
central partition. Figure 1 is a schematic drawing of the equipment. As 
indicated above. the particles to be coated are pneumatically conveyed upwardly 
through the central tube, (b). of the coating chamber. As the 
particles pass the atomizer, (d). they are wetted by the coating fluid and 
then Immediately subjected to drying conditions created by the heated COnveying 
air moving upwardly in the column. The partially coated solid particles 
move downwardly in a near-weightless condition along the periphery 
of the column. (c). where further drying occurs. When the solid particles 
reach the lower end of the column they are directed back into the 
upwardly-moving bed and the entire process is repeated. The air pump, 
(g). and heater (f), provide the heated support air for the process, and 
the distribution plate (e) directs the proper volume of air to the central 
and peripheral regions of the column. 
The proper adjustment of the airflow, the temperature, and the fluid 
application rate are all critical to the successful operation of the process. 
Obviously. the drying kinetics are influenced by the airflow rate and the 
temperature of the air. These kinetics in turn dictate the fluid application 
rate. Since drying is a cooling process. the temperature of the particle 
surface is lower than either the inlet or exhaust air temperatures. 
This permits the coating of heat-sensitive materials, since process conditions 
can be adjusted so that the exhaust temperature will not exceed the 
temperature which the product can tolerate. Thus, it is readily apparent 
that the drying kinetics can be enhanced by increasing either the airflow 
rate or the air temperature while maintaining the fluid application rate 
constant. 
C. Control of Airflow 
The proper airflow rate is most important for the successful operation of 
the Wurster process. It is apparent from the general description of the 
process that the two-component fluidized bed employed in this process 
*Before using this or other fluidized bed processes. it is important to become 
familiar with the basic principles that govern fluid-bed systems. 
The following textbooks are included in a long list of textbooks that are 
very useful for this purpose. (1) Cheremisinoff, N. P., Hydrodynamics of 
Gas -Solids Fluidization. Gulf Publishing Co Houston, 1984; (2) Davidson, 
J. F., Fluidization, Academic Press, New York, 1971; and (3) Howard, 
J. R., Fluidized Beds, Applied Science Publishers Ltd., London, 1983.

164 
---+--- Settling chamber (a) 
.....+----- Central tube (b) 
....---- Peripheral Tube (c) 
Atomizer (d) 
~E~~"""--- Distribution plate (e) 
Heater (1) 
Figure 1 Schematic drawing of air-suspension coating apparatus. 
Wurster 
differs considerably from a conventional fluidized bed. Since the solid particles 
undergo pneumatic transport up the central portion of the column 
and descend in the peripheral region, different air velocities are required 
in the two regions. Although an air distribution plate is positioned at the 
base of the column (see Fig. 1). an air distribution zone also exists just 
above the plate. It is in this zone in the loaded column that the air undergoes 
further distribution to the directional flow and velocity conditions 
which prevail above the plate and which differ markedly from the conditions 
imposed by the plate alone [19]. Nevertheless, it is extremely important 
that the plate is properly designed for the particular production 
process for Which the method is being used. 
Minimum Fluidization Velocity 
When particulate solids are placed on a perforated plate in a vertical column 
and a gas, usually air, is passed upwardly through the bed of particles 
the bed at lower air velocities will initially remain fixed. However, 
as the air velocity is increased the particulate bed expands, the individual

Particle-Coating Methods 165 
particles begin to move in the air stream. and an increase in the void 
space of the bed is observed. The transition of the bed from the fixed 
to the fluidized state occurs at the point where the pressure drop across 
the bed is equal to the weight of the bed per unit of cross-sectional area. 
This is often referred to as incipient fluidization, and the air velocity required 
to produce this state is known as the minimum fluidizing velocity. 
Thus. the pressure drop across the bed at incipient fluidization is given 
by [20.21] 
(1) 
Where &Pb := pressure drop across bed 
Emf =bed voidage at condition of minimum fluidization 
p =density of solid particles s 
o =density of fluidizing gas 
g 
Hmf = height of bed at minimum fluidization 
g =gravitational constant 
For uniform. small spherical particles in the approximate range of 
20-100 um and densities up to 1.4. the equation derived by Kozeny [2023] 
and tested by Carman over the range of bed voidages of O. 26 - 0.89 
[24.25] shows that the relationship between the pressure drop and the 
minimum fluidizing velocity at incipient fluidization can be written in the 
following manner 
3 
E 
V:= mf 
mf 5(1 _ E )2 
mf 
(2) 
Here Vmf = gas velocity at minimum fluidization 
S = specific surface area of solid particles 
J.l =the viscosity of the gas 
From equations (1) and (2). it follows that 
3 e 
V = mf 
mf 5(1 - Emf) 
(3) 
If it is assumed that the bed is composed of uniform spherical particles. 
S = 6/d, where d is the particle diameter and correspondingly. the bed 
voidage, Emf' is considered to be 0.4 then [20) 
0.4
3 
V := mf 5(1 - 0.4) 
( 4)

166 Wurster 
Another simple and convenient method for predicting the approximate 
minimum fluidization velocity for solid particles in the 50- to 500-jJm size 
range takes advantage of the mathematical expression recommended by 
Woodcock [21,26) 
( 5) 
Here Vmf = minimum fluidization velocity in mls 
p =the solid particle density in kg/ m3 
p 
d =mean particle diameter in meters 
v 
When the bed is composed of larger particles it has been suggested by 
some [20] that more general type equations such as those given by Ergun 
[27] and Black [28] be employed to arrive at the pressure drop across 
the bed. 
Effects of Increasing Air Velocity 
The influences on the bed created by increasing air velocities are shown 
in the idealized graph [29] presented in Figure 2. As stated previously, 
the pressure drop across the bed increases with an increase in the velocity 
of the air directed through the bed. Initially. the bed remains fixed, but as 
the air velocity is further increased the bed expands somewhat and the 
0.. 
 
0.7 .... ;:r 
0
~
CI.l 
0.6 1- 
:
, 
0.5 .~ 
"0
?: 
u 
0.4 '"c, 
'" OJ 
III 
~ 
0.3 '0 
::E 
0.2 
0.1 
100 90 80 70 
Wet bulb 
temperature 
of 
0.021 , 
?: :c 
'E
" J: 
"-I '" ~ 
!~ 
TEMPERATURE (Degree F) 
Figure 6. Humidity chart. 
~
~

~a~
~ 
180 160 140 120 
Temperature IDegree F) 
100 80 60 
Alcohol-drying chart for coating solution. Figure 7 
.... 
~ 
PERCENTAGE SATURATION I 
15% 10% 5% 
005I I i ./ / /  I. 1 2 
5 
Safe operating 
limit 
I I I2.0 ~ 
0041 I I . I - { --,., 1 I I I '" if ... ... E 
't
~~ 
o I I Im--.:-='\l: ~~ .r:. '- - I) o ;;; ~ > ~.c 003 - - - - I 15 0-- ~-=- -~ ~ ~'~~'.".'~I"'" I =1 i~ 
u 
;;; 
'0 
DOlt I ~~'* -=---t==:= - - - -10 E 
001 - - - - - - - - - - - - ~ - t ~, J 05

Particle -Coa ting Metho ds 173 
is maintained, then attrition of the particles may occur. In actual practice, 
then, a humidity condition above 85% for some materials can lead to aggregation, 
whereas below 45% attrition may occur. 
Drying charts can be constructed and used for organic solvents or solvent 
mixtures in a manner similar to the above use of the humidity chart. 
In Figure 7, a drying chart for ethyl alcohol solutions of coating materials 
is shown. The required calculations for chart construction are conventional 
and need not be treated here.* As in the case of humidity charts, 
these charts ignore the influence of dissolved substances on the solvent removal 
rate. 
The determination of the fluid application rates using solvent-drying 
charts such as shown in Figure 4 differs slightly from that of a humidity 
chart. This, of course, is because the atmosphere employed as the support 
air does not normally contain a significant amount of the organic solvent. 
From the alcohol-drying chart shown in Figure 5, it can be observed 
that if the air is 140F and if an outlet temperature of 98F is desired, 
then 0.024 lb of alcohol/1b Qf dry air can be used. From the righthand 
scale it can be observed that under the above conditions, 1.13 ml of 
the coating solution per cubic foot per minute of air can be employed. 
Then if the support air is 100 efm , the fluid application rate for the coating 
solution is 113 ml min-1 
Since alcohol is an inflammable solvent, the process conditions can be 
set so that a wide margin of safety exists. The lower inflammability limit 
for alcohol is O. 0716 1b of alcohol vapor/lb of dry air. In Figure 4, the 
safe operating limit is set at two-thirds of this value or 0.0477 lb of alcohol/
1b of dry air. The maximum inlet temperature is also indicated as is 
the process limit. By setting operating conditions within these parameters, 
a wide margin of safety is achieved [30]. 
E. Drying Properties of the Process 
When particles are wetted by a solvent it can be assumed that normally the 
solvent penetrates into the particle and also that a pool of solvent resides 
on the surface. When the wetted particle is subjected to a drying process, 
the solvent on the surface is readily removed at a constant rate or a steady 
state exists. The solvent which has penetrated the particle subsequently 
returns to the surface by diffusion and capillarity, and thus a nonsteady 
state exists for the removal of the solvent residing within the particle. 
Figure 8 shows a typical drying curve for the solvent loss from a particle 
as a function of time. 
In the Wurster process, a thin layer of the coating fluid is atomized 
onto the surface of the solid particles. Because of the elevated temperatures 
and the large volume of air passing over the particles, the solvent 
is rapidly removed and drying occurs primarily under the steady-state 
condition. 
*The interested reader is referred to Perry, R. H. and Chilton, C. H., 
Chemical Engineers' Handbook, 5th Ed., McGraw-Hill Book Company, 
New York, 1973, Chap. 20; and Pilot Plant Operation, Wurster Coating and 
Granulating Process, Wisconsin Alumni Research Foundation, Madison, 
Wisconsin, Sec. VI.

174 Wurster 
Time 
Figure 8 Water loss as a function of time. 
Falling rate period 
Constant rate period 
Drving 
rate 
(W) Free moisture 
Figure 9 Drying rate versus free moisture.

Particle-Coating Methods 175 
In drying processes, the nonsteady state or falling rate and the steady 
state or constant rate of solvent removal is often depicted as shown in 
Figure 9, in which the drying rate is plotted against the free solvent content. 
The following relationship is also often employed to determine the 
constant drying rate in conventional drying processes [32J. 
dw 
Cit =
h A (t - t ) 
t a s =k A (P _ P ) 
A. gsa (7) 
= wet surface temperature 
= mass transfer coefficient in Ib/(hr)(ft2)(atm) 
=vapor pressure of H2
0 at t s 
=the partial pressure of H
2
0 in air 
where dw dt =drying rate in Ibs , H20 /h 
h
t = total heat transfer coefficient in Btu /(hr)(ft2)(OF) 
A = area in ft 2 
A =latent heat of evaporation at t s 
t =air temperature a 
t s 
k g 
Ps 
Pa 
To obtain the falling rate in drying processes, we can use [32] 
( dw) = K (W - W ) 
dt F e 
(8) 
Here W = average moisture content at time, t (dry basis) 
W =average moisture content (in equilibrium with external eondieditions) 
(dW) =(dW) =K(W - W ) 
dt C W=W dt F W-W c e 
'c J C 
where Wc = critical moisture content, and F =falling rate and C =the 
constant rate, or 
(9) 
K =
(dw)/(dt)C 
W - w c e 
(10) 
( 11) 
Figure 10 shows the difference in the rate at which water is removed 
from a product in the air-suspension method as compared to more traditional 
drying methods. As indicated previously. the process can he monitored 
by folloWing the exhaust temperature. Also J as shown in Figure 11,

176 
... s'" ... ~ iii 
~~ 
"0 
G> 
>oE
e... 
J!l s 
----,I  Air suspension drying 
I
\,\
\ 
1----- \ 
\
\ 
\ 
Elapsed drying time .... 
Wurster 
Figure 10 Comparison of air-suspension drying with traditional drying 
methods. 
Inlet air temperature 
r 
Dried product 
/ removed 
Product temperature 
Elapsed drying time .... 
Figure 11 Air-su spension drying.

Particle-Coating Methods 177 
., 
:; ... 
~., 
Q. 
E., 
IInlet 
air temperatu re 
Product 
..--temperature 
Elapsed drying time .. 
Figure 12 Traditional drying process. 
the exhaust temperature remains relatively constant during the steady-state 
drying which occurs during the coating process. When atomization is 
stopped. the temperature rapidly rises and the dried product can be immediately 
removed without exposing it unnecessarily to a high temperature 
for a long time. If during the actual coating process the exhaust temperature 
falls below that set for the process. this suggests that the fluid 
application rate is too great; the particles may become too wet. and aggregation 
will occur. Conversely. if the exhaust temperature rises, then the 
column condition is drier than desired and particle attrition may occur. 
The equipment can be instrumented to monitor such changes and to make 
corrective changes. Figure 12 shows the drying curve of a wetted product 
by more traditional methods. In the case of substances which form hydrates. 
the slight temperature changes can actually be utilized to follow 
the conversion of one hydrate form to another (Fig. 13). 
F. Uniformity of Coat 
One of the main advantages of the air-suspension coating process is the 
uniformity of coat that can be achieved on both small and large particles. 
If the coating fluid is applied at a constant rate, both the weight of the 
particles and the cube of the radius for spherical particles should increase 
linearly with time. Figures 14 and 15 show this to be the case [5]. Even 
a very thin. 1-lJm thick coat applied to a small crystal is extremely uniform. 
as is shown in Figure 16.

178 
Inlet air temperature 
Wurster 
Exhaust air temperature 
Drying tirn 
Figure 13 Air-suspension drying of a hydrate.

o 60 120 
Time (min) 
180 
Figure 14 Weight of particles as a function of process time (constant 
atomization rate). 
o 60 120 
Tmu- {Ill Ill) 
180 
Figure 15 Particle size of spheres as a function of process time (constant 
atomization rate). 
179

180 Wurster 
Figure 16 A t-um thick coat on a single crystal. 
G. Particle Aggregates, Granulations, and 
Particle Build-Up 
As previously stated, it is possible to prepare particle aggregates of different 
densities and geometries depending upon column conditions. For 
example, one can prepare aggregates which are comparable to those made 
for a compressed tablet granulation by the wet method. By utilizing materials 
which are tacky when wet, a column condition approaching saturation 
of the support air can be employed. In the case of water solutions 
containing such materials as sugars and gums, a humidity condition in the 
column exceeding 85% relative humidity (RH) will usually result in particle 
aggregation. Irregular particles prepared by this process are shown in 
Figure 17. If a friable, low-density spherical particle is desired. this

Particle-Coating Methods 
Figure 17 Irregular aggregate of particles (1500 um) , 
181

182 Wurster 
Figure 18 Porous low-density spherical aggregate of particles (1000 um) ,

Particle-Coating Methods 183 
can also be accomplished. In this case a high-humidity column condition 
together with the atomization of the binder solution as large liquid particles 
is required. By utilizing a very small particle size of the solid material 
(less than 15 um) and a large droplet size of the atomized solution. 
the small solid particles are allowed to impinge upon and be entrapped by 
the large liquid particles. Upon the subsequent removal of the solvent. a 
porous. low-density particle results. This type of particle is shown in 
Figure 18. The fragility of this type particle is evident by the presence 
of the fractured spheres in the figure. 
Spherical particles of near-theoretical density can be prepared by coating 
particles with a slurry which contains both suspended solids and a 
binder. In this case, column conditions are adjusted so that a coating 
process rather than an aggregation process results (Fig. 19). If water is 
Figure 19 High-density, slurry-coated particles (2000 um) .

184 Wurster 
the solvent, a 65% humidity condition in the column can be used as a 
starting point. 
Granulations of effervescent materials are normally quite difficult to 
prepare by conventional methods because of the close control which is required 
over the reaction rate, the drying rate, and the residual water. 
The air-suspension process is well suited for the preparation of these 
granulations [33] because of the ease with which the process conditions 
can be controlled and monitored. 
In air-suspension coating procedures. the lower particle size limit is 
approximately 50 um , but smaller particles have been coated. There is no 
practical upper limit for larger particles. In fact, very large particles 
are efficiently coated with great ease. When particle aggregates (tablet 
granulations, etc.) are prepared. very fine particles of only a few micrometers 
can be aggregated into larger particles without difficulty. Of course, 
the particle aggregates can subsequently be coated, if desired, without removing 
them from the column. 
Lastly. because the air-suspension process operates as a closed system 
with respect to the working area, people are protected from exposure to 
dangerous chemicals and solvents. Similarly, the loss of solids can be prevented 
and solvents can be reclaimed from the exhaust so that contamination 
of the environment does not occur. 
III. CENTRIFUGATION 
The centrifugation method" is a unique modification of the simple extrusion 
technique of producing microcapsules [34-40]. As shown in Figure 20. 
the simple extrusion method utnizes a device consisting of two concentric 
tubes containing aligned fluid nozzles. The liquid material to be coated is 
extruded through the nozzle of the inner tube into the coating fluid contained 
in the outer tube. Initially. the fluid extrudes as a rod surrounded 
by the coating fluid, but the rod ultimately breaks up into droplets which 
are then immersed in the coating fluid. As the extruded droplets pass 
through the nozzle orifice of the outer tube. the coating fluid forms a surface 
coat which encases the extruded particle. Spherically shaped particles 
are formed by the surface tension of the liquid. By suitable means 
the formed coat is converted to a more rigid structure. Hardening baths 
are usually employed for this purpose. These baths are designed according 
to the coating material used. Thus, in some cases the bath contains a 
chemical agent which will react with the coating material to yield an insoluble 
compound. A common example of this is the use of calcium chloride 
in the bath to convert sodium alginate in the coat to the insoluble calcium 
alginate [39]. In other cases, the bath may simply be a nonsolvent for 
the coating material, whereas in still other cases only a decrease in temperature 
is needed to harden the coat. 
This process is primarily employed to prepare microcapsules of liquids. 
Thus, the coating fluid is immiscible with the liquid to be encapsulated. 
As previously stated. however, the main concern of this chapter is a discussion 
of methods by which discrete solids can be coated. When this 
"'Southwest Research Institute, San Antonio. Texas.

186 Wurster 
method is used to coat solid drugs it is convenient to prepare a slurry of 
the solid material. The alurry is then encapsulated in the same manner as 
described above for a liquid. Also, in some cases solids, such as fats, 
resins, waxes, or like materials, can be extruded and coated while in the 
molten state [37]. Obviously, other particulate solids can also be included 
in the molten solid. Substances in the molten state can also be used as 
coating materials. 
The initially employed gravity flow and simple extrusion devices were 
found to have some general processing problems. Thus, in gravity flow 
systems it is apparent that certain limitations are imposed upon the size of 
the capsule produced. Also, with simple extrusion devices capsule uniformity 
is a problem. To overcome such problems and yet maintain a high output 
of product, devices utilizing centrifugal force and having multiorifice 
extrusion heads, as shown in Figure 21, were designed. It is important to 
note here that the capsule size can be controlled by varying such factors 
as the orifice size, the rotational speed J and the flow rate of the fluid to 
be encapsulated. As would be expected, with a uniform orifice size and a 
constant rotational speed, an increase in the fluid flow rate results in an 
increase in the capsule size. Conversely, with a uniform orifice size and 
a constant fluid flow rate, an increase in the rotational speed yields smaller 
Material to be 
coated 
I
I f 
=J-=- I -- 
- - 
.....__ Coating 
fluid 
Coated 
particle ----. 
Figure 21 Schematic drawing showing one nozzle unit of a multiorifice 
centrifugal extrusion head.

Particle-Coating Methods 187 
capsules. The centrifugation method is capable of producing microcapsules 
in the 100- 200 um range. 
A still further modification [39) of this method, the so-called submerged 
nozzle, utilizes three concentric tubes in which the outermost tube 
contains a carrier fluid. As the fluid to be encapsulated is extruded from 
the innermost tube. it is surrounded by the coating fluid in the center 
tube and encapsulation is effected in a manner similar to that described 
above. However, in this case the carrier fluid in the outermost tube carries 
the microcapsules away from the nozzle. Naturally. the carrier fluid 
must not be miscible with the coating fluid. This modification of the 
process is stated to be most useful when the fluid coat is fragile and ruptures 
upon impact with the hardening bath used with the centifugal devices. 
The size of the microcapsules produced in this system is again a 
function of the nozzle size and fluid flow rate; however, the carrier fluid 
flow rate is also important in this regard. Thus, an increase in the carrier 
fluid flow rate, other factors remaining constant, results in a decrease 
in the capsule size. 
IV. SPRAY DRYINC 
The application of the spray-drying process to the production of microcapsules 
has been found to be useful for a variety of materials and can be 
Water-immiscible liquid 
Ol' 
water- insoluble solid particles 
Aqueous coating 
solution 
Prepare an O/W emulsion or an 
aqueous suspension of the solid 
I Spray-dry o/: emulsion 
or 
aqueous suspension 
J 
Product 
Frae-flowtng dry powder of 
encapsulated Iiquid or coated solid 
Figure 22 Flow chart for spray-dry process of coating liquid or solid 
particles.

188 Wurster 
Fluid 
Exhaust 
Centrifugal 
collector 
Blower - ....., 
t
Atomizer 
... 
--,..,.. 
/ I 
/' 
'.( 
I " , - 
\ /' - ......, 
"....... 
I -- 
\ 
\ ....... -, 
)... J 
\ -.- 
\ 
\,I 
+ 
Filtered----...- ... 
heated__ 
inlet air__II 
DrV 
product 
Figure 23 Schematic diagram of spray-drying apparatus. 
employed to encapsulate both liquids and solids [1,41- 46]. In the case of 
liquids. the fluid to be coated is first emulsified. The film-forming coating 
material is contained in the continuous phase of the emulsion and the 
fluid to be coated becomes the dispersed phase. The emulsion is subjected 
to the spray-drying process and the solvent constituting the continuous 
phase is removed. The film former is thus deposited upon the surface of 
the dispersed particles. The resulting product is a free-flowing powderlike 
material containing the encapsulated liquid. Essentially, the same 
procedure is followed when this method is used to produce coated solids. 
Here, however, a suspension of the solid particles in a solution containing 
material is first prepared. Solvent removal during the spray-drying 
process deposits the coating material on the surface of the solid particles.

Particle-Coating Methods 189 
The spray-dry process usually produces coated aggregates rather than 
coated single particles. A simplified flow chart for the overall process is 
shown in Figure 22, and a schematic drawing of the spray-drying equipment 
is presented in Figure 23. Since emulsion systems are employed in 
the interfacial polymerization microencapsulation method (see page 194), 
the spray-drying process may also be utilized to recover the microcapsules 
prepared by this technique. The principles governing the spray-drying 
process are well known and need not be treated here. 
V. AQUEOUS-PHASE SEPARATION, COACERVATION 
In the coacervation coating method* [1,47 - 61], an aqueous colloidal solution 
of a hydrophilic polymer having film-forming properties is employed. 
The material to be coated may be either a liquid or a solid. When liquids 
are microencapsulated an oil-in-water-type emulsion is prepared, with the 
liquid to be coated occupying the dispersed phase and the aqueous colloidal 
solution the continuous phase. When solids are coated, a suspension 
of the particulate solid in the aqueous colloidal solution is prepared. In 
either case, by suitable means, phase separation is produced with a layer 
of the coacervate derived from the hydrophflic colloid forming around the 
dispersed particles. Finally, the coacervate layer is treated to cause it 
to become more firm. The process can be one of simple coacervation involving 
only a single colloidal solute, or complex coacervation utnizing two 
or more colloidal solutes can be employed. 
The steps involved in the coating process are presented in a general 
manner in Figure 24. 
In simple coacervation, the single colloid contained in the continuous 
phase can be caused to deposit on the surface of the dispersed particles 
as a result of such physical influences as salting-out effects or the addition 
of another solvent. Such influences, of course, result in the dehydration 
of the hydrophfiic colloid. Gelatin is commonly employed as the 
hydrophilic colloid here, since the above effects are readily observed by 
the addition of a highly soluble salt such as sodium sulfate or ammonium 
sulfate, or by the addition of alcohol. A flow chart of the simple coacervation 
process is shown in Figure 25. The process allows the use of other 
hydrophfiic film-forming colloids as well as other dehydrating and filmhardening 
agents. 
A. Particle-Coating Methods 
Complex coacervation, in contrast to simple coacervation, requires at least 
two hydrophilic colloids in the continuous phase of the fluid system. This 
type of procedure allows the application of the well-known phenomenon 
whereby two oppositely charged colloids discharge with each other to produce 
a coacervate, as is shown in the following general-type reaction: 
[Colloid 1]+ + [colloid 2]- ---- [colloid 1]+[colloid 2]- ~ 
*National Cash Register Company, Dayton, Ohio.

190 Wurster 
+---......1-Dispersed phase 
-oooo1l-Aqueous continuous phase -0 - 0 - containing fllmformer 
_ _ (gelatin) 
Phase separation 
(3 phasel 
Coacervate _ ..._0.0-~0 ~:: ~ 
o 0  -0-0 
o  0 0 
Hardened -II---~Io....o' 
film 
Continuous 
phase 
dispersed ----It-,,,,,,," 
phase 
Coacervate 
film 
\1~~-=_,._Dispersed 
phase 
OIWemulsion 
(2 phase) 
Coacervate film 
on particles 
Dispersed 
phase-lt-....
Coated particles 
Figure 24 Schematic diagram of steps involved in coacervation coating. 
Unless the coacervate remains highly hydrated it will separate from solution. 
Thus, when such a weak union between the charged colloids occurs 
fine droplets initially appear which subsequently coalesce to produce a 
continuous phase. Figure 26 is a flow chart for the complex coacervation 
process. 
The process is a batch method and can be conducted on an experimental 
basis with ordinary laboratory equipment. Pilot plant and production-
scale operations require only such simple equipment as suitable tanks, 
ffitration, or other separation equipment and means to control such process 
conditions as pH and temperature. 
The particle size of the dispersed phase (i.e  the solid particles or 
liquid droplets to be coated) will govern to a large degree the size of the 
coated particles produced. From this it is evident that coated particles, 
varying widely in size, can be prepared. The literature indicates this 
size range to be 5- 5000 '11m in diameter [2]. The thickness of the coat is, 
of course, a function of the amount of coating material on the surface of 
the particle. In normal commercial coating procedures the weight of the

Particle-Coating Methods 
Water-immiscible liquid 
or 
water-insoluble solid particles 
Aqueous coat in/; 
solution 
(gelatin 10% w/wj 
191 
Prepare 1 liter of an o/w emulsion (20% dispe rsed phase) 
or 
aqueous suspension of solid particles 
j 
Add slowly" ith mixing a 20% "Iw ~a2S04 solution 
to produce coacervation (approx, 400 mil; 
maintam temperature at 50'C above this point 
j 
Gel the colloid by pouring coacervate mixture into approx, 7-fold 
its volume of 7a;, wlw :\a2S04 solution. At this point 
and below maintain the temperature at 19C or le-,s 
j 
Filter and wash coacervate with cold water 
to remove salt 
j 
Treat Ii lte red mater-ial wtth J7% Ior rnaldehvde 
(approx , 2 liters) to harden coacervate 
j 
F iller and" as h part ic les \\ ith cold \\ atl' r 
to remove hardentna .urent 
j 
Dn to remove remaining solvent 
Figure 25 Flow chart for simple coacervation process.

192 
Water-immiscible liquid 
or 
water-insoluble soUd particles 
Aqueous coating solution 
(acacia 10% w/w) adjust to 
pH 6.5 with 10% NaOH 
Wurster 
Prepare 1 liter of O/W type emulsion 
(30% dispersed phase) or aqueous suspension of 
the solid particles 
I Add 700 ml of 10% gelatin (isoelectric point pH 8.0) 
solution with mixing 
I Add warm water until a coacervate is produced. The collotd 
concentration is reduced to approximately 3% (the less water the 
finer the particles). Adjust pH to 4.0 to 4.5 by gradual addition of 
10% acetic acid. Maintam temperature at 50C for above steps 
I Pour coacervate mixture into 2 times its volume of cold 
water. Maintain temperature at SC or below in this 
and subsequent step I Treat coacervate with 37% formaldehyde solution. Adjust 
pH to 9.0 with 10% NaOH (a macromolecular electrolyte such 
as CMC has been used in this step in place of NaOH 
to inhibit aggregation 
I Remove aggregate of encapsulated material and wash with water I Dry and comminute aggregated material 
Figure 26 Flow chart for complex coacervation process.

Particle-Coating Methods 193 
coat varies between 3 and 30% of the particle weight. but coatings of 
1-70% have been applied. 
The flexibility of this coating process is further emphasized by the 
wide variety of coating materials that can be utilized. A partial list of 
suitable coating materials which can be employed. depending on whether the 
aqueous-phase separation or nonaqueous-phase separation method is used, 
follows: 
Gelatin 
Gelatin /acacia 
Gelatin/acacia/vinylmethylether maleic anhydride 
Gelatin I acaciaI ethylenemaleic anhydride 
Carboxymethylce1lulose 
Propylhydroxycellulose 
Polyvinylalcohol 
Cellulose acetate phthalate 
Bthylcellulose 
EthylenevinyIacetate 
Nitrocellulose 
Shellac 
Wax 
While the coacervation method is capable of coating a large number of 
materials. it is readily apparent that the material to be coated must be 
stable to the process conditions. Particular consideration must therefore 
be given to the influence of temperature, pH, solvent system, etc., on 
product stability. 
VI. NONAQUEOUS-PHASE SEPARATION 
Phase separation [2.62,63] can be induced in organic solvent systems as 
well as aqueous systems. Again, the suspended particle may be either a 
solid or an immiscible liquid. Thus, for dispersed liquids, emulsions of 
the W10 type are employed in contrast to the more conventional coacervation 
method in which 0 IW-type emulsions are used. Obviously. watersoluble 
solids can also be included either by suspending them in the organic 
solvent or by dissolving them in the internal phase of the W10-type 
emulsion. 
The polymeric coating material is dissolved in the continuous organic 
solvent phase. Phase separation and the coating of the solid or liquid 
dispersed particles is accomplished by adding a solvent which is miscible 
with the continuous organic solvent phase but which is a nonsolvent for 
the polymeric coating material. Triangular phase diagrams are a most useful 
tool when dealing with phase separation in either nonaqueous [62] or 
aqueous [64] systems. 
Hardening of the polymer coat on the particles is usually accomplished 
either by the addition of more of the nonsolvent or by separating the 
coated particles from the system. washing them with a nonsolvent liquid, 
and drying.

194 Wurster 
VII. INTERFACIAL POLYMERIZATION 
The interfacial polycondensation or polymerization technique [63 - 65] has 
been applied to the microencapsulation of various liquids. However. as 
with the other processes discussed in this chapter. particulate solids can 
be suspended in the liquid SO that the microencapsulated particle contains 
both the solid and the liquid. 
The process consists of bringing two reactants together at the interface 
of the dispersed and continuous phases in emulsion systems [66]. 
This is usually accomplished by emulsifying the liquid containing the first 
reactant (dispersed phase) into the continuous phase, which is initially devoid 
of the second reactant. Additional continuous phase containing the 
second reactant is then added. This interfacial polymerization reaction 
produces a continuous fnm of the formed polymer around the dispersed 
phase. A diagram of the interfacial process is shown in Figure 27. The 
recovery of the microcapsules from the continuous phase can be accomplished 
by spray drying, flash evaporation, filtration, Or other separation 
techniques [67]. A flow chart of the process is shown in Figure 28. 
The various polymer-coating materials which have been utilized to prepare 
microcapsules by the described process include polyamides (nylon). 
polyurethanes. polysulfonamides, polyesters, polycarbonates, and polysulfonates. 
The particle size of the product created by this method varies 
in accordance with the particle diameter of the dispersed phase. Therefore, 
particles varying greatly in size. from approximately 3 to 2000 um in 
diameter, can be prepared. 
Water-soluble monomer 
.1IllI....-- Interfacial 
reaction 
Oil soluble 0  42 L 
Di = initial dose = 500 mg or 5,000.000 J.lg 
It is desired to formulate this drug into a sustained-release product releasing 
drug over a 12-h period such that the serum level is maintained at 
10 llg mI- l  Step 1: Using equation 2 from the text 
Rate in = rate out = k 0 = CtkelVd r 
-1 -1 =10 ].lg ml x 0.2 h x 42,000 ml 
-1 =84,000 ].lg h

Sustained Drug Release from Tablets and Particles 205 
o Step 2: After calculating the zero-order release rate constant. k r  calculate 
the total dose per tablet. Using equation 3 from the text 
W = D. + k ~ 
1 r 
-1 = 500,000 llg + (84,000 g h x 12 h) 
= 1.508.000 ug' 
=1.5 g per tablet 
Since a large tablet will be generated. the formulator may wish to prepare 
O.75-gm tablets so that the patient takes two tablets every 12 h. 
Conversely, it is possible to reduce the size of the tablet by recalculating 
for a shorter sustaining time. For example. suppose 6 rather than 12 h of 
sustaining time is used. 
-1 W= 500,000].lg + (84,000 g h x 6 h) 
= 1.004,000 ug 
= 1.0 gm per tablet 
Suppose the formulator finds that the particular sustaining mechanism is 
better approximated by first-order rather than zero-order release. From 
the earlier calculations. the formulator knows that for 12 h of release the 
tablet should contain about 1.5 gm and the zero-order release rate is 
84.000 1Jg h -1. From these data it is possible to approximate the firstorder 
rate constant k using equation 4 
r 
1 kelCtVd 
k =::-::"-~r 
W - D
i 
-1 -1 = 0.2 h x 10 llg ml x 42.000 ml 
1,508,000 - 500,000 llg 
B. Drug Properties Considerations 
There are a number of physical-chemical and derived biological properties 
of the drug that either preclude placement of the drug in a sustainedrelease 
system or have an adverse influence on product design and performance. 
Some of these considerations are listed in Table 2. With almost 
all of these properties we refer to them as restrictive factors. making 
formulation of a sustained-release system difficult, but not impossible. 
Thus, by changing the type of sustaining mechanism, the dose. or the

Table 2 Drug Properties Adversely Influencing a Sustained-Release Dosage Form 
Property Explanation 
~
~ 
Physical-chemical properties Dose size 
Aqueous solubility 
Partition coefficient 
Drug stability 
If an oral product has a dose size greater than 0.5 gm, it is 
a poor candidate for a sustamed-release system, since addition 
of the sustaining dose and possibly the sustaining mechanism 
Will, in most cases, generate a substantial volume product that 
will be unacceptably large. 
Extremes in aqueous solubility are undesirable in the preparation 
of a sustained-release product. For drugs with low water 
solubility, they will be difficult to incorporate into a sustainedrelease 
mechanism. The lower limit on solubility for such product 
has been reported [30] to me 0.1 mg/ml. Drugs with 
great water solubility are equally difficult to incorporate into 
a sustained-release system [311. pH-Dependent solubiltty , 
particularly in the physiological pH range, would be another 
problem because of the variation in pH throughout the GI 
tract and hence variation in dissolution rate [31]. 
Drugs that are very lipid soluble or very water soluble, i.e., 
extremes in partition coefficient, will demonstrate either low 
flux into the tissues or rapid flux followed by accumulation in 
the tissues. Both cases are undesirable for a sustainedrelease 
system [32, 33]  
Since most oral sustained-release systems, by necessity fare 
designed to release their contents over much of the length of 
the GI tract, drugs which are unstable in the environment of 
() 
;::T' 
I:l 
~
I:l 
;::l 
Q. 
~.... ;::l 
Cf.l 
C
;::l

Biological properties Absorption 
Distribution 
Metabolism 
Duration of action 
Therapeutic 
the intestine might be difficult to formulate into prolonged 
release systems [34]. Interestingly, placement of a labile 
drug in a sustained-release dosage form often improves the 
bioavailability picture [31]. 
Drugs that are slowly absorbed or absorbed with a variable 
absorption rate are poor candidates for a sustained-release 
system. For oral dosage forms, the lower limit on the absorption 
rate constant is in the range of 0.25 h- 1 [31] (assuming 
a GI transit time of 10-12 h) 
Drugs with high apparent volumes of distribution, which in 
turn influences the rate of elimination for the drug. are poor 
candidates [31]. 
Sustained-release systems for drugs which are extensively 
metabolized is possible as long as the rate of metabolism is 
not too great nor the metabolism variable with GI transit or 
other routes. 
The biological half-life and hence the duration of action of a 
drug obviously plays a major role in considering a drug for 
sustained-release systems. Drugs with short half-lives and 
high doses impose a constraint because of the dose size 
needed and those with long half-lives are inherently sustained 
[16,35]. 
Drugs with a narrow therapeutic range require precise control 
over the blood levels of drug, placing a constraint on sustained-
release dosage forms. 
~
OJ 
E' -::l 
(Il 
1:4 
o2
~
~
(Il 
(i) 
~
OJ 
(Il 
~
::I 
: 
(i) .... OJ 
s
1:4 
;' 
'"'$ .... 
0" 
(i) 
OJ 
~
C
"'1

208 Chang and Robinson 
route of administration, it might be possible to generate a sustained-release 
system. Frequently, a seeminly undesirable property of a drug or 
dosage form can be overcome or minimized by placement of the drug in a 
sustained-release system. For example, low drug bioavanability due to instability 
may sometimes be overcome by placement in a sustained-release 
system [311. 
III. FABRICATION OF SUSTAINED-RELEASE 
PRODUCTS 
Having established the desirable concentration versus time proflle as depicted 
in Figure 1, we can now ask two related questions: What approaches 
can be taken to achieve this type of profile, and how should the sustained-
release product be constructed? Our concern, therefore, is to 
examine the potential mechanisms available and to describe the general 
nature of the dosage form construction. 
A. Repeat-Action Release and Continuous 
Release 
To maintain the drug level at a constant desired value, we can employ 
frequent dosings of drug to generate a series of peaks and valleys in the 
blood level proflle, whose mean value lies on the plateau of the ideal case. 
This approach is shown in Figure 2. The success of this approach depends 
on the frequency of the multidoses because. obviously, the more 
frequent the dose the smaller the peaks and valleys and the closer the 
extreme drug level will adhere to the plateau value. This is the approach 
taken with the Spansules, where four dosage units were employed in each 
Spansule. One dose unit provided drug in a nonsustained form to establish 
the initial blood level of drug and the other three doses were intended 
to release drug at 2-, 4-, and 6-h intervals. Depending on the 
drug properties, other intervals can be used, as can a greater number of 
repetitive doses, although more than four becomes impractical from a manufacturing 
standpoint. 
An alternate approach is to employ a continuous release of drug. With 
this method, a nonsustained portion of the dosage form is needed to rapidly 
establish the therapeutic level of drug in the blood, and then by 
some suitable mechanism, drug is continuou sly provided in a zero- or 
first-order fashion. In this regard it is appropriate to comment on the 
drug concentration versus time profile for a system releasing drug via 
first-order kinetics. Contrary to the case where drug is released via 
zero-order kinetics, as depicted in Figure 1, first-order release produces 
a more or less bell-shaped proflle. Whether the bell shape is symmetrical 
or skewed and whether it is narrow or wide depends on the drug and 
the sustained-release system employed; that is, the kinetics of release. 
Examples of this type of profile will be discussed and demonstrated later 
in the chapter. 
B. Mechanisms of Sustained Release 
A zero-order release of drug is needed for the dosage form, which means 
that the rate of drug release is independent of drug concentration

Sustained Drug Release from Tablets and Particles 209 
Toxic level 
Minimum Effective \ 
level \
\
\
\
\
\
\
\ 
.... 
\... 
E
:l 
C 
.a1--4-----------------------"'""':~- s
~
88
C> 
2 o 
Time ) 
Figure 2 Repetitive release approach to sustained-release. The dotted 
line represents the ideal sustained-release profile. 
de =k 0 (5) 
dt r 
or expressed in amounts 
(6) 
At times it is not possible to generate a constant-release product and a 
slow first-order release of drug is employed. A slow first-order release 
will approximate a zero-order release as long as only a fraction of drug 
release is followed [291; that is. less than one half-life is followed. 
To attain a zero-order release rate, we have several mechanisms and 
dosage form modifications that we can employ. We will restrict our coverage 
of potential mechanisms to those that can be employed in the coating 
approach to sustained release.

210 Chang and Robinson 
Diffusion 
A number of sustained-release products are based on diffusion of drug. 
The follOWing discussion. although somewhat naive, will bring into perspective 
those properties that should be considered in the diffusion 
approach. 
Fick's first law of diffusion states that drug diffuses in the direction 
of decreasing concentration across a membrane where J is the flux of the 
drug in amount/area-time. 
dC J =-Ddx 
where D is the diffusion coefficient in area/time, C is the concentration, 
and x is the distance. Assuming steady state, equation 7 can be integrated 
to give 
6C 
J = -D T 
or expressed in more common form when a water-insoluble membrane is 
employed 
elM ADK 6C 
dt = i 
( 7) 
(8) 
( 9) 
where A is area. D is diffusion coefficient, K is the partition coefficient of 
drug into the membrane, i is the diffusional pathlength (thickness of coat 
in the ideal case), and !l C is the concentration gradient across the 
membrane. 
In order to have a constant rate of release, the right-hand portions 
of equations 8 and 9 must be maintained constant. In other words, the 
area of diffusion, diffusional path length, concentration increment, partition 
coefficient. and diffusion coefficient must be invariant. Usually, one 
or more of the above parameters will change in oral sustained-release 
dosage forms giving rise to non-zero-order release. 
The more common diffusional approaches for sustained drug release 
are shown in Schemes 3 and 4. In most cases, the drug must partition 
into a polymeric membrane of some sort and then diffuse through the membrane 
to reach the biological milieu. When the tablet or microcapsule contains 
excess drug or suspension. a constant activity of drug will be maintained 
until the excess has been removed, giving rise to constant drug 
release. In Scheme 3 the polymer is water insoluble. and the important 
parameter is solubility of drug in the membrane. since this gives rise to 
the driving force for diffusion. In Scheme 4 either the polymer is partially 
soluble in water or a mixture of water-soluble and water-insoluble 
polymers is used. The water-soluble polymer then dissolves out of the 
film. giving rise to small channels through which the drug can diffuse. 
The small channels would presumably give a constant diffusional path 
length. and hence maintain constant conditions as described earlier. Although 
diffusion through the channels should be much more rapid than 
diffusion through the membrane noted in Scheme 3, it is possible to have 
a situation whereby membrane diffusion, being quite rapid in this ease,

Sustained Drug Release from Tablets and Particles 
Membrane Reservoir 
211 
Scheme 3 Diffusion control of drug release by a water-Insoluble polymer. 
is within an order of magnitude of pore diffusion. In this event, both 
types of diffusion, membrane and pore, will provide contributions to the 
overall diffusion rate and the equations would have to be modified to account 
for these combined effects. 
Dissolution 
In this case, the drug is embedded (coated) in a polymeric material and 
the dissolution rate of the polymer dictates the release rate of drug. The 
Membrane Reservoir 
b~~J.~ 
a ::. :.\) 
D ' . 
\)~ . ' .... : . 
~. "O~ 
c:::J Pores produced by soluble portion 
of polymer membrane 
Scheme 4 Diffusion control of drug release by a partially water-soluble 
polymer.

212 
Membrane Reservoir 
Chang and Robinson 
Scheme 5 Dissolution control of drug release via thickness and dissolution 
rate of the membrane barrier coat. 
Scheme 6 Dissolution control of drug release via polymer core erosion or 
polymer-coating erosion. (Note: Although equations are based on spherical 
tablets, erosion of conventional flattened tablets is similar but there is 
a combination of various R terms where R depends on the axis being 
measured. See Ref. 38. It is assumed that diffusion of water, metabolites, 
or biologically active components is not rate limiting.

Sustained Drug Release from Tablets and Particles 213 
drug release rate, if governed by erosion or dissolution, can be expressed 
as 
dM =A dx fCC) 
dt dt (10) 
where (dx)/(dt) is the erosion rate, fCC) is the concentration profile in 
the matrix, and A is area. A constant erosion rate can produce zeroorder 
release kinetics, provided the drug is dispersed uniformly in the 
matrix and area is maintained constant [36,37). Oftentimes, swelling of 
the system or a significant change in area produces non-zero-order release. 
The common forms of dissolution control are shown in Schemes 5 and 6. 
In Scheme 5 we have a barrier coat across a microcapsule or nonpareil 
seed containing drug, and the release of drug is dictated by the dissolution 
rate and thickness of the barrier coat. Varying the coating thickness, 
or layering concentric spheres of coating material and drug reservoir material, 
gives rise to different release times, producing the repeat action 
dosage form. Once the polymer has dissolved, all of the drug contained 
in the capsule or seed is available for dissolution and absorption. In 
Scheme 6 the drug is either embedded in a polymer or coated with a watersoluble 
polmyer, which in turn is compressed into a slowly dissolving tablet. 
The release rate is controlled by the dissolution rate of the polymer 
or tablet. 
Osmosis 
Placement of a semipermeable membrane around a tablet, particle, or drug 
solution, which allows creation of an osmotic pressure difference between 
the inside and outside of the tablet and hence "pumps" drug solution out 
of the tablet through a small orifice in the coat, can be used as a sustained-
release mechanism. The key component of the system is the ability 
of a drug solution to attract water through a semipermeable membrane by 
osmosis. Since the drug solution is contained within a fairly rigid system, 
drug solution can be pumped out of the tablet or particle at a controlled 
constant rate if a small hole is created in the coating surface and a constant 
activity of drug, that is, excess drug, is maintained. Controlling 
the rate of water imbibition thus controls the rate of drug delivery. This 
can be seen in the following expression (12) 
dV = k A (6 1l' - 6P) 
dt t 
(11) 
where dVI dt is the flow rate of water, k , A, and t are the membrane 
permeability, area, and thickness, 6 11" is the osmotic pressure difference, 
and liP is the hydrostatic pressure difference. Keeping the hydrostatic 
pressure small relative to the osmotic pressure, equation 11 reduces to 
dV A -= k - (61l') dt .- 
(12) 
By maintaining the right-hand side of equation 12 constant, a zero-order 
release system will result.

214 Chang and Robinson 
COATING METHODS. Coating is a versatile process which imparts 
various useful properties to the product. Modifications of drug-release 
patterns such as enteric release, repeat-action release, and sustained 
release are the most important pharmaceutical applications of coating. Although 
many coating techniques, for various purposes, have been detailed 
in previous chapters, we have elected to discuss the coating methods for 
the purpose of modified release. 
Pharmaceutical coatings have been classified into four basic categories: 
sugar coating, microencapsulation, film coating, and compression coating. 
Sugar coating of compressed tablets and granules is regarded as the oldest 
process, involving the multistage build up of sugar layers through deposition 
from an aqueous-coating solution and coating powder. Sugar coating 
falls outside the scope of this chapter owing to the inability to control 
drug release through a highly water-soluble sugar barrier. 
A. Microencapsulation 
Microencapsulation is a process in which tiny particles or droplets are surrounded 
by a uniform coating (so-called microcapsule) or held in a matrix 
of polymer (so-called microsphere). A number of microencapsulation techniques, 
including aqueous phase separation, three-phase dispersion, organic 
phase separation, and interfacial polymerization, have been used to 
encapsulate pharmaceuticals and to retard the liberation of drug from 
microcapsules. 
Aqueous phase separation methods to prepare microcapsules Include the 
simple coacervation of hydrophilic colloids with ethanol or sodium sulfate as 
dehydrating agents. In addition, one can employ a complex coacervation 
of two dispersed hydrophilic colloids of opposite electric charges with subsequent 
pH change. Aqueous phase separation was patented as an encapsulation 
process by Green in 1955 [39]. and has been used commercially 
since that time for numerous applications. 
The three-phase dispersion method involves dispersion of the materials 
to be coated in a nonsolvent liquid phase containing colloidal or filmforming 
materials such as gelatin. This two-phase system is then dispersed 
in a third phase by emulsification. through spraying or other 
means. and the coating material is gelled, usually by cooling. The resulting 
gelled droplets are then either separated and dried or partially dehydrated 
with an aliphatic alcohol and then separated and dried. Variations 
on this process have been used commercially to encapsulate oilsoluble 
vitamins such as vitamin A. One of the earliest applications of 
this method was reported in a British patent in 1938 [40]. 
Generally, aqueous phase separation and three-phase dispersion methods 
are used to encapsulate water-insoluble or poorly water-soluble materials 
which are usually poor drug candidates to incorporate into a sustained-
release system. Gelatin is the most commonly used microencapsulating 
agent for the two processes described above. Even for poorly 
water-soluble drugs, gelatin is usually not able to achieve the desired 
dissolution profile owing to the hydrophilic properties of gelatin. The use 
of formalin in treatment to cross-link the gelatin and/or dual coating of 
gelatin microcapsules may be necessary to improve the dissolution profile. 
In addition, these encapsulation processes would be precluded for heatsensitive 
materials and substances with a stability and/or solubility problem 
at the pH of coacervation.

SUstained Drug Release from Tablets and Particles 215 
Nonaqueous phase separation involves dispersion of core material in 
an organic continuous phase in which the wall-forming polymer has been 
dissolved. Phase separation is induced by the addition of a nonsolvent, 
incompatible polymer, inorganic salt, or by altering temperature of the 
system. The organic phase separation method can be employed in the 
manufacture of microcapsules using various water-insoluble polymers as 
coating materials to enclose water-soluble drugs and to slow the drugrelease 
rate. 
Encapsulation via interfacial polymerization was pioneered by Chang 
[ 41, 42] in work designed to produce artificial cells. This method involves 
the reaction of various monomers, such as hexamethylene diamine 
and sebacoyl chloride. at an interface between two immiscible liquid 
phases to form a film of polymer that encapsulates the dispersed phase. 
Capsules formed by interfacial polymerization usually have relatively thin 
semipermeable membranes highly suited for artificial cell studies or applications 
requiring permeable walls. This method may give rise to questions 
about toxicity of the unreacted monomer, the polymer fragments, 
and other constituents in the process, instability of the drug in the reaction 
medium during the polymerization period, fragility of the microcapsules, 
and high permeability of the coating to low molecular weight 
species [43]. Various other polymerization procedures, tneluding bulk, 
suspension, emulsion, and micellar polymerization, have received considerable 
academic interest to entrap active materials in polymer matrices. 
However, inherent problems of polymerization procedures such as impurities 
in the system, limited drug solubility in the monomer, excessive 
drug degradation caused by reaction with the monomer or initiator. and 
possible entrapment of drug in polymers may prevent the pharmaceutical 
industry from actively engaging in this approach to control drug release. 
In general, microencapsulation techniques using liquid as a process 
medium are rather complicated and difficult to control. Several process 
difficulties such as hardening of the capsule shell, isolating the microcapsules 
from the manufacturing vehicle, and drying the microcapsules to 
form free-flowing powder should be solved in order to ascertain batch to 
batch uniformity. Equipment required for microencapsulation by these 
methods is relatively simple: It consists mainly of jacketed tanks with 
variable speed agitation. The process can be carried out on a production 
scale with good reliability. reproducibility. and control. However, 
process control, product quality control, and scale-up problems appear to 
be the limiting factors influencing general acceptance by the pharmaceutical 
industry. 
The most common mechanical microencapsulation process is the spraydrying 
technique, which consists of rapid evaporation of the solvent from 
the droplets. Spray-drying techniques may produce monodispersed freeflOWing 
particles which can be directly compressed into tablets, filled into 
capsules, and suspended in water. However, the microcapsules obtained 
by spray drying tend to be very porous because of rapid volatilization 
of the solvent. Spray-congealing techniques accomplish coating solidification 
by thermal congealing of the molten coating materials such as hydrogenated 
castor oil, cetyl alcohol, monoglyceride and diglyceride , etc. 
Spray-congealed coatings are less porous but require coating materials 
that melt at moderate temperature. 
Successful attempts using spray-drying and congealing techniques to 
control the release of sulfa drugs have been reported [44 - 47] .

216 Chang and Robinson 
B. Film Coating 
Film coating involves the deposition of a uniform film onto the surface of 
the substrate, such as compressed tablets, granules, nonpareil pellets, 
and capsules. Intermittent manual application or continuous spraying of 
coating solution onto a mechanically tumbled or fluidized bed of substrates 
allow the coating to be built up to the desired thickness. Because of the 
capability of depositing a variety of coating materials onto solid cores, 
this process has been widely used to make modified-release beads and 
tablets in the pharmaceutical industry. 
Properly designed film coating can be applied to pharmaceutical products 
to achieve performance requirements such as rapidly dissolving coatings, 
sustained- or controlled-release coatings, and enteric coatings. The 
polymer(s) used in coating formulations is the predominant factor for the 
properties of the film coat. Water-soluble fflm formers such as methyl cellulose, 
hydroxypropyl methylcellulose, hydroxypropylcellulose, polyethylene 
glycol, polyvinyl pyrrolidone, etc , , form a rapidly dissolving barrier. 
Enteric materials such as cellulose acetate phthlate, polyvinyl acetate 
phthalate, methacrylic acid ester copolymers, etc., form acid-resistant 
films. The hydrophobic water-insoluble polymers such as ethyl cellulose, 
cellulose acetate. cellulose triacetate, cellulose acetate butyrate, and methacrylic 
acid ester copolymers are used to extend the release of drug over a 
long period of time. Depending upon the physicochemical properties of the 
drug and the substrate formulation, several coating approaches have been 
employed to regUlate drug release. 
Partitioning Membrane 
Partitioning membranes, continuous hydrophobic polymeric films which remain 
intact throughout the gastrointestinal tract, can be applied onto the 
coating substrate by using a single polymer or a combination of waterinsoluble 
polymers. Since drug molecules cross the membrane by both a 
partition and a diffusion process, solubility of the drug in the polymeric 
material is a prerequisite to permeation. The polymeric material should be 
carefully selected to have the desired permeability to the drug and water 
in order to achieve the desired release profile, In addition to thickness 
of membranes, the permeability of the film can also be adjusted by mixing 
two water-insoluble polymers in any desired proportion. 
Dialysis Membrane 
Frequently, the partitioning membrane is too effective to regulate drug release. 
In other words, the drug within the coating would be released 
very slowly or be released not at all for a long period of time. The inclusion 
of hydrophilic additives within the coating along with hydrophobic 
polymer(s) creates pores when the additives are dissolved by water, which 
guarantees the penetration of water and elimination of drug entrapment. 
When the drug molecule leaves the membrane by diffusing through pores 
filled with dissolution media (dialysis mechanism) the size of the drug molecules 
and solubility of the drug in a dissolution medium are important 
factors in transport. Some water-soluble additives such as sodium chloride, 
lactose and sucrose have poor sohrbilfty in organic solvents and may 
be micronized and suspended in a solvent-based coating system. Watersoluble 
polymers such as methyl cellulose. polyvinyl pyrrolidone, and

Sustained Drug Release from Tablets and Particles 217 
polyethylene glycol are commonly mixed with hydrophobic polymers to regulate 
drug release owing to their excellent film-forming properties and 
solubility in organic solvents. In addition to film thickness, the ratio of 
soluble components to insoluble polymer in the coating influences the release 
rate. Porous membranes may also be prepared by incomplete coating 
of hydrophobic polymers. However, strict process control is necessary to 
ascertain the reprodUcibility owing to sensitivity to the coating weight. 
Fat Wax Barrier 
Mixtures of waxes (bees wax, carnauba wax, etc.) with glycerol monopalmitate, 
cetyl alcohol, and myristyl alcohol can be applied onto the substrate 
to form a barrier by hot-melt coating. Hot-melt coating is the most 
economical process owing to elimination of solvent cost and the inexpensiveness 
of the coating materials. However, a higher level of coating, compared 
to polymeric film coating. is normally required to retard the liberation 
of the drug. 
Incorporation of Enteric Materials into 
the Formulation 
In general, pH-independent dissolution is the ideal attribute of a controlledrelease 
dosage form. However, most drugs are either weak acids or weak 
bases; their release from delivery systems is pH dependent. If the drug 
has a higher solubility in acidic than in basic media. enteric material may 
be incorporated into the rate-controlling barrier or core matrix to minimize 
the effect of pH-dependent solubility. In another approach. physiological 
acceptable buffering agents can be added to the core formulation to maintain 
the fluid inside the rate-controlling membrane to a suitable constant 
pH. thereby rendering a pH-independent drug release [48]. Enteric material 
also can be incorporated into rate-controlling membranes or core 
matrices to create pH-dependent release of the drug. The dosage form 
with pH-dependent dissolution characteristics may be beneficial in some 
cases to improve the extent of absorption by dumping the dose in time 
and preventing the unabsorbed dose being entrapped in the stool. Sustained-
release preparations overcoated with enteric material can be utilized 
as an intestinal delivery system with sustained-release properties. Entericcoated 
dosage forms can be overcoated with a drug layer to form a repeataction 
preparation. 
CORE PREPARAT ION. Very few drug particles possess adequate 
physicochemical properties for the usual coating process. These properties 
include (1) suitable tensile, compaction, shear, impaction, and attrition 
strengths to avoid destruction during the coating process; (2) approximately 
spherical shape to obtain good flow and rolling properties in the 
coating equipment; (3) suitable size and size distribution; and (4) suitable 
density to avoid escape of the drug particles during the coating process. 
Certainly. different types of coating equipment have their own capabilities 
to handle the cores. leading to different requirements of the cores for 
various equipment. For the pan coating process, a relatively large particle 
size (larger than 500 urn) and a spherical shape are generally considered 
necessary to provide excellent rolling in the coating pan and to avoid 
the agglomeration and/or aggregation owing to inefficiency of drying and 
long contact time among the cores. Although fluidized -bed coating

218 Chang and Robinson 
systems expanded coating capabilities dramatically. suitable strengths and 
weight of the cores are needed to avoid excessive attrition of drug particles 
and suction of drug particles into the filter during the coating 
process. The major advantages of using pure drug particles as coating 
substrates are elimination of the core-making process and a less bulky final 
product. Potassium chloride and acetyl salicylic acid crystals are typical 
examples which have been satisfactorily coated in a coating pan or a 
fluidized-bed coating system. 
1. Compaction process. Apparently. tablets are the most common and 
easiest dosage form to coat. Tablets with excellent friability. hardness, 
and edge thickness are preferred for coating. However, sustained-release 
film-coated tablets may prematurely dose dump due to accidental rupture 
of the coating film. The use of a multiple-unit instead of a single-unit 
dosage form is a pharmaceutical trend because of the presumed reduction 
of the inherently large inter- and intrasubject variation linked to gastrointestinal 
transit time. Tablets of small dimensions have been successfully 
prepared from polyvinyl alcohol and subsequently cross-linked at the surface 
to form a quasimembrane-controlled system for a multiple-unit dosage 
form [49]. In order to achieve high output in large-scale manufacturing, 
this approach to the preparation of cores may face formulation difficulties 
and tablet tooling problems; i.e  multitipped punches. The limited size 
flexibility of the tableting method to manufacture cores for a multiple-unit 
device is another disadvantage. 
Other methods with production capacity. such as slugging, ehllsonator , 
and Hutt Compactor, can be used to produce granules in the compaction 
mode. However, irregular-shaped granules are commonly observed and 
extensive sieving is necessary to remove the fines and oversized granules. 
2. Surface-layering process. Another common approach to core production 
involves the use of substrates and enlargement of the substrates 
by a surface-layering technique. Thus, nonpareil seeds of various sizes 
or sugar crystals are used as the substrate. Application of an active 
substance onto an inert substrate can be carried out by uniform coating 
in a rotating coating pan in the presence of a suitable adhesive. In detail. 
the substrate is uniformly wetted by manual spreading of a binding 
solution. followed by attachment of the active substance to the surface of 
the substrate. Commonly used adhesives include solutions of polyvinyl 
pyrrolidone polyethylene glycols, cellulose ethers, natural gums, shellac, 
zein, gelatin, and sugar syrup. Suitable binder(s) and solvent systems 
for the binder( s) must be found in order to have smooth production of 
cores without excessive agglomeration of the cores or separation of the 
drug particles. Enteric binders. such as cellulose acetate phthalate and 
shellac, may impart pH-dependent dissolution properties to the final product. 
Separating agents, such as talcum and magnesium stearate, may be 
used to eliminate or reduce tackiness of the adhesives. Trituration technique, 
to blend the potent drug with the auxiliary agents, is usually required 
to obtain a uniform distribution of the drug onto the substrate 
surface. 
The powder layering process requires a great deal of repetition, and 
is thus time consuming. Moreover. undesired agglomeration or aggregation 
and adhesion to the wall of coating equipment can occur. To avoid 
the labor-intensive powder layering process in a coating pan. a centrifugal-
type fluidized bed with a powder feed device (CF-Granulator) has

Sustained Drug Release from Tablets and Particles 219 
been used to produce high-quality pellets. The stirring chamber of the 
CF-Granulator consists of a fixed specially curved wall stator and a directed 
rotating plate rotor. Fluidization air, through a gap slit between 
the stator and rotor, prevents the substrates from falling. The substrates 
are whirled up along the wall of the stator owing to centrifugal 
force of the rotor and to the upper part of the wall due to the fluidization 
air. SUbsequently, they drop due to gravitational force. During the 
spiral stirring operation, layering powder is metered to the fluidized bed 
from a powder feed unit. A binder solution is sprayed from a spraying 
gun to cause binding of the powder to the substrate surface. 
It is also possible to dissolve or to suspend the drug in the binder 
solution and to apply this liquid uniformly to the surface of the substrate 
using a coating pan or fluidized-bed system. However, there are several 
difficulties with this approach, including the tendency to clog the nozzle 
with the slurry. A large quantity of solvent may be needed to dissolve 
or suspend the active substance. In addition, drug loss to the air stream 
and possible adverse aggregation of the cores can occur. Another inherent 
disadvantage of the layering process is the possible formation of 
unduly large pellets owing to the use of nonpareil seeds as a substrate. 
Small-sized substrates, such as sugar crystals, can be used to eliminate 
bulkiness of the pellets. The finer the substrate, the finer the drug particle 
should be and the more difficult the process. 
3. Agglomeration process. Alternatively, the drug particles in the 
powder bed can grow by wet agglomeration. The extent of granule growth 
depends on the amount of granulating solution, the type of binder, the 
force of agitation, and heat applied. The conventional wet granulation 
method to prepare the substrate for coating can give rise to problems 
such as irregular-shaped particles with a coarse and porous surface, soft 
and pliable particles, and a broad granular size distribution. Application 
of relatively large amounts of coating material may be required owing to 
capillary suction of the coating fluid to pores. The porous structure and 
irregular shape of the granules may lead to an unpredictable sustainedrelease 
coating. Additional powder layering to round off the granules 
into a sphere or to smooth surfaces or perhaps to increase the strength 
of the pellets may be important. However, Kohnle et al , [50] have successfully 
produced microspherules which are suitable for enterlc- and 
sustained-release coating through agglomeration of fine drug particles by 
using a Twin Shell Blender with an intensifier bar assembly. 
The inclined dish granulator or disc pelletizer is well known and high1y 
utilized in the fertilizer, iron ore, and detergent industries. It also 
has been adopted throughout the pharmaceutical, chemical, food, and 
allied industries. The equipment, known as the nodulizer and pelletizer, 
are available for continuous production of spherical pellets. The unit 
normally consists of a shallow cylindrical dish, motor drive, adjustable 
scrapers, spraying system, and powder feed device. As the pan rotates 
about an inclined axis, the raw material bed is rolled by centrifugal force 
and maintained as a uniform deposit of material onto the base of the pan 
by a plow. Scrapers also prevent buildup of materials on the dish surface. 
Powdered ingredients must be milled, premixed, and deaerated in 
order to have a uniform chute fed to the unit. Powder materials are 
continuously metered to the pan at a specific location, normally at a point 
three-fourths of a radius unit from the top of the dish. The spray angle 
depends to a large extent on positioning of the sprays and their distance

220 Chang and Robinson 
from the bed powders; commonly, a 60 spray angle is used. The spray 
droplet size should be adjusted according to feed size and desired granule 
size. In other words, if small granules are desired, a fine droplet spray 
should be used and vice versa. Also, the finer the feed material. the 
finer the spray droplet. 
There are several theoretical equations that can be used to calculate 
the rotational speed of the pan. However, appreciable discrepancy exists 
in theory and practice. Usually 20-30 rpm seems a reasonable rotation 
speed. Following agglomeration, the finished granules are raked over by 
the dish rim, and the rim height can be adjusted to control granule size. 
Pronounced size segregation is the principal feature of dish granulation. 
This ensures almost perfectly spherical pellets with a narrow particle size 
distribution. Important parameters in the dish pelletizer include powder 
feet rate, position of powder feed chute, spraying rate, position of the 
spraying gun, spray nozzle size, angle of inclination, rotational speed, rim 
height, powder bed depth, and pan size. These variables interact to 
some extent to produce the final granules. 
However, the noncontinuous granulation process in which spraying and 
drying stages are alternately repeated has been employed to maintain constant 
moisture levels and to produce high-density granules. A high level 
of perfection in shape and size of the granules cannot be obtained by 
agglomeration mechanism using a conventional fluidized-bed granulator. 
Recently, modified fluidized-bed units. such as the Roto-Processor, the 
Spir-A-Flow, and the Glatt Rotor Granulator/Coater, ell utilize a rotating 
disc at the bottom of a fluidized-bed, replacing the air-distribution plate. 
This modification supposedly combines the advantages of the dish granulator 
and the fluidized-bed granulator. It has been demonstrated that the 
rotary fluidizer-bed granulator can be used to produce spherical granules 
with high density by an agglomeration mechanism [51]. In general, the 
layering mechanism using nonpareil seeds or sugar crystals as a substrate 
to build spherical-shaped pellets is relatively easy compared to the agglomeration 
mechanism. 
4. Bxtrusion-eptierontzatton process. Spherical pellets can also be 
produced using an extrusion-spheronization process. The main processing 
steps include (1) dry blending, (2) wet granulation, (3) kneading, (4) 
extrusion, (5) spheronization, (6) drying, and (7) screening. A thoroughly 
wet granulation containing the drug, diluent. and binder is forced 
through a radial or axial extruder with a suitable die design, such as a 
perforated die or multiple-hole die, by means of a screw feeder to produce 
roughly cylindrical extrudates. The extrudate size and final pellet size 
are determined by the size of the die used on the extruder. The pellet 
mill, a radial extruder, was initially developed for the agricultural industry 
to densify and upgrade the particle size of poultry and animal 
feeds. In operation, the preconditioned material is fed continuously in a 
controlled fashion to the pelleting chamber. The motor-driven outer perforated 
die ring causes the roller( s), Which is mounted inside the die ring, 
to turn. The feed, carried by the rotation of the die ring, is compressed 
and forced through the holes in the die ring. As pellets are extz-uded , a 
knife, or knives, mounted at the exterior of the die ring. cuts the pellets 
to length. Application of the pellet mill to pharmaceutical products has 
been extremely limited. However, it deserves special mention owing to its 
ability to produce pellets with high density and low friability at a high 
output.

Sustained Drug Release from Tablets and Particles 221 
The extruded granules can be converted into consistently sized 
spheres by use of a Japanese device called a marumerizer or an English 
version of the device called a spheronizer. This device consists of a stationary 
cylinder with a smooth wall and a grooved rotating disc. The 
centrifugal and frictional forces, generated by the rough rotating baseplate, 
spheronize and densify the extruded granule. A typical time for 
the spheronization process would be approximately 5 min per batch, depending 
upon the nature of the material. Recently, a unique device called 
the Roto-Coil has been designed 8S a continuous spheronizer with no moving 
parts. This device consists of a spiral-shaped pipe. The extrudate 
is spheronized by passing through the pipe in a rotation movement with 
the aid of negative pressure generated by a fluidized-bed system. The 
advantages of the extrusion-spheronization process include: (1) production 
of the spherical pellets without using seeds, leading to reduction of 
the bulk of final product; (2) the ability to regulate size of the pellets 
within a narrow particle size distribution; (3) the ability to produce highdensity, 
low-friability, spherical pellets; and (4) the ability to achieve 
excellent surface characteristics for subsequent coating, leading to an 
homogeneous distribution of coating material( s) onto the spherical pellets. 
It is also possible to agglomerate the finely divided solids into spherical 
matrices from a liquid suspension [52]. In the spherical agglomeration 
process, fine pow del'S are dispersed in the liquid. With controlled agitation, 
a small amount of a second liquid, which is immiscible with the first 
liquid and preferentially wets the solids, is added to induce formation of 
dense, highly spherical agglomerates. Another approach to prepare 
spherical matrices in the liquid state is the instantaneous crosa-Iinking of 
drug-containing droplets of aqueous solution of sodium alginate in a suitable 
hardening bath, such as calcium chloride solution. This entrapment 
technique in recent years has become the most Widely used method for 
immobilizing living cells and enzymes. It enjoys several advantages, such 
as a simple production process, a wide size range of beads, and a narrow 
size distribution [53]. The spray-drying process has been used to produce 
a spherical matrix. However, the spray-dried cores may be porous 
and fluffy because of rapid volatilization of the solvent. The spraycongealing 
process, also called the prilling process, is well known in the 
fertilizer industry for production of urea pellets and ammonium nitrate 
pellets. This process can be defined as the process by Which a product 
is formed into particles, usually of spherical shape, by spraying a melt of 
the product into a chamber of suitable configuration through which cooling 
air is passed. The process is fairly restricted to matrix materials 
having suitable properties; namely, a high melting point and low heats of 
crystallization [54]. These several techniques may have potential applicability 
to produce spherical cores containing drug for SUbsequent sustainedrelease 
coating, and thus deserve further investigation. The physical 
properties of the product, such as pellet size and size distribution, pellet 
density, strengths, globocity, pore and pore distribution I ate , , are different 
for various methods and may be important for subsequent coating 
as well as in product performance. Table 3 summarizes the various possible 
methods to core production and some selected pharmaceutical examples. 
LATEX/PSEUDOLATEX COATING. The strict air-quality controls 
instituted by different federal agencies, spiraling solvent costs. the high 
price of solvent recovery system, and potential toxicity as well as to some

Table 3 Possible Methods for Core Manufacture and Some Selected Pharmaceutical Examples t\,) 
t\,) 
t\,) 
Method and example 
Crystallization 
Compressed tablet 
Min-Tablet [49J 
Granular 
Layering [55J 
Layering [56] 
Equipment 
Oslo crystallizer 
Tablet press 
Tablet press 
Chilsonator, Hutt 
Compactor 
CF-Granulator 
Fluidized-bed 
coater 
Drug 
Potassium chloride 
acetyl salicylic acid. etc. 
Various 
Diprophylline 
Various 
Theophylline, pseUdoephedrine 
hydrochloride. diphenhydramine 
hydrochloride 
Dexamphetamine sulfate 
Carrier binder 
N/A 
Various 
Polyvinyl alcohol 
Various 
Gelatin, sodium 
carboxymethylcellulose. 
Kaolinl 
Eudragit E-30D. 
Povidone 
Gelatin 
Comments and 
variable studied 
Very few drug crystals 
possess adequate properties 
for coating. 
Single-unit device. The 
accidental rupture of the 
film barrier may cause 
premature dumping of 
drug. 
Relatively large matrices 
for multiunit device. 
Irregular shaped granules. 
Extensive screening 
and recycling of undesired 
granules , 
Evaluation of CF-Granulator 
for pelletization. 
As cores for hot-melt and 
cellulose acetate phthalate 
coating to obtain sustained 
reslease and enteric 
properties.

Layering [57] Coating pan Sodfum salicylate Ethyl cellulose As cores for fluidized-bed 
coating to obtain a product 
with enteric and sustained- 
release properties. 
Agglomeration [58] Planetary mixer. Hydrochlorothiazide Microcrystalline 
high shear mixer cellulose 
Agglomeration [50] P.K. Blender with Aspirin, caffeine, phenyl- Povidone Extensive screening and 
intensifier bar ephedrine hydrochloride. recycling of undesired 
chlorpheniramine maleate granules. 
Agglomeration [59] Dish granulator N/A Maize starch Evaluation and studies of 
operating conditions for 
the formation of pellets. 
Agglomeration [51] Rotary fluidized Butalbital Lactose, corn Comparison of rotary 
bed starch. and fluidized-bed granulator 
povidone with conventional fluidized-
bed granulator. 
Agglomeration [58] Rotary fluidized Hydrochlorothiazide Microcrystalline 
bed cellulose 
Extrusion-spheroniza- Extruder and N/A N/A General description and 
tion [60] marumerizer or discu ssion of extru sion 
spheronizer spheronization technology. 
Extrusion-spheroniza- Extruder and Dibasic calcium phosphate. Microcrystalline Comparison of extrusiontion 
[61] marumerizer or magnesium hydroxide, cellulose spheronization process 
spheronizer sulfadiazine. aeatoamlno- with conventional wet 
w 
phen granulation. 
w
~

Method and example 
~
~ 
Table 3 ( Continued) 
Equipment Drug Carrier binder 
Comments and 
variable studied 
Extrusian-spheronization 
(62] 
Extrusian-spheronization 
[63] 
Extrusion- spheronization 
[64] 
Extrusion-spheronization 
[651 
Extrusion- spheronization 
[66J 
Extruder and 
marumerizer or 
spheronizer 
Extruder and 
marumerizer or 
spheronizer 
Extruder and 
marumerizer or 
spheronizer 
Extruder and 
marumerizer or 
spheronizer 
Extruder and 
marumerizer or 
spheronizer 
N/A 
Acetoaminophen 
Theophylline. quinidine 
bisulfate, chloropheniramine 
maleate, hydrochlorthiazide 
Acetoaminophen 
N/A 
Microcrystalline 
cellulose. sucrose, 
lactose 
Microcrystalline 
cellulose 
Microcrystalline 
cellulose, sodium 
carboxymethylcellulose 
Microcrystalline 
cellulose, carboxymethylcellulose 
Lactose, dicalcium 
phoshydrate 
povidone and 
microcrystalline 
cellulose 
Effect of the spheronization 
processing variables, dwell 
time and speed, on the 
final granule properties. 
Effects of spheronization 
processing variables including 
water content, extrusion 
speed. screen size, 
spheronizer speed and 
spheronizer time on tablet 
hardness and dissolution 
rate. 
Effect of different diluents 
and drug-diluent ratio on 
the final granule properties. 
Use of factorial design to 
evaluate granulations prepared 
by extrusionspheronizatton 
. 
Elucidation of the factors 
that influence migration of 
solvent-soluble materials 
to the surface of beads 
made by extrusion-spheronization.

~
~
til 
Extrusion -spheroniza- Extruder and Theophylline, quinidine Microcrystalline Microcrystalline cellulose 
tion [58] marumerizer or sulfate, chlorpheniramine cellulose has excellent binding 
spheronizer maleate, hydrochloro- properties for granulation 
thiazide to be spheronized. 
Spherical-agglomera- Liquid agitator Sulfamethoxazole, White beeswax, Parameters affecting the 
tion [52] sulfanilamide ethylcellulose size and release behavior 
of resultant matrix. 
Gellation [53] Dripping device Enzymes and living cells Calcium alginate Widely used method for 
and calcium chlor- immobilizing living cells 
ide solution as a and enzymes. Possible 
hardening agent pharmaceutical application 
for pellet making. 
Gellation Dripping device Diphenhydramine chloride Gelation, glycerin 
and coolant 
liquid 
Spray congealing Spray congealer N/A Materials with high Variables affecting the 
[67,54] melting point and spray congealing process, 
low heats of and possible pharmacrystallization 
ceutical application for 
pellet making.

226 Chang and Robinson 
extent explosiveness and danger of these solvents have given pharmaceutical 
and food supplement processors considerable incentive to remove 
organic solvents from the coating process. The most commonly used methods 
to eliminate organic solvents are presented in Table 4. At present 
and in the foreseeable future, latex or pseudolatex coatings appear to be 
the best choice to eliminate solvent-based coatings for controlled drug release. 
Several techniques. including emulsion polymerization. emulsionsolvent 
evaporation. phase inversion, and solvent change. can be employed 
to prepare suitable latex{pseudolatex dispersion systems. Each method 
has advantages and disadvantages based upon ease of preparation. latex 
stability. convenience of use, film properties, and economics. 
METHODS TO PREPARE LATEX DISPERSIONS 
1. Emulsion polymerization. Polymerization in an emulsion state can 
be applied to a wide variety of vinyl, acrylic, and diene monomers with 
water solubility in the proper range, usually 0.001-1. 000% [89 - 911. The 
basic formula used in emulsion polymerization consists of water, monomer, 
surfactant, and initiator. The system contains three phases: Water containing 
small amounts of dissolved surfactant and monomer. monomer droplets 
stabilized by surfactant, and much smaller surfactant micelles saturated 
with monomer. The initiator decomposes into free radicals which 
react with monomer units at three possible sites for polymerization. The 
radicals can react with dissolved monomer in the aqueous phase. or can 
diffuse into the monomer droplets or the micelles. Obviously. there is 
very little initiation in the aqueous phase owing to low monomer concentration 
in the water phase. The diffusion rate of the radicals, which is 
directly proportionsl to surface area, is far greater into the micelles, and 
thus there is virtually no initiation in the monomer droplets. Free radicals, 
from initiator decomposition, begin polymerization in the monomer solubilized 
in the micelles. The micelles transform into growing particles. As these 
monomer-polymer particles grow, they are stabilized by more surfactant at 
the expense of uninitiated micelles, which eventually disappear. The 
growing latex particles are continually supplied with monomer by diffusion 
through the aqueous phase from monomer droplets. The latter gradually 
decreases in quantity as polymerization proceeds, until at a conversion of 
about 60%, they disappear completely. All free monomer has then diffused 
into the latex particles. The polymerization rate decreases as the 
monomer in the particles is depleted by further polymerization. The schematic 
process for emulsion polymerization is shown in Scheme 7. 
2. Emulsion -solvent evaporation technique. The emulsion -solvent 
evaporation technique [92 - 97] also called emulsion hardening, has been 
widely used to prepare microspheres for controlled drug release [98 -100]  
The technique involves dispersion of drug in an organic polymer solution, 
followed by emulsification of the polymer solution in water. After continuous 
stirring, the solvent evaporates and drug-containing rigid polymer 
microspheres are formed. The procedure for preparing pseudolatex is 
essentially the same as that described above (Scheme 8). The polymer 
emulsion, with droplets so small they are below the resolution limit of the 
optical microscope. can be accomplished by subjecting the crude emulsion 
to a source of energy such as ultrasonic irradiation or by passing the 
crude emulsion through a homogenizer or submicron dispenser. The 
polymer solvent is normally stripped from the emulsion at elevated temperatures 
and pressures to leave a stable pseudolatex. If foaming is not a 
problem. the solvent may be removed under reduced pressure.

Sustained Drug Release from Tablets and Particles 227 
Purified monomer by extraction 
or adsorption 
initiator 
Water + surfactant and/or 
emulsion stabilizer + 
Emulsify monomer as internal 
phase in water (oil in water 
emulsion) 
Bubble nitrogen through the 
emulsion to remove air and 
oxygen 
Use heat and agitation to 
induce polymerization 
True latex 
Scheme 8 
3. Phase inversion technique. The phase inversion technique [101104] 
involves a hot-melt or solvent gelation of the polymer, which is then 
compounded with a long-chain fatty acid such as oleic acid, lauric acid, 
or linoleic acid using conventional rubber-mixing equipment such as an 
extruder. When the mixture is homogeneous a dilute solution of an slkali 
is slowly added to the mixture to form a dispersion of water in polymer. 
Upon further addition of aqueous alkali under vigorous agitation, a 
phase inversion occurs and a polymer in water dispersion is produced 
(Scheme 9). 
4. Solvent change and self-dispersible technique. An ionic water 
insoluble polymer, which may be generated by acid-base treatment or 
chemical introduction of functional groups, such as ammonium groups, 
phosphonium, Or tertiary sulfonium groups, may be self-dispersible in 
water without any need for additional emulsifier [105,106]. Generally, 
the polymer is first dissolved in a water-miscible organic solvent or in a 
mixed water-miscible organic solvent system. The pseudolatex can then 
be obtained by dispersing the polymer solution in deionized water into

~
~
Oc) 
Table" Common Methods to Eliminate Organic Solvents in the Coating Process 
Method 
Compression coating 
Aqueous solution 
Mixed organic aqueous 
system [68] 
Alkali salts [69. 70J 
Function 
Compressible materials 
Water-soluble film 
formers 
Enteric materials 
Ent-eric materials 
Examples of coating materials 
Su gars, hydroxypropylmethylcellulose, 
polyvinyl alcohol 
Methylcellulose. hydroxypropyl 
cellulose, hydroxypropylmethylN 
cellulose 
Polyvinyl acetate phthalate, 
carboxylmethylethylcellulose. 
hydroxypropyimethylcellulose 
acetate phthalate. 
Shellac. hydroxypropylmethylcellulose 
phthalate. cellulose 
acetate phthalate, cellulose 
acetate trimellitate. 
Comments 
Totally eliminates organic solvents. 
It is not well accepted by pharmaceutical 
industry owing to complicated 
mechanical operation and 
formulation problems. 
Film formers giving solutions of low 
viscosity are the most suitable for 
use. Totally eliminates organic solvents. 
but unusitable for controlled 
drug release. 
Parti8lly eliminates organic solvents. 
May be suitable for enteric coating, 
but not practical for controlled 
drug release. 
To form gastric fluid resistant coatings, 
a volatile neutralizing agent, 
ammonium hydroxide or morpholine, 
is preferable to neutralize the 
enteric materials. Totally eliminates 
organic solvents.

t" 
t" 
to 
Hot melts 
Aqueous dispersions 
of waxes and lipids 
[ 71] 
Coating emulsions 
Latex: dispersions 
[73 -80] 
Materials with low melting 
point 
Waxes and lipids 
Almost all waterinsoluble 
polymers 
AImost all waterinsoluble 
polymers 
Hydrogenated oil. wax, solid 
polyethylene glycol 
Castor wax. carnauba wax. 
Cu tina HR. Hoechst Wax E. 
Durkee 07 
Cellulose acetate phthalate. 
hydroxypropylmethylceI1ulose 
Ethylcellulose pseudolatex , 
Eudragit RL/RS pseu dolatex , 
Eudragit E-30D latex 
Organic solvents can be eliminated 
completely. However. organic solvents 
may be needed to thin the 
hot melts, in some cases. Heating 
devices such as steam jackets or 
heating tape is needed for the 
spraying system to avoid solidification 
of the coating material. 
Ladle process may be more practical, 
less troublesome. 
Totally eliminates organic solvents. 
Aqueous dispersions of waxes and 
lipids may not be superior to hot 
melt coating. 
Partially eliminates organic solvents. 
Still in their infancy as pharmaceutical 
coatings. 
Totally eliminates organic solvents. 
Latex dispersions usually have low 
viscosity and a high solids content. 
Latex systems have some applications 
in ophthalmic delivery systems 
[81]. injectable colloidal delivery 
system [82]. and molecular entrapment 
techniques for sustainedrelease 
dosage forms {83-88].

230 
Polymer + water 
immiscible solvent 
Chang and Robinson 
Water + surfactant and/or 
stabilizer 
Scheme 8 
Emulsify polymer-solvent as 
internal phase in water (crude 
emulsion) 
Subject to ultrasonic 
irradiation, homogenizer or 
subm1cron disperser to 
generate a fine emulsion with 
sUbmicroscopic droplet size 
Eliminate the organic solvent 
Pseudolatex 
the polymer solution under mild agitation. The organic solvent(s) is subsequently 
eliminated from the aquous-organic solution to leave a stable 
latex (Scheme 10). The absence of emulsifiers has several interesting 
consequences, such as stability to heat and mechanical shear, and dilutability 
with organic solvents. Table 5 lists the general features of four 
commercially available latex-coating systems for controlled drug release. 
Recently, latex/pseudolatex coating has been further expanded to use 
cellulose acetate pseudolatex for elementary osmotic pumps [107] and 
water-based silicone elastomer dispersion for controlled-release tablet coating 
[108,109]. 
The aforementioned techniques also can be used to prepare latex or 
pseudolatex of enteric polymers. Because it is costly to ship aqueous dispersions 
and some enteric materials are susceptible to hydrolysis, sprayor 
freeze-drying techniques may be used to dry aqueous polymeric

Sustained Drug Release from Tablets and Particles 231 
Hot melt or solvent 
gelation of polymer 
Scheme 9 
long chatn fatty acid. 
such as oleic acid 
Mix thoroughly to form 
homogeneous mixture 
Add a dilute solution of an 
alkali slowly into the mixture 
Water in polymer dispersion 
f 
Further incorporation of 
aqueousal ka 11 
Polymer 1n water dispersion 
pseudolatex 
dispersion and form a redispersible aqueous enteric coating system. 
Table 6 lists the general features of three dispersible aqueous enter1ccoating 
systems. 
Basic Considerations in Coating and Accessory Coating Equipment 
COATI NG EQUIPMENT. A perforated pan as well as a conventional coating 
pan equipped with hot air supply, spray system, pan baffles, and variable 
coating pan speed can be used for latex coating. However, the relative 
inefficiency of drying and longer contact time in the coating pan may cause 
penetration of water into the core and thus discontinuity or irregularity of 
the film {1l0]. In the past 10 years, there has been a significant increase in 
the use of fluid-bed technology to granulate materials for improved compression 
and to coat cores for desired properties such as controlled drug release, 
enteric release, appearance, or taste masking. Fluid-bed coating using

232 
Polymer with ionic character. 
Polymer undergoes acid-base 
treatment to generate ionic 
character or polymer undergoes 
chemical modification to yield 
ionic character + watermiscible 
organic solvents Water 
Chang and RObinson 
Mix under agitation to form 
latex dispersion in aqueous 
organic solvent system 
I 
Eliminate the organic solvent 
(s) 
Pseudolatex 
Scheme 10 
centrifugal-type or Wurster column-type equipment provides ideal conditions. 
such as rapid surface evaporation. controllable inlet air temperature. and 
short contact time, for latex coating. 
ACCESSORY EQUIPMENT 
1. Nozzle systems. Characteristics of three different types of nozzle 
are listed in Table 7 [111]. The ultrasonic nozzle is a relatively new 
and entirely different type of atomizing nozzle that offers several advantages 
over conventionsl nozzles. However, application of ultrasonic nozzles 
is still in its infancy. Thorough investigations are necessary to dedermine 
the feasibility of their pharmaceutical applications. Hydraulic 
guns are sometimes used in place of air-atomizing nozzles for large filmcoating 
processes. The nozzles tend to clog with latex coating because 
the airless system generates a shear which may coagulate the formulated 
latex. Pneumatic nozzles have been adapted for fluid-bed systems, and 
have been shown to be an acceptable nozzle system for latex coating. 
The atomizing air is exposed to the product and, therefore, must be 
free of oil and other contaminants.

Sustained Drug Release from Tablets and Particles 233 
Table 5 General Features of Four Latex Coating Systems for Controlled 
Drug Release 
Latex system 
Eudraglt E-30D 
(Rohm Pharma) 
Aqua-Coat 
(F .M.C. Corp.) 
Surelease 
(Colorcon, Ine .) 
Budz-agft RS30D 
and RL30D 
(Rohm Pharma) 
Method 
Emulsion 
polymerization 
Emulsion-solvent 
evaporation 
Phase inversion 
Self-dispersible 
General features 
Poly (ethylacrylate, methylmethacrylate) 
latex, 30% w/w solid content. 
No plasticizer is required. May 
contain residual monomer, initiator. 
surfactants , and other chemicals 
used in the polymerization process. 
Unplasticized ethyl cellulose dispersion. 
Contains sodium lauryl sulfate 
and cetyl alcohol as stabilizers. 
30% w/w solid content. 
Fully plasticized ethyl cellulose 
dispersion. Contains oleic acid, 
dibutyl sebacate, fumed silica, and 
ammonia water. 25% w/w solid 
content. 
Unplasticized poly (ethylaerylate , 
methylmethacrylate. trimethylammonioethylmethacrylate-
chloride) 
dispersions. Contains no emulsifiers. 
30% w/w solid content. 
Table 6 General Features of Three Dispersible Aqueous Enteric Coating 
Systems 
Coating system 
Aquateric 
(F .M.C. Corp.) 
Coateric 
( Colorcon, Inc.) 
Budragft L - 100-55 
(Rohm Pharma) 
Method 
Emulsion-solvent 
evaporation followed 
by spray 
dry technique 
Mechanical means 
to reduce particle 
size of 
the polymer 
Emulsionpolymerization 
followed by 
spray dry 
technique 
General features 
Redispersible cellulose acetate 
phthalate coating system. Contains 
polyoxypropylene block copolymer 
and acetylated monoglycerides. 
Plasticizer is required. 
Completely formulated dispersible 
polyvinyl acetate phthalate coating 
system. 
Redispersible poly (ethyl acrylatemethacrylate 
acid) coating system. 
Contains polyvinylpyrrolidone, 
polyoxyethylene sorbitan fatty acid 
ester, and polyethylene glycol. 
Plasticizer is required.

~
(,,) 
"'" 
Table 7 Nozzle Characteristics by Type 
Ultrasonic nozzles Hydraulic (pressure) Air atomfzing (two fluids) 
Principal of operation 
Average microdrop 
size 
Spray velocity variability 
flow rate 
Minimum achievable 
flow rate 
Maximum achievable 
flow rate 
Ornice &ze/cloggabllity 
Ultrasonic energy concentrated 
on atomizing surface. 
causes impinging liquid to 
disintegrate into a fog of 
microdrops 
20-50 Il (depending on frequency) 
Low: 0.2-0.4 ms, Infinity 
variable from zero flow to 
rated capacity 
o gph 
30-40 gph 
Large: up to 3/8" -uneloggable 
Pressurized liquid is forced 
through orifice. Liquid is 
sheared into droplets. 
100 - 200 u at 100 psi (higher 
pressure reduces size) 
High: 10-20 mls  10% of 
specified rating 
0.5 gph 
No limit 
Very small, usually subject 
to clogging 
High-pressure air or gas 
mixes with liquid in the nozzle: 
Air imparts velocity to 
liquid which is then ejected 
through an orifice 
20-100 1.1 (air pressure from 
10-100 psi) 
High: 50- 20 ml s , Infinitely 
variable from 20% of maximum 
capacity to maximum 
0.3 gph 
No limit 
Very small, usually subject 
to clogging

Sustained Drug Release from Tablets and Particles 235 
2. Pumping systems. Peristaltic or gear pumps are used in combination 
with nozzles to form a spray system. The ab'fiity of a pumping system 
to deliver the coating liquid at the required rate for the duration of the 
coating cycle is critical for a uniform coating. A flow integrator can be 
used to eliminate pulsation of output flow which may cause uncontrolled 
wetting disruption of the spraying process. 
3. Humidity control. In order to maximize the drying efficiency of 
the fluid-bed machine, it may be necessary to dehumidify the inlet air. 
Furthermore, the amount of moisture in the inlet air can significantly influence 
batch-to-batch variabfiity of the coating process. Therefore, it is 
important to control ambient air humidity in the coating operation. 
PROCESS VARIABLES 
1. Fluidization air temperature. Film formation from a solvent-based 
system is dependent upon the entangling and packing of polymer molecules 
as the solvent evaporates. Relatively low fluidization air temperatures 
should be used to prevent spray drying of coating materials because of 
low heats of vaporization for commonly used solvents. The mechanisms of 
film formation from a latex system involves the softening of latex spheres 
caused by plasticization and/or temperature, the contact of latex spheres 
resulting from loss of water, followed by deformation and coalescence of 
the latex spheres owing to capillary force and surface tension of the 
polymer to form a continuous film [1121. The temperature of the inlet air 
has a dual function; to evaporate water and to soften and coalesce the 
latex spheres. Latices, as contrasted to aqueous solutions, have a very 
low affinity for water, and therefore relatively low temperatures can be 
used to efficiently evaporate water. However, column temperature is critical 
for latex softening and coalescence. In order to generate a continuous 
film, the column temperature must be higher than the minimum film-formation 
temperature. If the temperature is too high, it may cause excessive 
drying and softening of the latex film, and hence result in electrostatic 
interaction and agglomeration problems. Minimum film-formation temperature 
[1131 should be used as a guideline to select the temperature of the 
inlet air. The glass-transition temperature [1141 and ffim-softening temperature 
[761 can also provide useful information for choosing the column 
temperature. 
2. Spray rate. The liquid spray rate affects the degree of wetting 
and droplet size. At a given atomization air pressure, increasing the 
liquid spray rate will result in larger droplets and a higher possibfiity to 
overwet the coating substrates. Slowing the spray rate may cause electrostatic 
problems owing to low bed humidity, especially at high temperature 
settings. 
3. Volume of the fluidized air. Since a sluggish or vigorous fluidization 
can have detrimental effects on the coating process, such as side-wall 
bonding and attrition of core substrates, proper fluidization should be 
maintained throughout the coating process. 
4. Atomization pressure. Atomization pressure affects the spraying 
pattern and droplet size. Excessive high atomization pressure may result 
in the loss of coating materials and breakage or attrition of the substrates. 
Excessive low atomization pressure may overwet the core and cause sidewall 
bonding.

236 Chang and Robinson 
FORMULATION VARIABLES 
1. The nature of the plasticizer. There are many plasticizers that 
are compatible with ethyl cellulose and polymethyl methacrylate and can be 
used for plasticization [115]. For the polymer with a relatively high glasstransition 
temperature, a plasticizer with a strong affinity to the polymer 
must be found in order to form a resistant film. Plasticizers with low 
water soIubfiity are generally recommended for controlled drug release. 
Dibutyl sebacate, diethyl phthalate, triacetin, triethyl citrate, and acetylated 
monoglyceride often give satisfactory results. 
2. The amount of the plasticizer. Experiments should be performed 
to determine the most favorable proportion of plasticizer. Low levels of 
plasticizer may not overcome the latex sphere's resistance to deformation 
and result in incomplete or a discontinuous film. On the other hand, a 
high proportion of plasticizer may result in seed agglomeration, sticking, 
and poor fluidization problems caused by excessive softening of the polymer 
film. The best result generally is obtained with plasticizer concentration 
in the range of 15- 30% based upon the polymer. 
3. Incorporation of plasticizer. Plasticizer can be incorporated into 
the latex system during the preparation process which provides more consistent 
plasticization, more effective use of plasticizer, and a relatively 
nonseparable plasticized latex system. Plasticizer also can be added to the 
latex system under mild agitation. Agitation speed, mixing time. and separation 
of plasticizer during the coating process should be considered in 
the preparation of the plasticized latex system. 
4. The solids content of the latex system. Generally. 8-20% solids 
content give the best results [112]. However, higher or lower solids content 
can be used to achieve a rapid buildup of film thickness or coating 
uniformity, respectively. 
5. Additive. Water-soluble chemicals can be incorporated into the 
latex film to enhance its dissolution rate. On the other hand, the addition 
of hydrophobic powder such as talc. magnesium, stearate, or silica in a 
latex-coating system not only alters drug release, but also facilitates 
processing by reducing tackiness of the polymer film. 
6. Dual Latex Ipseudolatex coating. Most latice or pseudolatices are 
stabilized by high surface potential of deflocculated particles arising from 
ionic functional groups on the polymer or ionic surfactant or stabilizer. 
For example, the positive charge on Eudragit RS30D and RL30D pseudolatex 
particles arising from quaternary groups on the polymers and the 
negative charge on Aquacoat and Surelease pseudolatex particles originated 
from the anionic surfactants such as sodium lauryl sulfate and oleic acid 
are the major stabilizing factor. Also, the size of the latex sphere and size 
distribution are important factors which affect stability, rheological properties, 
and film properties. Small, monodispersed latex particles are 
required to have complete coalescence of the latex sphere. Generally. it 
is not recommended to use dual latex/pseudolatex coating systems because 
of the possible incompatibfiity of two latex/pseudolates systems, the different 
glass-transition temperatures of the polymers. and the different sizes 
of latex spheres. However, in a British patent, Eudragit E-30D was mixed 
with Aquacoat to prevent the coated granules sticking together and to

Sustained Drug Release from Tablets and Particles 237 
improve the dissolution-retarding effect [116]. It has been demonstrated 
that Eudragit RS pseudolatex can be mixed in any proportion with Eudragit 
RL pseudolatex. A wide range of release rates for theophylline could be 
obtained by changing the ratios of Eudragit RS pseudolatex and Eudragit 
RL pseudolatex , The enhancement of theophylline release caused by increasing 
the amount of Eudragit RL pseudolatex is due to its high permeability 
to water and theophylline [80]. 
7. Overcoating. During the curing or storage stage, the pellets 
coated with latex or pseudolatex may adhere to one another because of the 
softening and tackiness of the film. This could have a detrimental effect 
on the dissolution properties of film-coated products. Nevertheless, an 
overcoat that is water soluble can solve the problem of tackiness of latex 
film without changing the dissolution profile. Immediate mixing of latexcoated 
pellets with some separating agents such as talcum. magnesium 
stearate. and other dfiuents also can prevent the formation of clumps of 
pellets during storage. 
C. Compression Coating and Embedment 
Specially constructed tablet presses such as Drycota and Prescota are 
available for compressing a polymeric or sugar composition onto a drugcontaining 
core. This technique has been utilized to create a polyvinyl 
alcohol diffusion barrier surrounding a core tablet containing various active 
ingredients as described by Conte et al , [117]. In vitro dissolution tests 
show that zero-order release kinetics of drug from compression-coated tablets 
can be achieved as long as the thermodynamic activity of the drug 
within the closure and the barrier characteristics are maintained constant. 
Salomon et al, [118] coated potassium chloride tablets with a thin layer of 
hydroxypropyl methylcel1ulose by a compression technique for delayedrelease 
purposes. Such compression-coated tablets release potassium chloride 
at a constant rate. Enteric coating by a double-compression technique 
has been reported [119] using a mixture of triethanolamine cellulose acetate 
and lactose as coating materials. 
Other variations of compression coatings such as inlaid tablets and 
layer tablets may have application in preparing a sustained-release tablet 
with an immediate-release and a separate slow-release portion. In general, 
the release rate from compression-coated tablets may be modified by core 
composition and characteristics. thickness of membrane layer, composition 
of membrane layer, and geometry of core tablet and final tablet. However, 
the expense of compression coating and layer tablet production. complicated 
mechanical operation, production problems such as multiple granulations, 
improper centration, capping, and limited compressible and permeable barrier 
materials limits its adoption as a popular technique to control drug 
release. The compression-embedding technique has received increasing 
attention to prepare controlled-release matrix tablets, and intensive research 
in this area is being conducted by pharmaceutical scientists. There 
are three different types of matrix tablets; I, e., hydrophilic matrices. 
plastic matrices, and fat-wax matrices. which can be differentiated by the 
matrix-bufiding materials.

238 Chang and Robinson 
Hydrophaic Matrix Tablet 
Utilization of a hydrophilic matrix as a means to control drug release was 
disclosed in U. S. Patent 3,065,143. Sodium carboxymethyl cellulose, 
methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene 
oxide. polyvinyl pyrrolidone, polyvinyl acetate. carboxy polymethylene. 
alginic acid, gelatin, and natural gums can be used as matrix 
materials. The matrix may be tableted by direct compression of the blend 
of active ingredient(s) and certain hydrophilic carriers, or from a wet 
granulation containing the drug and hydrophilic matrix material( s)  Several 
commercial patented hydrophilic matrix systems are currently in use, 
such as the Synchron Technology I 120J and hydrodynamically balanced 
system [121J. The hydrophilic matrix requires water to activate the release 
mechanism and enjoys several advantages, including ease of manufacture 
and excellent uniformity of matrix tablets. Upon immersion in 
water, the hydrophilic matrix quickly forms a gel layer around the tablet. 
Drug release is controlled by a gel diffusional barrier that is formed and/or 
tablet erosion. The effect of formulation and processing variables on 
drug-release behavior from compressed hydrophilic matrices has been 
studied by a number of investigators [122-134] and can be summarized as 
follows: 
1. The matrix building material with fast polymer hydration capability 
is the best choice to use in a hydrophilic matrix tablet formulation. 
An inadequate polymer hydration rate may cause premature diffusion of 
the drug and disintegration of the tablet owing to fast penetration of water. 
It is particularly true for formulation of water-soluble drugs and excipients. 
2. The amount of hydrophilic polymer in tablet formulations was reported 
to have a marked influence on the disintegration time and dissolution 
of the tablet. The disintegration time was extended as polymer content 
increased. The release rate of drug was decreased when the proportion 
of polymer was increased but differed quantitatively with different 
drugs and different matrix-building materials. Slower hydration polymers 
can be used at higher concentration level to accelerate gel formation or 
reserved for water-insoluble drug( s) . 
3. Generally, reduced particle size of the hydrophilic polymer ensures 
rapid hydration and gel formation, leading to a good controlled release. 
The impact of polymer particle size on the release rate is formulation 
dependent, but may be obscured in some cases. The particle size of 
a drug. within a normal size range, may not significantly influence the 
drug release from the matrix tablet. Extremes of drug particle size may 
affect release rate of the drug. 
4. Viscosity characteristics of the polymers are of great importance 
in determining the final release properties of the matrix tablet. Generally, 
the drug-release rate is slower for a higher viscosity - grade polymer. 
5. Commonly, water-soluble excipients in the matrix tablet can increase 
drug release. However, addition of water-soluble materials may 
achieve a slower rate by increasing viscosity of the gel through interaction 
with hydrophilic polymers or by competition with matrix material for 
water. When water-insoluble nonswellable excipient(s) or drug(s) is used 
in the matrix system stress cracks can occur upon immersion in water because 
of the combination of SWelling and nonswelling components on the 
tablet surface.

Sustained Drug Release from Tablets and Particles 239 
6. For some hydrophfiic matrix building materials, pH may affect the 
viscosity of the gel which forms on the tablet surface and its subsequent 
rate of hydration. Under acidic conditions. carboxypolymethylene and 
sodium carboxymethyl cellulose have little or no retarding effect on the 
drug-release rate. Gelatin forms gels of higher viscosity in acidic media 
and is more effective in retarding drug release as compared to a basic 
media.
7. No conclusions could be drawn as to the effect of compression 
force on drug-release behavior owing to the different properties of the 
various hydrophilic matrix materials. However. tablet size and shape can 
significantly influence drug-release kinetics. 
Fat-Wax Matrix Tablet 
The drug can be incorporated into fat-wax granulations by spray congealing 
in air [135 -13S}. blend congealing in an aqueous media with or without 
the aid of surfactants I 139 -142}. and spray-drying techniques [44]. 
In the bulk congealing method. a suspension of drug and melted fat-wax 
is allowed to solidify and is then comminuted for sustained-release granulations 
[143]. The mixture of active ingredients. waxy mat erial( s). and 
filler( s) also can be converted into granules by compacting with a roller 
compactor. heating in a suitable mixer such as a fluidized-bed and steamjacketed 
blender, or granulating with a solution of waxy material or other 
binders. Fat-wax granulations containing drug obtained from all of the 
above processes may be compressed to form tablet cores or directly compressed 
into a final tablet form with sustained-release properties. 
The drug embedded into a melt of fats and waxes is released by 
leaching and/or hydrolysis as well as dissolution of fats under the influence 
of enzymes and pH change in the gastrointestinal tract. Enteric 
materials such as cellulose acetate phthalate. polyvinyl acetate phthalate, 
methacrylate copolymer, zein. and shellac may be used to prepare matrix 
tablets with somewhat a similar drug-release mechanism. In general, the 
primary constituents of a fat-wax matrix are fatty acids and/or fatty 
esters. Fatty acids are more soluble in an alkaline rather than an acidic 
medium. Fatty esters are more suscepitble to alkaline catalyzed hydrolysis 
than to acid catalyzed hydrolysis. The surface erosion of a fat-wax matrix 
depends upon the nature and percent of fat-wax and extenders in the 
matrix [136]. Other factors such as drug particle size and drug concentration 
affects release of the drug from the matrix system [141]. The addition 
of surfactants to the formulation can also influence both the drugrelease 
rate and the proportion of total drug that can be incorporated into 
a matrix [137  142} Polyethylene. ethylcellulose, and glyceryl esters of 
hydrogenated resins have been added to modify the drug-release pattern 
[135]  
Plastic Matrix Tablets 
Sustained-release tablets based upon an Inert compressed plastic matrix 
were first introduced in 1960 and have been used extensively clinically 
[144]. Release is usually delayed because the dissolved drug has to diffuse 
through a capillary network between the compacted polymer particles. 
Commonly used plastic matrix materials are polyvinyl chloride. polyethylene. 
vinyl acetate/vinyl chloride copolymer, vinylidene chloride/acrylonitryle 
copolymer. acrylate/methyl methacrylate copolymer, ethyl cellulose.

240 Chang and RObinson 
cellulose acetate, and polystyrene [145]. Plastic matrix tablets, in which 
the active ingredient is embedded in a tablet with coherent and porous 
skeletal structure, can be easily prepared by direct compression of drug 
with plastic material( s) provided the plastic material can be comminuted or 
granulated to desired particle size to facilitate mixing with drug particle. 
In order to granulate for compression into tablets the embedding process 
may be accomplished by: 
1. The solid drug and the plastic powder can be mixed and kneaded 
with a solution of the same plastic material or other binding agents 
in an organic solvent and then granulated. 
2. The drug can be dissolved in the plastic by using an organic solvent 
and granulated upon evaporation of the sol vent. 
3. Using latex or pseudolatex as granulating fluid to granulate the 
drug and plastic masses. 
Drug release from the inert plastic matrices was affected by varying 
formulation factors such as the matrix material, amount of drug incorporated 
in the matrix, drug solUbility in the dissolution media and in the 
matrix, matrix additives, and the release media. Since the mechanism of 
controlling drug release in the plastic matrix is the pore structure of the 
matrix:, any formulation factors affecting the release of a drug from the 
matrix may be a consequence of their primary effect on apparent porosities 
and tortuosities of the matrices. These release factors can be summarized 
as follows: 
1. The release rate increases as the solubility of the drug increases, 
but there seems to be no direct relationship between the two variables. 
2. The release rate increases as the drug concentration increases. 
An increase in release rate cannot be explained on the basis of increasing 
matrix porosity [146]. Rather it has been attributed to changes in matrix 
tortuosity with drug concentration [147] and to decreased diffusional resistance 
by shortening the length of the capillary joining any two drug 
particles [148]. 
3. It is possible to modify the release rate by inclusion of hydrophilic 
or hydrophobic additives to the matrix. The release of a sparingly soluble 
substance can be increased by the addition of physiologically inert but 
readily soluble material such as polyethylene glycol, sugars, electrolytes, 
and urea [146,149]. The decrease in the release rate on the addition of 
hydrophobic substance may be due to decreased wettability of the matrix 
[150]  
4. The release rate from plastic matrix tablets could be decreased by 
exposure to acetone vapor without changing the release mechanism. The 
extent of the reduction was found to be dependent on the amount of 
acetone absorbed [147,151]. The tensile strength of the tablets increases 
by heating the polymer matrix above the glass-transition temperature. 
However, porosity also increases with a marked increase in the release 
rate [152,153]. 
5. The release rate increased as the particle size of the matrix material 
increased and as the particle size of the drug decreased. 
6. Increasing compaction pressure up to the full consolidation point 
tends to decrease the pore formed among the polymer particles, resulting 
in a slower drug-release rate [154].

Sustained Drug Release from Tablets and Particles 241 
Microcapsules. microspheres, or coated pellets also can be compressed into 
tablets or embedded in a drug-containing matrix. Sustained-release tablets 
made from individual coated particles may have very different release characteristics 
than the original coated particles depending upon whether or not the 
tablets disintegrate to expose the majority of the coated particles to the dissolution 
environment and whether the coated particles are damaged by the compression 
process [155]. Generally. nondisintegrating tablets made from ethyl 
cellulose microcapsules followed matrix -release kinetics are much slower than 
the uncompressed microcapsules. When compression force was sufficient to prevent 
breakup of the tablets, greater compression force had little effect on 
rate of dissolution I 156 - 160]  Apparently. nondisintegrating tablets made 
from individual coated particles did not provide any advantages over matrix 
tablets but a more complicated manufacturing process. A dispersible tablet 
containing individual coated particles distributes the drug-containing coated 
particles in the gastric content to minimize the high local concentration of 
drug and to reduce the inter- and intrasubject variation linked to gastrointestinal 
transit time. 
However. the sustained-release properties of the coated particles may 
be lost due to cracking of the membranes and rupture of the characteristic 
microcapsule tails. The amount of damage was found to be related to the 
compressibility and particle size of excipients in the tablet formula as well 
as to the compression pressure. Large particles led to greater damage 
as noted by increased dissolution rates of the disintegrating tablets [161]. 
It also has been found that a combination of microcrystalline cellulose and 
polyethylene glycol provides maximum protection from the damage of potassium 
chloride microcapsules by reducing interparticle friction [162]. 
Matrix: particles have the advantage of being very rugged, less subject to 
dose dumping, and more resistant to compression damage than membrane 
systems. Little change in the dissolution rate of cellulose acetate butyrate 
microspheres containing succinyl sulfathiazole has been reported when tableting 
with microcrystalline cellulose and carboxymethyl starch under compression 
force between 35 and 350 MPa [163]. 
IV. SUSTAINED-RELEASE PRODUCTS THROUGH 
COATING 
The preceding discussion has provided the framework for the design of 
sustained-release products. Application of these principles in the pharmaceutical 
industry has resulted in varying degrees of success in achieving 
consistent, nonvarying blood levels of drug from sustained-release dosage 
forms. It is instructive to examine some of these dosage forms more closely, 
and to analyze where and why they fail to provide sustained release 
and whether the failure can be detected in vivo or in vitro. Of course, 
the reader should keep in mind that these are "failures" only in a relative 
sense; some forms are very much superior to others, but all do provide 
some sort of sustained therapy beyond their nonsustained counterparts. 
Whether this sustained blood or tissue level results in a measurable improvement 
clinically is often debatable. 
It would appear from the earlier sections of this chapter that one can 
employ the theoretical calculations on release-rate and dosage-form design 
with great precision to formulate a prolonged-action dosage form. In 
point of fact, although this has been done in a few studies, the vast

242 Chang and Robinson 
majority of published work has employed these principles and calculations 
as a working guideline. The formulator obtains the desired release-rate 
constant and size of tablet by suitable calculation and attempts to generate 
this release pattern by some sustained-release mechanism. such as 
coating. If the release rate of drug is dissimilar to the calculated value. 
the dosage form is appropriately modified. Since the ideal release pattern, 
resulting in a tissue drug concentration -time profile similar to that shown 
in Figure 1. is seldom obtained, the formulator will usually be satisfied 
with either a bell-shaped profile that has a broad. relatively flat plateau, 
or an extension of biological activity. This qualitative approach. which at 
times is very empirical, is clearly evident when one reads the literature 
dealing with prolonged-action dosage forms. Thus. unless the formulator 
has good control over the release mechanism, which is rarely the case. he 
or she wfil be working empirically or semiempirically in preparing the 
dosage form. Moreover. because of this lack of control over the release 
mechanism, a blood drug profile will usually result that shows simple prolongation 
rather than the invariant drug level of the sustained type. 
In the following discussion, we have arbitrarily classified the approaches 
used in coating sustained-release products into various SUbdivisions. A 
good argument could be constructed that all of the following subdivisions 
are artificial. since all coated sustained-release dosage forms utilize dissolution 
and diffusion to varying degrees. However. the dosage forms mentioned 
in each section usually appear to have one major mode of providing 
sustained action. These modes can derive from the way the material is 
produced. as in the case of microcapsules and bead polymerization, or from 
the way the body handles the dosage form, as in the case of soluble coated 

granules or impermeable films coated in a tablet. The division has been 
created solely for the purpose of organizing the literature in the area and 
should not be viewed as being rigid or exclusive. 
At the end of some of the SUbdivisions, the reader will find a section 
entitled case study. These sections are intended to provide sufficient experimental 
detail to allow the novice formulator to initiate preparation of a 
prolonged-action dosage form. We will thus examine selected published reports 
in more detail, providing as much of the experimental methods employed 
as is practical. In addition. when available, the appropriate equations 
to describe the release of drug from the dosage form and the type 
of in vitro and in vivo profile generated will be noted. 
A. Sustained Release Utilizing Dissolution 
Dissolution methods in sustained release generally refer to coating the individual 
particles, or granules, of the drug with varying thicknesses of 
coating material so that dissolution of the coat, resulting in release of the 
drug contained within, occurs over a long time span owing to the thickness 
differences of the coats. These coated particles are then either compressed 
directly into tablets (e.g . Spacetabs), or they can be placed in capsules 
(e.g the Spansule or Plateau Cap dosage forms), as shown in Scheme 11. 
Alternatively. the dissolution may be that of an exterior tablet coating 
Where a portion of the drug is placed in the tablet coat and dissolves rapidly 
to provide enough drug to quickly reach therapeutic levels. whereas 
the sustained-release interior of the tablet utilizes some other method, to 
be discussed subsequently. to provide controlled, long-term release of

Sustained Drug Release from Tablets and Particles 243 
WAX OR 0 
00 
DRUG 0 POLYMER  + 00:0 > 00 c::::=o  000 0 
0 WAX OR 
BLANK DRUG POLYMER NON SUSTAINED SEEDS COATED COATED DOSE 
CAPSULES 
TABLETS 
Scheme 11 
medicament. Exterior tablet coats may also have differentially soluble constituents 
that dissolve and provide an outer shell to maintain diffusion 
path lengths for the drugs contained in the shell. This form of sustained 
release is particularly useful for relatively insoluble drugs because it keeps 
the dose from disintegrating and being spread out over the gastrointestinal 
tract, thus providing some regulation of the dissolution medium and area 
for control in maintaining slow release of drug. 
Pulsed Dosing 
Included in the pulsed dosing category are slowly dissolving coatings such 
as the various combinations of carbohydrate sugars and cellulose-based 
coatings as well as polyethyleneglycol bases, polymeric bases, and waxbased 
coatings. Colbert [1641 and Johnson [165] provided a particularly 
complete cross section of patents issued since 1960 based on these digestible 
bases. These coating materials are used in preparing sustained-release 
dosage forms that follow the approach of various thickness coated granules 
or seeds combined with uncoated granules which are dispensed in capsule 
or compressed tablet form. Examples are the Spansule [166-175] and 
Spacetab [176 -180] formulations. These coatings vary in thickness and 
when they COver a drug granule their digestion by fluids in the gastrointestinal 
tract results in abrupt release of the medicament at selected 
time intervals to provide pulsed dosing for periods up to approximately 
12 h. 
With digestible coating materials, the important factors a formulator 
must take into account are the dissolution rate of the coating material, the 
thickness of the coat, and the changed are for disintegration and dissolution 
that the increased thickness provides [3 - 5. 10, 18, 181 , 182]. As the 
drug-coated granules traverse the gastrointestinal tract, the coating is 
slOWly solubilized by the gastrointestinal fluids. Since the granules have 
varying thickness coats, one anticipates a staggered release of drug. 
Therefore, by combining a large number of mixes of different thickness 
coated granules, a horizontal, or very nearly so, blood drug concentration

244 Chang and Robinson 
versus time curve for extended periods of time should result. In practice. 
it is often difficult to combine a large number of granules having many different 
thicknesses of coating. so that the more common approach is to employ 
one-quarter of the granules in uncoated form, thus providing for immediate 
release and rapid attainment of therapeutic blood levels of drug. 
with the remaining three-quarters of the granules being split into three 
groups of varying coating thicknesses to provide a sustaining effect, 
through pulsed dosing, over the desired time period. Although the approach 
of one-quarter uncoated, three-quarters coated is very common. 
other combinations, such as one-third coated, two-thirds uncoated. have 
also been employed. The ratio is determined by properties of the coated 
granules; that is, dissolution rate and derived drug properties such as the 
elimination rate constant. 
CAPSULES. Since the introduction of the Spansule sustained-release 
dosage form in the early 1950s. there have been numerous studies on the 
release of active drugs from this type of preparation [172,173,183 -1981 , 
and also on the clinical effectiveness of these preparations in maintaining 
therapeutic activity over extended time periods [166 -171,174]. Examples 
of the types of drug formulated as coated granules include antihistamines 
[166,167], belladonna alkaloids U68,171}, phenothiazines [173,174,185,1871. 
combinations of the above [169], antihypertensives [45], cardiac muscle 
dilators [199 - 201], anorexigenic agents [175, 184, 187,192, 193], steroid 
anti-inflammatories [183], and nonsteroidal anti-inflammatories such as 
aspirin [191]. 
There are several ways to prepare drug-coated beads or granules. A 
common procedure is to coat nonpareil seeds with the drug and follow this 
with either a slowly dissolving wax or polymer coat of varying thickness. 
Conventional pan-coating or air-suspension coating techniques can be employed 
for this purpose. Types of coating materials and properties will be 
discussed later in this chapter. Coatings such as these can also be accomplished 
through microencapsulation, to be discussed shortly, wherein 
the drug solution or crystal is encapsulated with a coating substance. 
The selection of coating material dictates whether pulsed or sustained drug 
release occurs. 
An illustration of this approach is the series of papers by Rosen et ale 
I 189. 190] in which they describe the release of 14C-labeled Dextroamphetamine 
sulfate and 14C-labeled amobarbital from both non-sustainedand 
sustained-release dosage forms employing wax-coated granules. As 
can be seen in Figure 3. the amount of drug released in each time period 
is progressively less as the percentage of wax-fat in the coating increases. 
This is the expected behavior, and indicates that sustained release can 
be varied quite readily by changing the makeup of the coating material for 
the drug granules. Other studies [185,191] along these same lines have 
indicated that such behavior of coated granules is the general rule. Note 
in Figure 3 that continuous release of drug occurs. This is because a 
spectrum of granule size was employed in the study, The dashed line in 
Figure 3 indicates the release pattern when only a few granule sizes are 
combined. 
The coated granules or seeds can be placed into a capsule for administration 
to the patient. Actual photographs of the in vivo disintegration 
and dispersal of coated sustained-release granules in a capsule were 
provided in a series of papers by Feinblatt et al , [200,201]. Using

Sustained Drug Release from Tablets and Particles 
C) zz
;;: 20 
::ii: 
wa:: 
w
C) 10 
ct: 8 ~z
w 6 o
II: 
W 4 0... 
F 
2
I
0 2 
245 
Figure 3 In vitro release pattern of dextroamphetamine sulfate pellets 
pan coated with various amounts of wax-fat coating. (A) 17% coating, 
(B) 15% coating, (C) 13% coating, (D) 11% coating, (E) 9% coating, 
(F) 7% coating, and (G) selected blend of uncoated pellets and coated pellets. 
(From Ref. 189, used with permission.) 
roentgenography, the authors showed that after 10-12 h the coated granules 
in a sustained-release capsule were well dispersed in the gastrointestinal 
tract and the active ingredient was completely dissolved. 
In a different study concerned with in vitro measurement of drug release 
from sustained-release coated granules in a capsule, Royal [192] described 
a modification of the United States Pharmacopeia CUSP) tablet disintegration 
apparatus that allowed him to follow the release of drug from 
capsule dosage forms. Further modifications [193] allowed him to test different 
brands of capsules containing a wide range of granule sizes, and 
thus be able to compare the brands as to their efficiency in maintaining 
continuous release of medicament for extended time periods. Souder and 
Ellenbogen [175] described a method for "splitting" (separating) sustainedrelease 
coated granules to ensure an even mix of large and small granules 
and to prevent the stratification of such mixes that often occurs when 
pooling granules for analysis. They then measured timed release of drug 
in a manner differing somewhat from the approach used by Royal. The 
results, however, were the same, and indicated that the blending of larger 
and smaller coated granules, presumably due to thickness of the sustainedrelease 
coating, was effective in maintaining the characteristics of sustained 
drug release. There are several approaches that can be employed for

246 Chang and Robinson 
dissolution testing of coated pellets. and most investigators employ modifications 
of the rotating vial techniques. such as is described in the National 
Formulary (NF) XIII. or modification of the dissolution test presented in 
uss XIX. 
In clinical evaluations of capsule pulsed dose, prolonged-action dosage 
form, and sustained-release products. the objectives of the experimental 
techniques change from that of ensuring that drug release is indeed occurring 
gradually over a long time to that of (1) showing that the sustained-
release dosage form adequately maintains therapeutic blood or tissue 
levels for extended times (l72.173,183,185-188,191I, (2) provides relief to 
the patient over a long period [166 -169, 171,174], and (3) perhaps reduces 
the incidence of side effects due to the "peak" effects of non-sustainedrelease 
dosing [166,167,169]. Of course, many of the earlier studies were 
conducted before development of the sophisticated methods now employed in 
gathering and interpreting blood or tissue drug level data. [166.167, 169, 
171,174], and indeed many such studies were rather qualitative in their assessment 
of prolonged-action dosage forms. As a result of this lack of 
sophistication. the focus was either on monitoring some biological response 
or on urinary receovery of active drug or its metabolites. For example, 
the reports of Heimlich et al , [172,173] on sustained-release phenylpropanolamine 
and trimeprazine and of Sugerman and Rosen [188] on sustainedrelease 
chlorpromazine present very detailed and thorough urinary analyses 
of drug content and provide, within the limitations set forth by the authors. 
a very good analysis of sustained-release characteristics and their worth 
with respect to administration of these drugs. While results of urinary 
drug analysis alone can give quantitative information on sustained-release 
characteristics, it has been pointed out [202] that there are dangers in 
this approach and comparisons of blood and urine data do not always coincide. 
When possible. both blood and urine samples should be collected and 
analyzed. 
In the early 1960s, the first really good effort at measuring and ana1yzing 
drug levels in the blood began to appear in the literature [183 -186] . 
One of the earliest of these is the study by Wagner et al , [183] on the 
sustained action of prednisolone in dogs and humans and the comparability 
of these data to in vitro findings. The work by Rosen and Swintosky 
[187,189,190] contributed to this field by employing radioactive-labeled 
drug. 
Hollister [1861. in a report on sustained-release meprobamate products, 
presented both urine and blood drug level data and pointed out how they 
reinforce the interpretation based solely on one or the other. 
Of course the nature of the disease state itself can be a major reason 
for publtshlng more qualitative results, as was one in some of the earlier 
work. Those studies measuring relief of symptoms due to sustained-release 
antihistamines [166.167] have few measurable effects that are easily quantitated, 
whereas other reports in the area, such as those dealing with ulcer 
patients and relief of pain, can at least quantitate volume and acidity of 
gastric acid and digestive juices [168]. The literature is speckled with 
data that show a sustained effect is operative, but give no indication as to 
how well it compares to multiple dosing of ordinary tablets. 
The question of the bioavailabUity of sustained-release dosage forms as 
compared to conventional systems is an important issue. For most drugs 
placed in a sustained-release system, the bioavailabUity is less than in conventional 
dosage forms. There are the occasional drugs that are unstable

Sustained Drug Release from Tablets and Particles 24'1 
in gastrointestinal fluid or have absorption problems [31] which become 
stabilized or show improved absorption when placed in a sustained-release 
system. A typical example of reduced bioavailability is the study by 
Henning and Nybert [203] on quinidine, in which the rapidly dissolving 
tablet was shown to have greater bioavailabUity than either quinidine 
Durules or Longacor. Compared to the rapidly dissolving tablet, the 
Durules had a bioavailability of 76% and the Longacor 54%. 
TABLETS. With the tablet dosage form the concern for the thickness 
and area of granular coating remains, the distinguishing feature of this 
dosage form being that of tablet disintegration as contrasted to gelatin 
capsule dissolution. An added problem here may be the influence of excipients 
used to produce a compressed tablet in the disintegration/dissolution 
process. Of course, When no fillers or excipients are used. the 
coated granules alone are compressed and can fuse together, resulting in 
altered dissolution patterns [18], depending on the properties of the coating 
material. The role of excipients on the dissolution pattern of compressed 
coated granules has not been investigated extensively. One would 
not expect substantial effects on the dissolution process of the individual 
seeds or granules, but perhaps there would be an influence on fracture or 
fusing of seeds. Reports using other sustaining mechanisms show, as one 
would expect, that in compression some of the coated particles are fractured. 
Green [204]. for example, found that in microencapsulated 
sustained-release aspirin Which was subsequently tableted, a small amount 
of aspirin was immediately released, suggestive of fractured coats. This 
need not be a problem, since the degree of fracture and immediate release 
is frequently small and can usually be incorporated into that portion of the 
dosage form that provides for immediate blood drug levels. Other studies 
have shown that the dissolution pattern was very much influenced by tablet 
hardness, so that compression force would be important. These findings 
were with specific formuations , but they suggest that these variables must 
be considered. 
Because the dissolution patterns of sustained-release coated granules 
are essentially the same whether the granules are filled into a capsule or 
compressed with excipients into a tablet, the dissolution studies described 
earlier are applicable here provided extensive fusing of the granules does 
not occur in the tableting process. 
Here, as in the case of capsules, there has been a wide range of drugs 
formulated as sustained-release coated granules and compressed into tablets. 
Antispasmodic-sedative combinations have been investigated [176], 
as have phenothiazines [172 -180], anticholinesterase agents, and aspirin 
[205,206]. 
Steigmann and coworkers [176] described the clinical evaluation of 
Belladenal Spacatabs , a combination of the natural levoratory alkaloids of 
belladonna and phenobarbital, in patients with peptic ulcer and other 
gastrointestinal disorders. They measured gastric secretion and bowel 
motility and found that. for the most part, the results with the Spacetabs 
formulation were as good or better than those obtained with conventional 
nonsustained forms, and the convenience to the patient of once or twice a 
day dosing was recognized. 
The treatment of myasthenia gravis with neostigmine bromide formulated 
as Mestinon Bromide Timespan was examined by Magee and Westerberg

248 Chang and Robinson 
[2051. The need for sustained release is particularly acute here. since 
with treatment via non-sustained-release dosage forms, the patient generally 
is very weak upon arising in the morning and remains in this state 
until the morning tablet dose can be absorbed. A means of maintaining 
patient strength and comfort throughout the hours of sleep was needed. 
The results of their study show that the value of this sustained-release 
dosage form is greatest when taken at bedtime. at times even allowing the 
patient to arise with sufficient strength to dress before taking morning 
medication. Results of daytime use were variable, and absorption appeared 
to be less than optimal in comparison with non-sustained-release 
tablets. 
Probably the largest body of clinical data has been compiled for the 
phenothiazine tranquilizer thioridazine. Mellinger [177], in an early 
evaluation of thioridazine formulated as Me1laril Spacetabs, examined 
serum concentrations following administration of the drug as a liquid concentrate. 
as tablets crushed in a mortar, as intact tablets, and as the 
Spacetab sustained-release tablet. He found that the drug persists in 
the blood for long periods from all the dosage forms studied, and attributed 
its slow excretion to possible slow metabolism. There were no 
striking advantages to the sustained-release formulation over that of conventional 
tablets. This last finding has been reiterated by other workers 
{178] , and as of this time, the Spacetab formulation of thioridazine 
is not being marketed. 
The clinical evaluation and comparison of sustained-release and nonsustained-
release aspirin tablets was reported by Cass and Frederik [206. 
207]  They measured the duration of analgesic relief obtained via a 
series of different dosage regimens in patients suffering from a variety 
of eoronie illnesses. In all cases, the sustained release form provided 
longer and more predictable analgesic relief than any of the other nonsustained-
release tablets tested. 
Case Study of Slowly Soluble Wax Coating on Nonpareil Seeds [189]. 
Prolonged action mechanism. Pulsed dosing in repeat action fashion. 
Drug-containing nonpareil seeds were coated with various thicknesses of 
digestible waxes which were intended to release drug at various times after 
dosing. 
Type and method of coating. A kilogram of medicated non-sustainedrelease 
pellets was prepared in a 12-in coating pan. The pellets were 
composed of 31.2 gm of dextroamphetamine sulfate; 58.8 gm of a 1:1 mixture 
of starch, USP, and pOWdered sucrose, USPj and 90 gm of U.S. 
No. 16 to 20-mesh sugar pellets. The nonpareil seeds were placed in a 
conventional coating pan and wetted with a waterI alcohol! gelatin mixture 
consisting of gelatin 10% wlv, hydrochloric acid 0.5% vlv, and water 30% 
v lv , and alcohol 70% v I v (90% ethanol, 10% methanol). When the mixture 
became tacky the drug diluent was added to the rotating seeds. After a 
short period of drying. one-fourth of the seeds were removed (these 
represented the uncoated portion). The remaining seeds Were then coated 
to varying thicknesses with a wax formula consisting of glyceryl monostearate 
11% wlw, glyceryl distearate, 16% wlw, white wax 3% wlw, in 
carbon tetrachloride 70% wIw. Six different groups of pellets with approximately 
7. 9, 11, 13, 15, and 17% of wax coating were initially prepared 
and, through trial and error, a final blend consisting of 25% noncoated 
pellets, 55% of the 11% wax-coated seeds, and 20% of the 9% waxcoated 
seeds gave a satisfactory in vitro release pattern. Each group of

Sustained Drug Release from Tablets and Particles 
Table 8 Blend and Desired in Vitro 
Release Patterns, [14C] Dextroamphetamine 
Sulfate 
%In vitro release 
at time interval (h) 
249 
Blend 
Desired
a 
0.5 
34 
39 
2 
56 
62 
4.5 
79 
80 
7 
92 
90 
aAverage in vitro pattern of 15 commercial 
lots of sustained release dextroamphetamine 
[ 190]. 
pellets was screened through U.S. No. 12 onto U.S. No. 25 standard mesh 
sieves to remove lumps and ffnes , 
In vitro test. In vitro dissolution tests in artificial gastrointestinal 
fluids were conducted according to the method of Souder and Ellenbogen 
[50]  The dissolution pattern for all six coated seeds is shown in Figure 
3, and the results on the blend in Table 8. A satisfactory prolongation 
is obtained. 
In vivo release. The in vivo release study was conducted in humans 
and employed the following dosage regimens: 
1. I5-mg sustained-release dosage form 
2. 15-mg nonsustained dosage form 
3. 5-mg nonsustained dosage form 
4. 5-mg sustained-release dosage form given at intervals of 0, 4, and 
8 h 
This particular plan was chosen to determine performance criteria of 
1. Whether the sustained-release formulation provided a prompt initial 
dose 
2. Whether it was similar to 3 times daily drug administration 
3. Whether it was dissimilar to an equivalent nonsustained dose 
4. Whether equal doses in different dosage forms were equally effective 
in making drug available for absorption 
5. Whether there was any significant variability among subjects receiving 
the various regimens 
The study was conducted in a crossover sequence, as shown in Table 9. 
Blood and urine samples were collected at various times postdosing, 
and the results are shown in Figures 4 and 5. The cumulative urinary 
excretion data for human subjects is shown in Table 10. From the table 
the following conclusions were drawn: 
1. In the first 3 h following administration of the drug, the sustainedrelease, 
3 times daily regimen, and the 5-mg single dose were

250 
Table 9 Human Study Plan of Various Dosage 
Regimens 
Subject Initial
a 1 Week later 
1 A B 
2 B C 
3 C D 
4 D A 
5 A C 
6 B D 
7 C A 
8 D B 
9 A D 
10 B A 
11 C B 
12 D C 
13 A D 
14 B C 
15 C B 
16 D A 
aA, 15-mg sustained release dosage form given 
at 0 h; B, I5-mg non-sustained-release dosage 
form given at 0 h; C. 5-mg non-sustainedrelease 
dosage form given at 0 h; D, 5-mg 
non-sustained-release dosage form given tid, 
at 0, 4, and 8 h. 
Source: From Ref. 189, used with permission. 
Chang and Robinson 
similar. Thus, the sustained-release formulation did provide a 
prompt initial dose. 
2. The plasma and urine plots for the sustained and 3 times daily 
regimen were similar, whereas the sustained and I5-mg plain capsule 
were dissimilar. 
3. The sustained-release dosage form made as much drug available 
as the other two I5-mg regimens. 
4. The variation in plasma and urine data is not greater with the 
sustained-release dosage form than with the 3 times daily regimen.

Sustained Drug Release from Tablets and Particles 251 
240 
 I ........ 0., 
..' 
_..- 
6 8 10 12 24 32 48 
POSTDRUG SAMPLING TIME (hours) 
.~, _.~.......-.- ,. -.. f ".,,0-  ...  ...i .. 
, ~ --1. ~~_ 
; .............-~ 
......- _. 
..J 
UJ > 120 w
..J 
~80 
~
Q. 40 
,....-._,,,,,.------1 
~ 200 ' 
E ' I 
~ 160 
Figure 4 Adjusted average human plasma levels. Each line represents 
eight subjects per regimen in a balanced incomplete block crossover design. 
---, lS-mg dextroamphetamine sulfate sustained-release dosage form; 
.. , S-mg dextroamphetamine sulfate capsule, tid; - - - -, 15-mg 
dextroamphetamine sulfate capsule; -' -  -, 5-mg dextroamphetamine sulfate 
capsule. (From Ref. 189, used with permission.) 
0.6 
Vl 
~ 0.5 
- 0.2 
a: 
<
z 0.' a: 
::> 
o 3 6 9 12 24 32 
END OF POSTDRUG COLLECTION INTERVAL 
(hoursl 
Figure 5 Adjusted average human urinary excretion rates. Radioactive 
counts are expressed as average milligrams of dextroamphetamine sulfate 
per collection interval divided by the number of hours in each interval. 
---, lS-mg dextroamphetamine SUlfate sustained-release dosage form; 
. , 5-mg dextroamphetamine sulfate capsule, tid; - - - -, lS-mg 
dextroamphetamine sulfate capsule; -' -' -, 5-mg dextroamphetamine sulfate 
capsule. (From Ref. 189, used with permission.)

252 Chang and Robinson 
Table 10 Adjusted Average
a 
Urine Recoveries in Humans, mg of 
Dextroamphetamine Sulfate Equivalent 
Collection interval (h) 
Dosage form 0-12 0-24 0-48 
5-mg capsule 2.18 3.90 4.89 
15-mg sustained-release capsule 4.30b 8.24b 
11.78
b 
5-mg capsule, 3 times each day 4.32 8.48 12.30 
15-mg capsule 6.14 9.31 11.86 
~ach figure is the average for eight humans. 
bNo figure included in a brace is significantly different from any other 
figure included in that brace (p < 0.05). 
Source: From Ref. 189, used with permission. 
Sustained Dosing 
Although the principal factors controlling drug release are very similar in 
this case to those noted in the previous section, they do differ in at least 
one important aspect; that is, the drug is made available in a continuous 
rather than a pulsed fashion. The continuous release of drug is a result 
of the drug being impregnated in a slowly dissolving film; as dissolution 
occurs, drug becomes available [10,18,208 - 210]. This type of coating is 
very similar to the embedding of the drug in an insoluble matrix, which 
will be described later in this chapter. The difference lies in the fact 
that these products are microencapsulations of drug particles or granules, 
whereas the matrix tablets are formulated in a different manner. 
MICROENCAPSULATION. Tanaka and coworkers [95] investigated the 
effects of formalin treatment on the hardness of gelatin microcapsules of 
sulfanilamide and riboflavin. As can be seen in Tables 11A and 1ill, the 
treatment of gelatin micropellets containing sulfanilamide by immersion in 
10% formalin/isopropanol for 24 h results in a lO-fold increase in time to 
release 100% of the drug. These results were mirrored when sulfanilamide 
and riboflavin micropellets were administered to dogs and blood levels of 
Table l1A Dosages and Contents of SA and RF Micropelletsa 
Sample Dosage and contents 
1 Gelatin micropellet containing 33.2% SA 
3 Micropellet, treated for 24 h, and containing 10.0% SA 
aSA and RF refer to sulfanilamide and riboflavin, respectively. 
Source: Reproduced with permission of the copyright owner.

Sustained Drug Release from Tablets and Particles 
Table 118 Percentage of Accumulative SA Recovered in 
the in Vitro Dissolution Testa 
Sample 1 Sample 2 
Time % Time % 
5 min 32.9 5 min 5.9 
10 min 59.5 10 min 9.9 
15 min 76.5 20 min 30.7 
35 min 80.0 30 min 39.6 
1 h 89.6 45 min 53.4 
2h 99.5 1 h 61.5 
3 h 99.7 2h 82.0 
3 h 86.0 
5 h 91.6 
7 h 94.1 
23 h 98.2 
30 h 99.6 
aSA and RF refer to sulfanilamide and riboflavin. respectively. 
Source: Reproduced with permission of the copyright 
owner. 
253 
the drugs versus time were measured. Figures 6 and 7 show that, indeed, 
sustained blood levels of sulfanilamide and riboflavin were obtained 
when the micropellets were hardened. Nixon et al , [211,213] studied 
gelatin coacervate microcapsules of various sulfa drugs and the effect of 
various coacervating agents on in vitro release of drug. They found that 
hardened microcapsules gave a more prolonged release of drug in both 
acid and alkaline pepsin medium. Temperature and pH effects were also 
investigated. and from the data it was concluded that dissolution was the 
controlling step rather than diffusion of drug through a microcapsular 
wall.
The development of the complex form of coacervation as a tool for coating 
pharmaceuticals was developed by Phares and Sperandio [214]. The 
technique was further investigated and developed by Luzzi and Gerraughty 
[217,219] and by Madan et al, [215,216]. They examined the effects of 
varying starting pH. starting temperature, ratio of solid to encapsulating 
materials, quantity of denaturant, and final pH. Their results indicate 
that manipulation of all these variables affects some degree of change in 
the microcapsules and the resulting drug-release rate. When the drug to 
be encapsulated by the gelatin/acacia system was a waxy solid, such as 
stearyl alcohol. the coacervation procedure had to be modified because 
microscopic examination showed that, in the case of drug particles smaller

254 Chang and Robinson 
--~-.--- .......... .-- . ..--.... -.. ~
co 
.E 
o
aa
-J 
ClJ: 
Z 
o.~---"":":----~---~---~---~--~ 
TIME (hours) 
Figure 6 Logarithm of SA levels in blood against time after administration 
of SA gelatin micropellets to dogs. (0) Unitreated micropellets, (.) micropellets 
treated with formalin/isopropanol for 24 h. (From Ref. 213, used 
with permission.) 
"ij. 
.5 
oo9
al 
~
Zo
i= -c 
ex: 
Iz
woz8 
TIME (hours) 
Figure 7 Logarithm of RF concentration in blood after administration of 
RF solution and its gelatin micropellets to dogs. ( 0) RF solution, (.) 
untreated micropellets, ( ...) micropellets treated with formalin /isopropanol 
for 24 h. (From Ref. 213, used with permission.)

Sustained Drug Release from Tablets and Particles 255 
than 250 urn, encapsulation was accomplished by several droplets aggregating 
and coalescing around the particles rather than by a single droplet as was the 
usual case. With drug particles larger than 250 um, they suggested that encapsulation 
was the result of a direct interaction of gelatin with acacia on the 
surface of the particles. Scanning electron micrographs lend credence to their 
suggestion. Merkle and Speiser [218] prepared cellulose acetate phthalate 
coacervate microcapsules and evaluated them with respect to optimum coacervation 
and encapsulation conditions. Their findings indicate that while the 
amount of drug encapsulated had no significant effect on the particle size distribution 
of the microcapsules, it did influence the release rate. The suggested 
mechanism for this system is drug diffusion through the shells. When the 
shells are plasticized in a manner similar to that described earlier. the release 
rate control is altered from drug diffusion through the shells to dissolution of 
drug in the microcapsules. 
More recently, Birrenbach and Speiser [220] employed polymerized micelles 
to produce very small particles. termed nanocapsutes , to be distinguished from 
microcapsules. Although this approach is suggested for colloidal solutions to 
administer antigenic material, it has potential for parenteral drug delivery. 
Nylon microcapsules have been examined by McGinity et al , [221], who 
described an improved method for making them. and by Lu zzi et al . who evaluated 
the prolonged release properties of nylon microcapsules that had been 
either spray dried or vacuum dried. Both methods of drying produced a large 
reduction in the dissolution rates of the microcapsules, but since the spraydried 
material was free flowing as compared with the vacuum-dried material, 
the authors felt that spray drying would result in more uniformity and reproducibility 
of release rates. On the other hand. increased release rates can be 
obtained by incorporating sucrose into the nylon microcapsules [18]. Interestingly. 
and perhaps not surprisingly, Luzzi et al , found when compressing 
thesa microcapsulated drugs into tablets that the release rate was inversely 
proportional to the tablet hardness. 
Bead polymerization as a technique for preparing sustained -release 
dosage forms was described by Khanna et al , [222] and further evaluated 
by Khanna and Speiser [223]. This technique results in drug being embedded 
in the coating so that its release characteristics are similar to those 
to be described in the section on the plastic tablet below. By varying the 
concentration of the a -methacrylic acid content of the polymer solution, the 
coating can be made to release drug over a wide range of pH values and 
the release is prolonged for 12-15 h. By combining mixtures of beads with 
various concentrations of a -methacrylic acid, the correct sustained-release 
pattern can be made. Seager and Baker [224] described a somewhat different 
system for making microencapsulated particles in the subsieve size range. 
These resulted in drug being embedded in an inner core, whereas the outer 
core was a shellac coating. The release pattern showed good sustainedrelease 
properties. 
Si-Nang et al, examined the diffusion rate of encapsulated drug as a 
function of microcapsule size. The influence of the coating on diffusion and 
the determination of the coating thickness were presented in terms of complex 
mathematical equations. The equations used were of a general nature 
and allow a quick estimation of the coating thickness, and thus can be useful 
in modifying the microencapsulation procedure to attain desired release 
capabilities. 
Crosswell and Becker [225) reported a bead polymerization technique 
for producing sulfaethylthiadiazole and acetaminophen microencapsulationa.

256 Chang and Robinson 
When polystyrene beads were produced in the presence of drug solution, 
no sustained release was evident; whereas if the beads were produced 
without drug present and allowed to expand via exposure to n-pentane 
and subsequent boiling in water, and then the drug solution was allowed 
to seep into the deep channels produced in the expanded polystyrene 
beads, the release pattern exhibited good sustaining properties. 
The extensive use of polymer-drug interactions to produce sustainedrelease 
dosage forms was promoted by Willis and Banker [226]. The drug 
was made to interact with a cross-linked copolymer such as 1, 12-dihydroxyoctadecone 
hemiester of poly(methylvinylether/maleic anhydride) and the 
salt that was formed as a result of this exhibited good sustained-release 
properties upon dialysis testing in artificial gastric and intestinal fluids of 
tablets and granules fashioned from the polymer-drug salt entities. 
Banker and various coworkers [227 - 231] further studied molecular 
scale drug entrapment as a means of producing sustained-release dosage 
forms. Although the technique employed appears to be similar to bead 
polymerization, it is not clear whether each drug particle was coated (entrapped) 
within the polymer or whether the drug was actually chemically 
bonded to the polymer. For purposes of this discussion. the results are 
similar to those obtained via bead polymerization processes, so they are 
Included here. The authors prepared and tested cationic drugs such as 
methapyrilene hydrochloride. chlorpromazine hydrochloride, atropine sulfate, 
etc; , for their amenability to the entrapment procedures. The subsequent 
increases in sustained-release properties Were tested and 
reported. 
Further exploration revealed that additives SUch as organic acids 
could greatly facilitate drug entrapment by increasing the degree of interaction 
between the drug and the polymer, and could provide more control 
over the sustained-release characteristics. Other variables, such as 
flocculation pH, rate of agitation, use of different polymers , etc., can 
exert significant effects on sustained-release properties. Some of the important 
variables and their influences are described in Table 12. 
Anionic drugs, such as sodium phenobarbital, sodium salicylate, 
chloral hydrate, etc; , were also entrapped via coagulated (gelled) polymer 
emulsion systems. These polymer-drug products were tested in a manner 
similar to that employed for the cationic drugs and the increase in and 
reproducibility of the sustained-release products was noted. The authors 
make special mention of the fact that their procedures result in a highly 
uniform distribution of drug throughout the polymeric system and no drug 
segregation, with resultant variability in blood levels of drug after dosing, 
was evident upon scale-up processing and blending for incorporation into 
sustained-release dosage forms. 
All the procedures mentioned thus far in this section are at least 
loosely related via their production of microencapsulated drug particles 
that employ slowly soluble films or coatings as the encapsulating material. 
A good portion of the literature in this area is experimental, usually resulting 
in statements that reflect how well these methods might be for 
actually producing commercial sustained-release products. As was mentioned 
earlier. very few products. aside from aspirin, have been actually 
formulated from these microencapsulated particles. and thus there is a 
scarcity of clinical evaluations in the literature. In in vitro evaluation of 
sustained-release systems, one would like to have linearity in drug release 
versus time up to 60-70% or more of drug content. However. it is

Sustained Drug Release {rom Tablets and Particles 
Table 12 Summary of Effects Produced by Variables on the Molecular 
Scale Drug Entrapment Method of Banker and Coworkers 
257 
Variable studied 
Methapyrilene base and 
hydrochloride salt 
Entrapment of cationic 
drugs by polymeric 
flocculation 
Addition of a suitable 
organic acid to the system 
described in Ref. 
227 
Flocculation pH and rate 
of agitation 
Entrapment of anionic 
drug by polymeric 
gelation 
Effect on entrapment 
No appreciable difference in equilibrium 
dialysis release rates between free base 
and hydrochloride salt. either as solutions 
or as solids. Prolongation of release 
of drug from granular and tableted 
forms in vitro was shown. 
The flocculation of highly concentrated 
colloidal polymeric dispersions (latices) 
in the presence of the drug in solution 
which is to be occluded provides the 
entrapment mechanism. Significant increases 
in duration of action and reduction 
in acute toxicity were demonstrated. 
Excellent control of sustained-release 
characteristics. Drug entrapped as 
the carboxylate salt or in conjunction 
with the appropriate dicarboxylic acid. 
while demonstrating SUbstantially complete 
drug dissolution release in intestinal 
fluid. could be maintained in 
the entrapped form in aqueous suspensions 
during storage periods in 
excess of 1 month. Greater binding 
of drug was also shown. 
Effect of an increase in flocculation pH 
was twofold. It increased both the 
amount of drug bound and the rate at 
which drug was released. Increase in 
the stirring rate during flocculation 
resulted in an increase in the amount 
of drug bound to the polymer. 
The phenomenon of gelation of the 
polymer emulsions by the addition of 
divalent cation (Mg2+) was utilized for 
the entrapment of various anionic drug 
materials. Good control both in vitro 
and in vivo sustained release characteristics 
were shown. With increases in 
drug concentration. release was rapid 
and a poor release pattern resulted. 
With diminished drug concentration. too 
small an amount of drug was released 
initially to provide therapeutic levels. 
Smaller size gel particles resulted in 
more rapid and complete release of 
Ref. 
226 
227 
228 
229 
229 
230

258 
Table 12 (Continued) 
Chang and Robinson 
Variable studied 
Uniformity of dlstrdbution 
of amine drug in 
solid dispersions 
Effect on entrapment 
drug. This suggests mixing gel particle 
sizes to get a particular release 
pattern. 
Excellent reproducibility of drug content 
throughout the entire entrapment 
product as demonstrated in both flocculated 
(high drug levels) and deflocculated 
(low drug levels) systems. Dry 
blending was inferior to molecular scale 
drug entrapment in distributing small 
quantities of drug uniformly. 
Ref. 
231 
common to see studies showing linearity in the sustained effect for only 
30-40% of the system. The study by Nixon and Walker [211] using gelation 
coacervate showed linearity up to 60% release. 
Of the clinical evaluations reported, microencapsulated aspirin has received 
the lion's share of attention. Bell et al , [232] pointed out the 
need to monitor blood levels of both acetylsalicylic acid (ASA) and its 
metabolite. salicylic acid (SA). The need for this is obvious because ASA 
is reportedly far more potent as an analgesic than SA, so that modification 
of sustained-release products to provide more ASA and protect it from 
metabolism to SA become very important. The Bell study compared sustained 
-release aspirin versus regular aspirin administered as a single dose 
and in divided doses and analyzed the blood levels of ASA provided by 
each dosage form or regimen. This resulted in statements to the effect 
that sustained-release aspirin gave greater analgesic effects than regular 
aspirin because the ASA blood level remains higher for longer periods of 
time. When total salicylate blood levels are measured all salicylates presumably 
producing and contributing to the anti-inflammatory effect of 
aspirin, the sustained-release product still gave release rates that were 
too small for sustained-release aspirin. Optimum levels were achieved with 
about 3% of the drug in the encapsulated material. 
Green [80] investigated sustained-release aspirin tablets formulated 
from microencapsulated particles and found the blood level curves of 
salicylate to be virtually flat with repeated dosing as opposed to a sawtooth 
effect exhibited with repeated dosing of regular aspirin. No conclusion 
was drawn from this observation, but the influence is that a flat 
blood level curve represents better control over the therapeutic regimen. 
Rotstein et al, [233] examined sustained-release aspirin for use in the 
management of rheumatoid arthritis and osteoarthritis. In short-term 
double-blind crossover studies, the doses employed were large enough that 
the patients received relief from both regular and sustained-release aspirin 
and observable differences between the two were obscured. However, in 
long-term usage studies, all the patients who had been on any type of 
previous salicylate therapy preferred the sustained-release aspirin

Sustained Drug Release from Tablets and Particles 259 
formulation because it reduced the frequency of dosage and supplied more 
medication during the night hours, thus relieving the morning aches and 
pains of arthritis. In both studies the incidence of side effects was significantly 
lower with sustained-release therapy. These clinical studies 
have thus established that microencapsulation of aspirin formulated into 
sustained-release dosage forms is an attractive and effective alternative to 
nonsustained dosage forms. 
IMPREGNATION. There are two general methods of preparing drugimpregnated 
particles with wax: (1) congealing and, (2) aqueous dispersion. 
In the congealing method, the drug is admixed with the wax material 
and either screened or spray congealed. The aqueous dispersion approach 
is simply spraying or placing the drug-wax mixture in water and 
collecting the resulting particles. 
In a series of papers by Becker and associates [225,234 - 239], the 
formulation and release characteristics of wax impregnations of sulfaethylthiadiazole 
were thoroughly investigated. The authors looked at dispersant 
concentration, effects of surfactant addition, effects of different waxes and 
modifiers, etc., as to their effect on release rate and proportion of total 
drug constituting the prolonged-release fraction. As might be expected. 
the size of the microcapsules produced and the physical properties of the 
various wax coating materials had profound effects on the release patterns 
reported. When the spray-congealed formulations of wax and sulfaethylthiadiazole 
were compressed into tablets the release mechanism appeared to 
be due to erosion, solubilization, and leaching of the drug from the tablet. 
Noone model could describe the release pattern over the 48-h period of 
the study. It has been reported, in general terms, that the aqueous dispersion 
method gives higher release rates for all waxes tested, presumably 
due to increased area and perhaps the physical entrapment of water. Further, 
with aspirin as the test drug, the dissolution rate increases in the 
order stearic acid > spermaceti > hydrogenated cottonseed oil. 
Case Study of Slowly Soluble Wax Microencapsulation [234]. Prolonged 
action mechanism. Drug is impregnated in a slowly dissolving wax. 
Type and method of coating. Bleached beeswax or glycowax S-932 is 
mixed with drug, in a ratio of 1 part drug to 3 parts wax. and heated on 
a water bath to 75QC. Typical amounts were 24 gm beeswax and 8 gm 
sulfaethylthiadiazole (SETD). In a separate container heated to 80C was 
1 ml sorbitan mono-oleate and 1. 15 ml polysorbate 80 in 400 ml of distilled 
water. The aqueous phase was slowly added to the wax mixture with continuous 
stirring at a predetermined speed until the mixture cooled to approximately 
45QC. Stirring at around 300 - 400 rpm produced particles that 
were primarily in the size range of 30-100 mesh. The drug-wax particles 
were separated from the aqueous phase by filtration, washed with distilled 
water, and dried. Fractionation of the resulting particles into three 
mesh sizes 16-20, 30-40, and 50-60 was accomplished with USP sieves, 
and only the 50- to 60-mesh particles were retained for in vitro and 
in vivo testing. 
In vitro test. Dissolution tests were conducted in a modified USP 
disintegration apparatus, and the results are shown in Figures 8(a) and 
8(b). Drug release during the first 15 min was in direct relation to the 
specific surface, since the particles were assumed to have a uniform distribution 
of drug on the surface. After the first 15 min period, the rate 
of drug release varied as a function of mesh size and appeared to follow

260 
e 
Chang and Robinson 
(a)
400 
I 
TIME (hours) 
2 
o 
(b) 
2 3 
TIME (hours) 
4 
Figure 8 (a) In vitro dissolution rates of SETD from various mesh sizes of 
SETD-glycowax particles in 0.1 N HCI. (e) 16-20 mesh, (A) 30-40 mesh, 
Ce - C = O. (b) In vitro dissolution rates of SETD from various mesh sizes 
of SETD-glycowax particles in alkaline pancreatin solution. (.) 16- 20 
mesh, (A) 30-40 mesh, (0) 50-60 mesh. (From Ref. 234, used with 
permission. 
first-order kinetics. The first-order dissolution appears to be due to the 
changing surface area. 
In vivo release. Urinary excretion rates of SETD-glycowax, 50-60 
mesh size range, were compared to rates for plain SETD in four humans. 
The 50-60 mesh size was selected because the in vitro release data were 
most similar to the in vitro release of a similar commercial prolongedrelease 
SETD product. Figure 9 shows the comparison of the excretion 
rates for the plain SETD and the prolonged release form. The SETDglycowax 
particles released 50% less drug during the first 3 h , and then 
the rates increased so that at the end of 24 h , 71% of the total SETD had 
been excreted as compared to 85% for plain SETD. Over 72 h, the

Sustained Drug Release from Tablets and Particles 
080 
060 
261 
o 
TIME (hours) 
12 15 
Figure 9 Average urinary excretion rates of free SETD for four humans 
receiving a 3.9-gm oral dose of SETD in (a) plain form and (b) SETDglycowax 
combination. (e) plain SETD, (0), SETD-glycowax combination. 
(From Ref. 113, used with permission.) 
in vivo SETD-glycowax release gave 85% excreted versus 81% in the 
in vitro experiment. 
B. Sustained-Release Utilizing Diffusion 
This section describes coated sustained-release systems that are distinguished 
from those in the previous section primarily by their mechanism 
of action (i.e., diffusion). as well as by their means of application and 
by the appearance of the final dosage form. Some of the microencapsulated 
materials discussed earlier released drug via a diffusion process, but the 
bulk of the diffusion systems will be discussed here. In the case of slowly 
soluble films and coatings, the reader will recall that these were generally 
applied via pan-coating techniques or by some form of polymerization 
with the end result being coated pellets or granules or microspherules 
that could then be compressed into tablets or placed in a capsule. The 
products in this section are, for the most part, press-coated films whereby 
a core is fed into the die and the coating material is then pressed onto 
it. resulting in a single-coated tablet. or they are whole tablets or particles 
that have been coated via air-suspension techniques. As in the previously 
described cases, the area and the thickness of the coating are important 
parameters. but they take on added importance here because diffusion 
of drug, either from the core or from the coating itself, must pass 
through the barrier represented by the coating Or film. Insoluble ffims 
will thus present a rigid barrier that will act to keep the diffusion path 
length of drug from the tablet interior to the absorption site (outside of 
tablet) relatively constant. Some of the ffims deserdbed below are also 
slowly soluble, but their maintenance of constant path length is still the 
most important activity.

262 Chang and Robinson 
As might be expected, a lot of the research in this area has to do with 
the mechanics of the coating process itself, in addition to the research on 
developing new coatings and measuring the efficacy of administering drugs 
in this manner. Of course, the patent literature is filled with polymeric 
systems that can be used via press-coating or air-suspension techniques 
[ 154,165, 240, 241]. and the research literature likewise [242 - 250]  However, 
since the press-coating and air-suspension processes are utilized in 
the pharmaceutical industry, a body of research has been developed to 
overcome some of the manufacturing difficulties presented by these techniques 
[251- 254]  
The original work that developed the air-suspension technique has 
been reported by Wurster [255,256]. This patented process is now widely 
used in the industry, since it is a fast. efficient way of making uniform 
coatings on granules and core tablets. The use of the technique for coating 
aspirin granules has been described by Coletta and Rubin [257]. 
Wood and Syarto [258] continued the same line of work involving coating 
aspirin with various ratios of ethylcellulose to methylcellulose. As the 
methylcellulose dissolved, whereas the ethylcellulose did not, the shell left 
behind presumably provided a restraining barrier for keeping the ASA 
diffusion path length constant. These authors attempted to correlate the 
in vitro dissolution pattern with that obtained in vivo, as shown in Figure 
10. As can be seen from the correlation lines, with high-content 
ethylcellulose the in vitro/in vivo correlations are good. As the percent 
of methylcellulose in the coating is increased, the correlation falls off, and 
this points out the fallacy of using in vitro data alone to predict in vivo 
performance of these tablet coatings. 
Many researchers have, of course, looked at the polymeric materials 
used in the coating processes with an eye to developing better, more 
durable, and more easily applied coats. Polyvinylpyrrolidone-acetylated 
monoglyceride [244], styrenemaleic acid copolymer [245], hydroxypropylcellulose-
polyvinylacetate [259, 260], and many other polymers have been 
studied for their value as enteric coatings [243, 248, 250] and for use in 
developing sustained-release preparations [246 - 248]  Enteric coating is a 
SUbject dealt with elsewhere in this text, but the application of enteric 
coats can be accomplished via press-coating and air-suspensions techniques 
just as described here. 
Donbrow and Friedman [259] reported the release of caffeine and 
salicylic acid from cast films of ethylcellulose and the release rates were 
found to agree with both the classic first-order equation (log drug retained 
in ffim versus time) and with the diffusion-controlled release models 
(drug release linearly related to square root of time) as developed by 
Higuchi [260]. More stringent mathematical treatment of their data resulted 
in the diffusion-controlled release model being most appropriate to 
describe their data. Borodkin and Tucker [261,262] also used cast fflms 
of drug in hydroxypropylcellu!ose, studying the release of salicylic acid, 
pentobarbital. and methapyrfiene. These drugs were released according 
to the same diffusion-controlled model described above. Further work to 
modify the system resulted in zero-order drug release obtained by laminating 
a second mm without drug to the releasing side of the film containing 
drug. Thus, the nondrug layer functions as a rate-controlling membrane, 
and the drug-containing film serves as a reservoir. In vitro zeroorder 
drug release for the three species mentioned was demonstrated 
using this technique.

Sustained Drug Release from Tablets and Particles 
3.0 
2.5 
/ 
263 
Ii; 
w
Io
a: 
!:: 
>~
>to 
W
:E 
t= 
/ , 
/
TIME IN VIVO [hours) 
8 10 12 
Composition and Characteristics of Test Delayed-Release Aspirin Products 
Used in This Study 
Code 
1348 134C 152 138 
Ratio ethyl to methylcellulose 75/25 25/75 82.5/17.5 10010 
Aspirin mesh size -20 -40 -20+40 -20+40 
Amount of coating (wt %) 2.7% 4.8% 6% 6% 
Tablet disintegration time (sec) 40-60 25-35 3 3 
Aspirin content 5 gr 5 gr 5 gr 5 gr 
Cornstarch 0.87 gr 0.90 gr 0.96 gr 0.96 gr 
Talc 0.13 gr 0.13 gr 
Figure 10 Correlation between in vivo absorption and in vitro release 
rates for corresponding fractions of total salicylate considered. (.) 152. 
(.) 138, ( ... ) 134C. (0) 134B. (From Ref. 258. used with permission.)

264 Chang and Robinson 
Since the technique described in this section can be used to coat core 
tablets or granules, it is conceivable that many of the clinical studies described 
earlier could be applicable in this case. However, a very good 
clinical study of the Sinusule sustained-release dosage form has been descrfbed 
[263]. This product is somewhat different from the others examined 
thus far in that the film applied to the granules actually functions 
as a microdialysis membrane. Thus, one need not worry about the acidity 
of the gut, the digestive process, nor the contents of the gut. The only 
requirement is that there be fluid in the gut. The fluid, primarily water, 
passes through the dialysis membrane into the sphere and dissolves the 
granule of drug. This drug then diffuses through the intact membrane at 
a rate proportional to the permeability of the membrane, the mobility of 
the drug molecule, and the concentration of the drug within the hydrated 
microdialysis cell. When this product was tested in patients having hay 
fever. upper respiratory infection, and miscellaneous respiratory allergies. 
good to excellent results with a' minimum of side effects were reported for 
a large majority of the test population, This novel sustained-release 
dosage form is not marketed anymore. 
Case Study of DuffusiDn-Controlled Coating [261] 
PROLONGED ACTION MECHANISM. Drugs are dispersed in a watersoluble 
polymeric coating which. when SUbjected to an aqueous environment, 
allows slow diffusion of drug into the leaching fluid. 
TYPE AND METHOD OF FILM FORMATION. Hydroxypropylcellulose, 
average molecular weight of 100,000, having viscosity 75-150 cps as a 5% 
water solution, and polyvinylacetate, average molecular weight 500,000, 
having viscosity 90 -110 cps as an 8.6% benzene solution. were used. 
Drugs were pentobarbital, salicylic acid, and methapyrilene. The films were 
cast from a solution containing 10% solids (drug plus polymer), using 
methylene chloride/methanol mixture (9:1) as the solvent. The polymers 
were added as dry powders, as was salicylic acid, While the pentobarbital 
and methapyrilene were added from stock methylene chloride solutions. 
Films were cast from the solutions at various wet thicknesses (0.64- 2. 54 
mm) using a knife on Teflon-coated plate glass. The films were allowed to 
air dry at least 48 h before evaluation. The percent drug in the dry film 
was calculated from the ratio of drug and polymer weights used. 
MECHANISM OF DRUG RELEASE. Release of drug from a matrix can 
be either via a first-order process or via a diffusion-controlled process. 
Which release is operative can be ascertained by appropriate data treatment. 
First-order release would be a linear plot follOWing the normal 
first-order equations, whereas a diffusion-controlled process should result 
in an S-shaped curve following the equation 
Q =In.. (2A - EC ) C t 
T S S 
where Q =amount of drug released per unit area of tablet exposed to 
solvent 
D = diffusion coefficient of drug in the permeating fluid 
E =porosity of the matrix 
(13)

Sustained Drug Release from Tablets and Particles 
T :::: tortuosity of the matrix 
A :::: concentration of solid drug in the matrix 
C :::: solubility of drug in the dissolution medium 
s
t =time 
The above equation is more commonly expressed as 
265 
(14) Q = k t 1/ 2 
H 
where kH:::: ED[(2A - Cs)C s]1/2 for plotting purposes. 
IN VITRO TEST. Rectangular films measuring 2.2 x 4.0 em (8.8 cm
2) 
were cut using a razor blade with a microscope cover glass as a template. 
The film was weighed and its thickness was measured at all four corners 
and the center with a micrometer. A thin coating of high-vacuum silicone 
lubricant was applied to a 2.54 x 7.62 crn microscope slide and the film 
was pressed into the slide, making sure that all edges adhered and no 
lubricant touched the exposed surface. The slide was placed at an angle 
into a 250-ml beaker in a 37C-water bath containing 200 m1 of pH 7 buffer 
preheated to 37C. A nonagitated system was used to eliminate turbulence 
effect on release rate and to maintain film integrity. Periodic 
assay samples (:tl0 min-I) were obtained by removing the slide, stirring 
the solution, and pipetting a 5-ml sample, and then reimmersing the slide 
with film into the buffer solution. Beakers were covered throughout the 
length of the runs (7 h at least and 31 h in the extreme for slow-releasing 
films) to prevent evaporation. The samples were assayed by ultraviolet 
(UV) spectrophotometry at 240 nm for pentobarbitsl in 0.1 N NH40H, at 
312 nm for methapyrilene in 0.1 N Hel, and at 297 nm for salicylic acid in 
O.1NNaOH. 
Table 13 shows the results of comparing the drug release to firstorder 
and square root of time equations. When these data were evaluated 
to determine which equation gave best fit, the correlation coefficients for 
the best statisticsl lines and the lag times (time intercept extrapolated to 
Q = 0) were used as the principal criteria. Although the corrslation coefficients 
looked good for either mechanism, when these types of data are 
plotted out, as is shown in Figure 11, the curvature in the first-order 
mechanism was evident. This indicated that the Q versus t 1/ 2 relation 
more readily described the mechanism. Correlation coefficients were generally 
greater than 0.995 for this type of plotting and deviations, when 
they occurred, were random rather than the result of curvature. Linearity 
in release held through 75-80% of drug release when a constant concentration 
gradient was operative. 
The effect of film thickness on the rate of dru g release for pentobarbital 
is shown in Table 14. These results indicate that the release 
rate constant, kH, is independent of film thickness. However, film 
thickness wID affect the duration of drug release, as is shown in the last 
column where t1/2 represents the time, in minutes, for 50% of the drug in 
each particular film to be released. 
Tables 15-17 show the effects of varying polymer ratio on the release 
rate, kH, for the drugs methapyrilene, salicylic acid, and pentobarbital, 
respectively. In general, an acceleration of release rate can be obtained

Table 13 Comparison between First-Order and Q Versus t 1/ 2 Treatments of Pentobarbital Release Rate Data 
First-order 
Q versus t 1/2 
Drug 
1ag 1ag concentration Hydroxypropylcel1ulosel Number Correlation Correlation 
(%)8 polyvinylacetate ratio of runs (min)b coefficient {min)b coefficient 
36.4 10:0 4 -3.2 0.996 3.1 0.997 
18.2 10:0 4 -14.0 0.957 2.6 0.993 
18.2 9:1 2 -9.8 0.986 2.8 0.996 
18.2 8:2 2 -6.5 0.986 2.3 0.993 
18.2 6:4 2 -84.0 0.982 1.4 0.996 
18.2 4:6 4 -142.0 0.983 0.3 0.998 
18.2 2:8 4 -176.0 0.981 0.6 0.998 
18.2 1:9 4 -176.0 0.982 0.7 0.998 
18.2 0:10 3 -214.0 0.979 1.0 0.997 
9.1 0:10 4 -199.0 0.981 1.3 0.990 
aWeight of drug per weight of dry film. 
b
All tIag and correlation coefficient values expressed are mean values. 
Source: From Ref. 259, used with permission. 
~
OJ 
9Q
;::J 
tQ
Q
;::J 
~
~
S' 
~
;::J

Table 111 Effect of Film Thickness on Pentobarbital Release Rate Constant and Half-Life 
Wet fUm 
Drug thickness Dry film 
kH t 1/ 2 concentration Hydroxypropylcel1ulose/ setting thickness Correlation 
(%)a polyvinylacetate ratio (mm) (J..lm)b (mg cm- 2 min- 1/ 2) coefficient (min) 
36.4 10:0 0.64 44.0  1.1 0.33 0.996 14.8 
1.27 56.2  2.1 0.29 0.996 25.2 
1. 91 100.2  4.6 0.33 0.998 49.8 
2.54 109.3  3.3 0.32 0.998 60.2 
18.2 4~6 0.64 61.4  4.9 0.032 0.999 360 
1. 27 113.2  9.9 0.034 0.999 1,280 
1.91 145.0  8.0 0.034 0.999 2,850 
2.54 204.2  3.1 0.037 0.997 3,850 
18.2 1:9 0.64 76.8  1. 2 0.0101 0.996 8,520 
1.27 118.4  2.6 0.0102 0.999 19.200 
1.91 202.8  2.2 0.0101 0.998 50.900 
2.54 268.0  2.4 0.0102 0.998 83,600 
~eight of drug per weight of dry film. 
bThickness =mean :t standard deviation of five measurements. 
Source: From Ref. 259, used with permission. 
t\) 
0) 
~

268 Chang and Robinson 
Figure 11 Comparison between first-order release treatment and Q versus 
t1/2 treatment of data from a film containing 26.3% methapyrilene at a 5:5 
ratio of hydroxypropylcellulose/polyvinylacetate. (e) log (QCQ - Q) versus 
t , and (0) Q versus t 1/ 2. (From Ref. 259, used with permission.) 
by increasing the proportion of hydroxypropylcellulose to polyvinylacetate. 
The large variations in the t 1/ 2 values reflect the changes in the polymer 
ratio and, in addition, the changes in film thickness. 
c. Sustained-Release Utilizing a Combination of 
Dissolution and Diffusion 
The products to be discussed in this section are those that provide the 
sustaining portion of the dose in some sort of relatively insoluble core that 
has been impregnated with the drug. This core is almost always coated 
and the coat contains that portion of the dose meant for immediate release 
upon dissolution of the coat in the stomach. Once this occurs, the gastrointestinal 
fluids are free to permeate the core and thus slowly leach out 
the drug. Of course, the possibility exists that the core material can 
sometimes be dissolved slowly to provide drug, but this is usually not the 
the case. The diffusion of drug out of the core is the major mechanism 
for providing drug in sustained release form. In these preparations the 
area over which diffusion cocurs remains relatively constant (especially if 
no core dissolution occurs) and the amount of drug is in excess. The

Sustained Drug Release from Tablets and Particles 269 
Table lS Effect of Hydroxypropylcellulose/Polyvinylacetate Ratio on the 
Release Rate from Films Containing 26.3% Methapyrilene 
HydroxypropylcelluloseI 
Dry film 
k
H t 1/ 2 polyvinylacetate thickness Correlation 
ratio (llm)a, b (mg cm- 2 min- 1/ 2) coefficient (min) 
10:1 210  7.4 0.549 0.999 33 
9:1 210  6.5 0.593 0.997 28 
8:2 216  9.1 0.497 1.000 42 
7:3 181  7.8 0.272 0.995 99 
6:4 218  4.4 0.217 0.998 226 
5:5 208  4.6 0.225 0.999 190 
4:6 142  4.5 0.191 0.997 124 
3:7 157  3.3 0.094 0.998 630 
2:8 136  3.3 0.089 0.999 523 
1:9 131  6.0 0.075 0.998 681 
0:10 185  0.9 0.074 0.996 1404 
aThickness :;: mean  standard deviation of five measurements. 
b All films cast using a wet thickness setting of 2.54 mm, 
Source: From Ref. 259. used with permission. 
factor that changes, in this case, is the path length term in Fick's first 
law. As more drug diffuses out of the core, the permeating gastrointestinal 
fluid must travel an increasingly longer and more tortuous path 
to get to the remaining drug. The dissolved drug, in turn, has to diffuse 
out via the same altered pathways. Thus, a tortuosity factor must 
be included in the equation to describe release. 
One of the earliest of these core-type products to be described was 
Duretter, developed by Sjogren and Fryklof [264] in Sweden. It differs 
from other core-type tablets, such as Ciba's Lontab, in that the core is 
produced by directly compressing a granulate of the drug and an insoluble 
plastic material so that a coherent, porous skeleton of the matrix material 
forms around the drug. In core tablets such as Lontab, on the other 
hand, the drug is incorporated into the melted matrix material and this is 
then spread out to dry. After drying it is granulated, and this granulation 
is then compressed into the core tablet [265]. In the final result the 
differences in manufacturing are not evident, and the release patterns of 
drug from these species are similar in many respects. 
The release rate and absorption characteristics of various drug incorporated 
into a plastic matrix type of tablet have been extensively studied. 
Sjogren and Ostholm [266] studied the release of nitroglycerin, lobeline 
hydrochloride, 82Br-Iabeled ammonium bromide, creatinine, potassium

270 Chang and Robinson 
Table 16 Effect of HydroxypropylcelIulose/Polyvinylacetate Ratio on the 
Release Rate from Films containing 20.0% Salicylic Acid 
HydroxypropylcelluloseI 
Dry film kH t1/2 polyvinylacetate thickness Correlation 
ratio (llm)a,b (mg cm- 2 min- 1/2) coefficient (min) 
10:0 189  2.8 0.403 0.997 28 
9:1 223  5.6 0.336 0.997 57 
8:2 210  0.9 0.328 0.993 53 
7:3 229  2.5 0.241 0.998 116 
6:4 209  6.6 0.216 0.984 120 
5:5 204  7.9 0.175 0.997 175 
4:6 145  0.5 0.115 0.997 206 
3:7 156  3.4 0.122 0.997 210 
2:8 181  7.9 0.112 0.998 338 
1:9 222  4.3 0.073 0.998 1190 
0:10 172  1.8 0.057 0.996 1040 
s..rhickness = mean  standard deviation of five measurements. 
bAll films cast using a wet thickness setting of 2.54 mm, 
Source: From Ref. 259. used with permission. 
penicillin V. and dihydromorphinone hydrochloride both in vitro and in vivo. 
in cats and humans. They noted good correlations between in vitro and 
in vivo results. both in blood levels of active drug. and also when monitoring 
a particular pharmacological effect produced by the drug, although of 
course in vivo determination of release rate was much more difficult to estimate. 
In a continuation of this type of study. Sjogren and Ervik [267] 
developed an automatic spectrophotometric method for studying continuous 
release rates of quinidine bisulfate and ephedrine hydrochloride from 
Duretter plastic matrix tablets and obtained highly reproducible results. 
The complex interplay between the processes of release and degradations 
of substances dispersed in polymeric matrixes has been described in 
great detail by Collins and Doglia [268J. Although their discussion is of 
general nature, the analogy to drugs and pharmaceutical systems is apparent. 
EI-Egakey et al , [269] and Asker et al , [270- 272] have delved 
into the in vitro release of drugs from polymeric matrixes and granulations. 
In the case of water-soluble drugs, merely granulating the drug with the 
melted matrix material will provide suitable sustained release of drug. 
whereas with more water-insoluble drugs, a coating providing drug for 
immediate release and absorption takes on increasing importance as the 
degree of water solubility decreases. Obviously, the limiting case here is 
a drug with virtually no water solubility. This drug would not need to

til r:: 
0.... QS 
Table 17 Effect of HydroxypropylcelluloselPolyvinylacetate Ratio on the Release Rate from Films ~
~ 
Containing 18.2% Pentobarbital t::l 
2 
Wet thickness Dry film cq 
Hydroxypropylcellulose! setting thickness k 
H Correlation t 1/ 2 ::tI 
(mg cm- 2 min- 1!2) ~ 
polyvinylacetate ratio (mm) ( llm)a coefficient (min) irn 
~ 
10:1 1. 27 98  5.4 0.225 0.995 20 a- :1 
9:1 2.54 163  3.4 0.224 0.995 57 hi 
Qe- 
8:2 1. 27 87  6.4 0.178 0.987 25 -~.... rn 
6:4 2.54 236  7.1 0.0767 0.997 1.010 Q
;:! 
~ 
4:6 1.91 145  8.0 0.0342 0.999 2.280 'tl 
Q
""$ .... .... 
2:8 1. 27 94  1.9 0.0161 0.999 3.630 So 
~
0 
1:9 1. 27 118  2.6 0.0102 0.999 19.200 
0:10 1.91 210  15.5 0.0260 0.998 6.960 
aThickness =mean + standard deviation of five measurements. 
Source: From Ref. 259. used with permission. 
~
~

272 Chang and Robinson 
be placed in a special sustained-release dosage form. since it is inherently 
long acting by nature of its poor aqueous solubility. Of course, the method 
of preparation of the granulating materials, the choice of in vitro dissolution 
media. and the plastic matrix material chosen will all have an influence 
on release of the drug from the sustained-release dosage form. 
Water-soluble drugs dispersed in hydrophilic matrixes were studied by 
Lapidus and Lordi [273]. Their results indicate that chIorpheniramine 
maleate dispersed in methylcellulose is release-rate controlled mostly by 
drug diffusivity rather than by polymer dissolution and water permeability. 
Thus, even for drugs formulated in a water-soluble matrix, one which 
would itself be subject to erosion and absorption in the body. the determining 
factor in providing sustained release is still diffusion of the drug 
out of the matrix. This important fact was further elaborated on by 
Huber et al , [274] for hydrophilic gums versus the matrix material. In 
this case. the mechanism of prolonged release was determined to be drug 
diffusion from, and eventual attrition of. a gel barrier at the periphery 
of the tablet core. 
A modification of this type of matrix tablet was described by Javaid 
et 81. [275]. They used a lipase-lipid-drug system to provide sustained 
release whereby the erosion of the matrix due to the hydrolytic action of 
lipase on the substrate was the desirable first step in obtaining release of 
the drug for absorption. Accelerators of lipase activity, such as calcium 
carbonate or glyceryl monostearate , could be used to tailor make a sustained-
release tablet to provide a desired release profile. Javaid and 
Hartman [276] then tested these enzyme-substrata-drug tablets in dogs, 
and the action of lipase to control drug release was confirmed. Tablets 
containing lipase consistently gave higher and more uniform blood levels of 
drug than those without. as is evident in Figure 12. It is apparent that 
the enzyme-substrate type of matrix tablet has potential for commercial use 
in providing sustained release. 
The type of plastic matrix sustained-release dosage form that has been 
investigated the most extensively is undoubtedly that of a drug dispersed 
in an insoluble. inert matrix [3-5,10,15,18,278-285]. The kinetics of 
release and the methods of treating the matrix tablets have been reported 
~
UJ 10 
i;j 
oJ 08 oo
906 
OJ 
0.5 ie "3 4 5 6 7 8 
HOURS 
9 
Figure 12 Average sulfamethizole blood levels (mg%) in dogs after receiving 
tablets containing 100% drug in drug-lipid granules with 5% 
glyceryl monostearate. (D) tablets with lipase and (0) tablets without 
lipase. Standard errors are plotted around the averages. (From Ref. 
276, used with permission.)

Sustained Drug Release from Tablets and Particles 273 
by Farhadieh and coworkers [277,279] for drugs dispersed in a methyl 
acrylate-methyl methacrylate matrix. As seen in Table 18, treatment of 
the tablets by exposure to acetone vapor results in a significant decrease 
in the release rate of drug from the matrix. This, coupled with control 
of the treatment temperature, allowed production of sustained release tablets 
with highly reproducible release rates. An investigation of the problems 
that could result from chewing an insoluble matrix was the subject of 
a paper by Ritschel [280]. If the drug is incorporated in the pores and 
channels of a matrix tablet, potential toxicity could occur if the tablet was 
inadvertently chewed by the patient, since this would result in the release 
of large quantities of the drug. For drugs with a narrow therapeutic 
range, such as nitroglycerin, this could be a problem. When the 
drug was dissolved directly into the plastic matrix material. the problem is 
alleviated since even with mastication the drug is not free to be absorbed. 
Sjuib et al , [281,282] continued the work of Higuchi on the study of 
drug release from inert matrixes. The original physical model described 
by Higuchi and coworkers [286 - 294] was tested for binary mixtures of 
acidic drugs and also for binary mixtures of amphoteric drugs. Analysis 
showed that the physical model could describe the experimental data quite 
well and also pointed out that the precipitation of the drug in the matrix 
during release into alkaline media, such as might be encountered in the 
intestinal fluids, has to be considered more important than theories involving 
supersaturation of the drug in the .matrix. The mathematics of 
both matrix-controlled and partition-controlled drug release mechanisms 
were elucidated by Chien et al , [285]. They pointed out that the transition 
that occurs between the two processes is dependent on the magnitude 
of the solution solubility of the drug and, via a series of equations, indicated 
that this term dictates the mechanism and rate of drug release from 
the polymer matrix. 
Other research in the area of drug release from insoluble matrix tablets 
has found that the square root of time relation originally proposed by 
Higuchf [260] described the advance of the solvent front into the tablet 
[ 283]  Compression force was not a major factor and drug release was, 
of course, proportional to the total surface area. 
As can be seen from the above cited work, a tremendous amount of 
time and effort has been expended to elucidate and quantify the factors 
that are important in obtaining controlled-release from plastic matrix-type 
tablets. The perturbations introduced by varying diluents, matrix material, 
and so on are all important in describing the in vitro release of drug 
from these tablets, and presumably are equally important in describing the 
in vivo release rates. However, we would be remiss if the clinical evaluation 
of these types of dosage forms are not included here, since the literature 
is full of examples in which systems showing good in vitro possibilities 
were unsuccessful in an actual clinical trial. 
The effects of gastric emptying time and intestinal peristaltic activity 
on the absorption of aspirin from a sustained-release tablet containing 
coated particles in a hydrophilic gel type matrix and conventional aspirin 
tablets were described by Levy and Hollister [295]. The lag times in the 
absorption profiles reported were undoubtedly due to the time required 
for transfer of the dosage form from the stomach to the intestine. The 
authors point out the pitfalls of plotting averaged individual absorption 
data versus time and how this could lead to erroneous assumptions about 
whether a dosage form is a good candidate for sustained release or not.

t\) 
Table 18 Effect of Acetone Vapor Pressure on the Release Rate of Drug from 100~mg Sodium ~ 
Pentobarbital Tablets at Three Different Temperatures 
Acetone vapor Acetone 
k x 101 t 1/ 2 pressure absorbed 
Temperature (mmHg) (mg/tablet) e: L (g cm2 sec- 1/ 2) (hr) 
Untreated 0 0.575 9.24 5.38 3.38 
tablets 
37 217 16.2 0.567 11.5 4.93 4.03 
244 19.0 0.559 13.3 4.64 4.54 
267 25.3 0.559 19.7 3.87 6.52 
307 30.7 0.535 52.2 2.44 16.4 
347 44.9 0.530 154.9 1.43 47.8 
34 217 18.4 0.560 12.2 4.79 4.26 
244 22.5 0.51 16.6 4.19 5.57 
267 27.9 0.539 43.2 2.67 13.7 
307 39.7 0.534 198.2 1. 26 61.5 
(") 
4.01 6.08 
;:3" 
31 217 26.1 0.551 18.6 Q
;:::l 
244 29.3 0.540 36.4 2.91 11.5 tQ
Q
;:::l 
267 32.8 0.528 86.2 1.93 26.2 Q, 
::tl 
0 Source: From Ref. 277, used with permission. t:r S 
~
;::I

Sustained Drug Release from Tablets and Particles 275 
Individual absorption data that results in a first-order plot can often appear 
to be zero-order, indicating good sustained release, when such data 
are averaged. Thus, it is necessary to look at the data for each individual 
in the test population when assessing sustained-release characteristics. 
Nicholson et al. [296] desertbed the blood and urine levels obtained in 
humans following ingestion of sustained-release tablets. It was noted that 
the sustained-release tablets gave less variation between maximum and minimum 
blood level concentrations and more uniform urinary excretion rates 
than conventional release tablets. Theophylline aminoisobutanol, administered 
in a tablet containing a sustained-release core having a matrix of 
hydrophilic gums, a delayed barrier coat on the core, and an outer coat 
containing the drug for immediate release was investigated by Kaplan [297]. 
Both in vitro and in vivo results were obtained and the blood level data 
correlated well. Although differences were noted in the urinary data, no 
explanation was tendered other than noting that these differences have 
been reported previously. The in vivo absorption and excretion of radioactively 
tagged [l0-14Clpentylenetetrazol was studied by Ebert et al. 
r278)  Human volunteers were given either a single dose of sustainedrelease 
insoluble matrix tablets or three divided doses of conventional tablets. 
It was shown that the sustained-release form gave absorption and 
excretion patterns similar to those obtained in the divided dose case. 
As noted earlier in the section on coated granules, the earliest commercially 
available sustained-release preparations available for clinical trials 
seem to be those providing antihistamines [166,167,298,299]. Such research 
has led to clinical trials of sustained-release triethanolamine trinitrate 
[300] for use in angina pectoris. The drug was provided in a 
plastic matrix that leached out drug over a 7- to B-h span. Patients reported 
no undesirable side effects and the frequency and severity of attacks 
were diminished in 80% of those tested. 
De Ritter [301] used urinary excretion rates to evaluate nicotinic alcohol 
tartrate administered to humans via Roche's Roniacol Timespan matrix 
tablets. This dosage form uses a coating containing drug to provide 
the immediate release portion of the dose and the sustaining portion is 
provided by erosion and/or leaching of the insoluble matrix in the gastrointestinal 
tract. The results indicate good correlation of in vitro and 
in vivo release rates, and the drug is as completely available in this form 
as in conventional tablets. In addition, the intense flushing caused by 
non-sustained-release tablets is absent with the sustained release form. 
The tension-relieving and sedative properties of pentobarbital sodium, 
administered via conventional capsules and Abbott's Gradumet plastic 
matrix sustained-release form, were clinically evaluated by Cass and 
Frederik [302]. Although the grading system employed was qualitative in 
nature, the results indicated that the Gradumet form was useful in providing 
daytime tranquiJization and it was virtually free of untoward side 
effects. 
The Gradumet matrix dosage form has also been evaluated for treatment 
of iron deficiency anemia via the sustained release of ferrous sulfate 
[303,304]. In all cases, the hematocrit and hemoglobin responses were 
virtually identical whether the non-sustained-release form or the matrix 
tablet was administered. However, the incidence of reported gastrointestinal 
upset due to ferrous sulfate, an important problem because more 
iron is absorbed by fasting patients while at the same time causing more 
gastrointestinal distress, was greatly diminished when the dose was given

276 Chang and Robinson 
as a sustained-release tablet. Crosland-Taylor and Keeling [305] formulated 
their own sustained-release ferrous sulfate tablets in an inert 
polymer matrix and they added [59pe] SO4 as a marker to aid in evaluation. 
They point out that the previoualy mentioned hematocrit and hemoglobin 
responses are relatively insensitive means for comparing conventional and 
sustained-release tablets, and their results indicate variable absorption 
from sustained-release forms. They found no real advantage, even in the 
area of management of side effects, to the use of sustained-release forms 
of ferrous sulfate. It is not clear, then, whether there is any significant 
advantage to providing oral hematinics in sustained-release form. 
Owing to the many unpleasant side effects of oral potassium supplementation, 
such as extremely salty taste and severe gastrointestinal upset, 
the past few years have seen a need for a slow-release potassium-providing 
product. Slow-K, marketed by Ciba, is the best example of this type of 
product. The sugar-coated wax matrix contains 600 mg of potassium chloride 
that leaches out gradually over a 4- to 6-h period. Tarpley [306) 
studied the patient acceptability of this product as well as its ability to 
msintain normal serum potassium levels in clinical trials comparing it to oral 
potassium liquid preparations. His findings indicate that both types of 
products maintain serum K+ levels, but the sustained-release tablet gives 
much less incidence of nausea, abdominal pain. cramps, diarrhea, etc., 
and, of course, since it has little or no taste before being swallowed, it 
was much more palatable and acceptable to all the patients involved. 
As was noted earlier, aspirin has been tested for delivery via every 
new dosage form developed for the past 20-25 years. Here, as in the 
case of oral antihistaminics, the simple arithmetic of profit and loss statements 
has compelled pharmaceutical firms to develop sustained-release 
aspirin preparations [307]. The market is largely due to the vast numbers 
of arthritics who need a preparation that will provide aspirin throughout 
the night and eliminate morning stiffness, the most common plight of 
arthritis sufferers. Many products have been extensively tested in clinical 
trials as well. 
Wiseman and Federici [308] have developed a sustained-release aspirin 
tablet utilizing the matrix principle. By carefully monitoring both in vitro 
and in vivo data, the authors were able to fashion a product that gave 
constant plasma salicylate concentrations on chronic administration. Wiseman 
[309] then extended the tests to the clinic where highly reproducible, 
stable plasma salicylate concentrations were attained that overcame the 
fluctuations due to multiple dosing of conventional tablets. The stable 
levels do not exhibit the peaks in serum salicylate levels shown by conventional 
tablets; therefore the incidence of gastrointestinal upset was reduced 
and the valleys, or low points, were eliminated, thus providing therapeutic 
levels of salicylate throughout the night. Harris and Regalado [310], however, 
compared conventional and sustained-release aspirin for their ability 
to provide relief to patients in order that the latter might perform simple 
tasks requiring phalangeal dexterity. They reported no difference between 
the two types of tablets, but a majority of the patients preferred the sustained-
release form. The -inference here is that the sustained-release 
product gave relief throughout the night and did not cause the unpleasant 
gastrointestinal side effects, thus contributing to the patient's preference. 
Also, the convenience of eliminating frequent daytime doses was significant 
in the preference for sustained-release aspirin.

Sustained Drug Release from Tablets and Particles 277 
These are just a few examples of the benefits obtained from providing 
aspirin in a sustained-release matrix tablet and of sustained-release dosage 
forms for administering aspirin. in general. The recent flourish of timed 
release and double- or triple-strength aspirin tablets to the market attests 
to the desirability and. consequently. the profitability of long-acting 
aspirin preparations. 
Case Study of Combination Dissolution -Diffusion 
Coating [280] 
PROLONGED ACTION MECHAN ISM. Coated or uncoated plastic matrix 
tablets. Solvent dissolves the coat containing the initial dose and drug is 
leached out of the plastic core to maintain therapeutic levels. A diagrammatic 
structure of the tablet is shown in Figure 13 for the drug combination 
nitroglycerin and proxyphylllne. 
Complete Depot Dosage Form 
Structure of Depot Phase 
Initial Phase 
Drug Liberation < 5 min 
Depot Phase 
Slow Drug Liberation 1 
Proxyphylline k
r 
Nitroglycerin kl
r 
0.40 hr- l 
0.092 hr- l 
~ Pla'ti, Pa,ti,l" 
.:..: "..... .: :.. Nit,091y,,"n Df s so l ved in Pl as t ic 
-: ,;: :', " Proxyphylline 
Drug Release from Depot Phase 
Nitroglycerin Diffuses 
f rom P1astic tla t r i x 
Release: q5~ in 5 hr 
57'X in 8 hr 
Proxyphylline Dissolves 
and Diffuses through Pores 
Release: 95t in 5 hr 
100'1 in B hr 
Figure 13 Diagrammatic structure of the peroral sandwich tablet with 
timed release and its release Characteristics. (From Ref. 280. used with 
permission. )

278 Chang and Robinson 
Table 19 Pharmacokinetics of Proxyphylline in a Timed-Release Tablet into 
Which Nitroglycerin Was to Be Incorporated 
Biological half-life 
Absorption rate constant 
Elimination rate constant 
Time to reach peak 
Therapeutic concentration to maintain 
for 12 h 
Single dose producing desired blood 
level 
Liberation constant from depot phase 
Equation for plasma concentration 
Percent absorbed relative to the 
amount ultimately absorbed 
Maintenance dose 
Initial do se 
t 1/ 2 == 4.3 (h) 
-1 
Ka = 1.3 (h ) 
K
el = 0.163 (h -1) 
T ::= 2.5 (h) 
P 
B
D ::= 0.8 (mg/100 L) 
DB ::= 0.48 (g) 
k 1 = 0.4 (h-1) 
r 
C ::: 11.5e- 0 I 53t -12.5.e-1. 3t 
AT A' 100 == CT + KelTCDT 
Percent after 0.25 h == 35.6 
0.5 h::: 45.5 
1. 0 h::: 74.4 
1.5 h == 100.0 
1 
D
1 ,
::= DB - D (k T) = O. 177 (g) 
M r p 
Total dose per tablet 
KelB D 
W ::: D - D '(k IT ) + =: 0.489 (g) 
B M r p k 1 
r 
Source: From Ref. 280, used with permission.

Sustained Drug Release from Tablets and Particles 279 
EXPERIMENTAL DESIGN. The pertinent design variables for this 
dosage form are shown in Table 19. Nitroglycerin was dissolved in 1: 1 
alcoholI acetone solvent and was then impregnated in plastic granules of 
either polyvinylchloride. ethylcellulose, polyamide, polyvinylacetate. or 
polyacrylate. The plastic granules must be partly soluble in the alcohol/ 
acetone solvent. The solvent was evaporated and the plastic mass containing 
nitroglycerin with screened to particle sizes of 0.5 -1.0 mm, These 
particles were then mixed with proxyphylline and compressed into tablets. 
The final two-layered tablet contained 0.2 mg nitroglycerin and 180 mg 
proxyphylline in the immediate-release coat and 5 mg of nitroglycerin, in a 
solid-solid solution matrix with the plastic material, and 310 mg of proxyphylline 
in the matrix: pores, constituted the sustaining section. 
IN VITRO TEST. The results of in vitro testing of the tablet are 
shown in Figure 14. The solid and open circles indicate that good sustainment 
is achieved with this tablet and that if accidental mastication 
occurs. as illustrated by the other lines in the figure, some of the sustaining 
effect is lost. Proxyphylline was released with an apparent first-order 
rate of k r 1 = 0.40 h-! and nitroglycerin had k r 
1 =0.092 h- 1. The data 
indicate that the proxyphylline, incorporated into the pores of the matrix, 
dissolves as soon as the artificial gastrointestinal fluid enters the pores 
resulting 95% release within 5 h. Nitroglycerin, because it is dissolved 
into the plastic matrix as a solid -solid solution, must diffuse through the 
plastic material into the artificial gastrointestinal fluid. Consequently, its 
release is much slower, resulting in only about 45% being released within 
5 h. 
8 7 6 5 :3 4 
HOURS 
2 
____Q /0- a 6 0_0 
., ,......., 1).--0 _0--- 
~C~~ 
~n~ ~O 
M~ o~ u/ ___e 
____8 
/ 
0 ~8. 
8 __8  ::;::::;" 
o /" ---%---t--e 
/'e .:::::.- .:::::::-.__ 
8/' .~.---. 
..........-:.---.~. 8/. ./ .---.--- .../ 
100 
~ 90 
0a: 80 t: 
> 70 zz
60 0
j:: a: 
w
2: 
...J 
e
;:) 
a: 
0 
Figure 14 In vitro drug liberation. Proxyphylline: (0) intact tablet, 
(A) cut into two parts, (lJ) cut into four parts, (Q) powdered. Nitroglycerin: 
(.) intact tablets, (~) cut into two parts, (.) cut into four 
parts, (e) powdered, (From Ref. 280, used with permission.)

280 Chang and RObinson 
2 3 456 
HOURS 
7 8 9 
Figure 15 Nitroglycerin blood level after peroral administration. (  ) 
intact tablet, ( ... ) cut into two parts, (.) cut into four parts. and (0) 
powdered and masticated. (From Ref. 280. used with permission.) 
Although the in vitro release study showed that in divided tablets the 
prolonged activity was essentially lost for proxyphylline. the nitroglycerin 
still maintained its sustaining activity. 
IN VIVO TEST. Figure 15 shows the results of the in vivo testing 
for sustained release of nitroglycerin in these products. These are the 
mean curves from three human subjects. As stated by the author, three 
SUbjects is too small a population to generate definitive statistics, so that 
this study should be repeated with more subjects. The results did indicate 
good sustained release of nitroglycerin and served as a useful experimental 
guide. 
D. Sustained Release Utilizing Osmosis 
An example of sustained release through osmosis is tbe so-called osmotic 
tablet [11,12.311]. The coating in this case is just a semipermeable membrane 
that allows penetration of water. but not drug, to dissolve its contents. 
The dissolved drug plus diIuents establishes an osmotic pressure 
and forces drug solution to be pumped out of a small hole in the tablet 
coating. The rate of this drug pumping can be controlled through core 
composition, coating material. and delivery orifice. A pictorial representation 
of the osmotic tablet is shown in Figure 16. 
The tablet imbibes fluid through its semipermeable membrane at a constant 
rate determined by membrane permeability and by osmotic pressure of 
the core formulation. With the system at a constant internal volume, the

SUstained Drug Release from Tablets and Particles 
SEMI PERMEABLE 
MEMBRANE 
281 
Figure 16 Elementary osmotic pump cross section. (From Ref. 12, used 
with permission.) 
tablet wID delivery, in any time interval, a volume of saturated solution 
equal to the volume of solvent uptake. The delivery rate is constant as 
long as an excess of solid is present inside the device, declining parabolically 
toward zero once the concentration falls below saturation, as is 
shown in Figure 17. 
The principles upon which this device is based were presented earlier 
in this chapter. A key factor in proper drug delivery is the size of the 
40 
...:c 30 
E
L1I 
~
cr: 20 
>- cr: 
L1I >
:J 
~ 10 
20 
'z (HOURS) 
Figure 17 In vitro release rate of potassium chloride from elementary 
osmotic pump in water at 37C. (I) range of experimental data obtained 
from five systems, ( ) calculated release rate. (From Ref. 12, 
used with permission.)

282
30 - ...
:c
g' 
~ 20 
~
a: 
>- 
~ 10 
>
:J 
wa 
Chang and Robinson 
5 
HOURS 
10 
Figu re 18 In vitro and in vivo release rate of potassium chloride from 
elementary osmotic pumps. ( ) average in vitro rate from systems 
of the same batch; and (6). (0). (e) average release rate in one system 
jn the GI tract of dogs 1, 2, and 3, plotted at the total time period 
each system resided in the dog. (From Ref. 12, used with permission.) 
delivery orifice. Two conditions must be met. relative to the size of the 
delivery orifice, in order for it to be successful. 
1. It must be smaller than a maximum size, Amax, to minimize the 
contribution to the delivery rate made by solute diffusion through 
the orifice. 
2. It must be sufficiently large, above a minimum size, Amin. to minimize 
hydrostatic pressure inside the system that would affect the 
zero-order release rate. 
Too small a hole will depress the delivery rate below that of the desired 
constant delivery. 
In vivo tests in three dogs are shown in Figure 18. That zero-order 
release is maintained for long periods is evident. 
It should be quite obvious from the mechanistic description of this 
apparatus that drug delivery would be independent of stirring rate and 
independent of pH. These are sizable advantages to a sustained release 
system and have indeed been shown operable both in vitro and in vivo. 
v, COATING MATERIALS 
Other sections of this text have dealt with coating substances insofar as 
describing their properties, coating technology, quality control, etc. 
Some of these coating materials. for conventional coating purposes, can be 
employed to produce sustained-release products depending on the thickness 
of coat employed as well as addition of fillers to the coating substance. 
Table 20 lists some of the more common coating substances and 
their properties. This listing is not intended to be comprehensive, but

Table 20 Coating Materials and Their Properties 
Type of coating 
Barrier coating 
(includes microencapsulation) 
Most suitable 
dosage forme s) 
1. Film-coated tablets 
2. Film-coated pellets 
or granules placed 
in gelatin capsules 
3. Compressed tablets 
containing mixtures 
of barrier-coated 
particles with 
filler particles 
4. Compressed tablets 
containing only 
barrier-coated particles 
forming a 
matrix 
Examples 
Various shellacs [18] 
Beeswax [18] 
Glyceryl monostearate [18] 
Nylon [18] 
Acrylic resins [18] 
Cellulose acetate butyrate 
[ 20] 
dl-Polylactic acid [20] 
1,6-Hexanediamine (20] 
Diethylenetriamine [20) 
Polyvinylchloride [20] 
Sodium carboxymethylcellulose 
{2431 
Various starches 1244] 
Polyvinylpyrrolidone [245] 
Acetylated monoglycerides 
[245J 
Gelatin coacervates [211] 
Styrene/maleic acid copolymer 
[245] 
1. 
2. 
3. 
Probable release 
mechanisms 
Diffusion and 
dialysis 
Some disintegration 
possible 
Also have had pHdependent 
dissolution 
and some enzymatic 
breakdown incorporated 
into some films, 
but these are, therefore, 
poor "barriers" 
1. 
2. 
3. 
4. 
Properties 
Slow or incomplete 
release 
Coating is subject 
to fracture during 
compression 
Release depends on 
solubility of the 
drug and pore 
structure of the 
membrane 
Obtain constant release 
when water or 
GI fluids pass 
through barrier to 
dissolve drug and 
form a saturated 
solu tion within the 
tablet

Table 20 (Continued) 
Most suitable Probable release 
Type of coating dosage formes) Examples mechanisms Properties 
Barrier coating Gelatin coacervates [881 
(includes micro- Styrene/maleic acid 00- encapsulation) polymer [124] 
(cont) 
Embedment into 1- Compressed granules Glycerol palmitostearate 1. Gradual erosion of 1. Slow or incomplete 
a fatty coating into a tablet [18J the coat. aided by release 
(similar to em- 2. Compressed granules Beeswax [18] pH and en zymatic 2. Difficult to control 
bedding in a placed in a gelatin 
hydrolysis of the 
release pattern due 
matrix: of fatty capsule 
Glycowax [181 fatty acid esters to variations in pH 
materials) Castor wax [18] 2. Coating may contain and enzyme content 
3. Multilayered tablets 
portion of the dose of the GI tract 
4. Compression-eoated 
Carnauba wax {18] 
for quick release 
tablets Glyceryl monostearate [18] upon hydrolysis with 
Stearyl alcohol [18] subsequent slow release 
from erosion of 
core 
Repeat action 1- Sugar coating of an Cellulose acetate phthalate 1. pH-Dependent disso- 1. Variations due to 
coatings enteric-coated core [l8] lution and enzymatic changing stomach 
tablet (Many of the examples breakdown emptying times 
2. Compression coating listed for "Barrier Coating" 2. Outel' coating re- 2. Not a "true" susof 
an enteric-coated apply here also) leases first dose tamed form as decore 
tablet rapidly in stomach fined in text 
fluids. inner entericcoated 
core releases 
a second dose at

some later time in 
intestinal fluids 
Coated plastic 1- Multilayer tablets Polyethylene [18] 1. Outer coating con- I. Slow or incomplete 
matrix 2. Compression-coated Polyvinylacetate [18] taining active drug release 
tablets 
dissolves rapidly to 
2. Only water-soluble 
Polymethacrylate [18] provide drug for im- or fairly water- 
Polyvinylchloride [18] 
mediate absorption soluble drugs can 
Ethylcellulose [18] 2. Above process is be used 
followed by leaching 
3. Plastic matrix skel- Silicone devices [20] of drug from inert eton is excreted in 
Methylmethacrylate [20] 
matrix via penetraits 
original. shape 
tion of 01 fluids into 
Ethylacrylate [20] pores of the matrix 
in the feces 
2-Hydroxyethylmetha- 
4. Drug liberation depends 
only on solucrylate 
[20] bility in 01 fluids, 
1.3-Butyleneglycoldimetha- completely indecrylate 
[20] pendent of pH, 
Ethyleneglycoldimethaenzyme 
activity, 
concentration. or 
crylate I 20] 
01 motility 
Coated hydro- 1. Multilayer tablets Carboxymethylcellulose 1. Outer coating con- 1. Drug liberation rate 
philic matrix 
2. Compression-coated U8l taining active drug is dependent on 
dissolves rapidly type and amount of 
tablets Sodium carboxymethyl- along with rapid dis- gum used 
cellulose [18] 
solution from the 
Hydroxypropylmethylcellu- surface of the 2. High water solubflfty 
lose [18] matrix to provide of the drug is abdrug 
for immediate 
solutely necessary 
Methacrylate hydrogels [19] 
absorption 
Polyethyleneglycols [106]

Table 20 (Continued) 
Type of coating 
Coated hydrophilic 
matrix 
(cont) 
Most suitable 
dosage form(s) Examples 
Probable release 
mechanisms 
2. Above process continues 
until a viscous 
gelatinous barrier 
is formed 
around the matrix 
surface 
3. Once the gelatinous 
barrier has formed. 
diffusion and dissolution, 
via erosion. 
occur at a slow. controlled 
rate 
Properties 
3. Release is controlled 
by drug diffusivity 
more than by gum 
dissolution or water 
penetrability as long 
as the hydrated 
gelatinous layer remains 
intact

Sustained Drug Release from Tablets and Particles 
rather is a starting point for the formulator interested in preparing a 
su stained-release product through coating. 
VI. SUMMARY 
287 
During the past several years we have witnessed an increased number of 
publtcatlons dealing with polymer coatings as a means of sustained drug 
action. Most of these approaches have been aimed at the parenteral Or 
specialty areas and as yet many have not been brought to the market 
stage, but their potential utility is apparent. Our ability to manipulate 
film properties gives us a powerful tool by which to prolong drug delivery 
and produce variable drug release rates. It seems reasonable to conclude 
that we are limited in attempting to produce variable release rates from 
conventional tablets or pellets if we rely strictly on dissolution rates and 
shape factors, but the addition of polymer coatings with variable properties 
gives us considerable latitude in producing sustained-release products 
with varying release rates. 
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spray-congealing. J. Pharm. sa., 60: 1709 (1971). 
276. Javaid, K. A. and Hartman, C. W., Blood levels of sulfamethizole in 
dogs following administration of timed-release tablets employing 
lipase-lipid-drug systems. J. Pharm. Sci 61:900 (1972). 
277. Farhadieh , B" Borodkin, S., and Buddenhagen, J. D Drug release 
from methyl acrylate-methyl methacrylate copolymer matrix. 
II: Control of release rate by exposure to acetone vapor. J. Pnarm, 
sa., 60:212 (1971). 
278. Elbert. W. R., Morris, R. W., Rowles, S. G., Russell, H. T  
Born. G. S., and Christian I J. E.. In vivo evaluation of absorption 
and excretion of pentylenetetrazol-10- 14C from sustained-release and 
nonsu stained -release tablets. J. Pharm. Sci., 59: 1409 (1970). 
279. Farhadieh. B., Borodkin , S., and Buddenhagen, J. D Drug release 
from methyl acrylate-methyl methacrylate copolymer matrix. 
1: Kinetics of release. J. Pharm. sct., 60:209 (1971). 
280. Ritschel. W. A. I Influence of formulating factors on drug safety of 
timed-release nitroglycerin tablets. J. Pharm. sct., 60: 1683 (1971). 
281. Sjuib, F., Simonelli, A. P., and Higuchi, W. I., Release rates of 
solid drug mixtures dispersed in inert matrices. Ill: Binary 
mixture of acid drugs released into alkaline media. J. Pharm. Sci., 
61: 1374 (1973). 
282. Sjuib, F., Simonelli, A. P., and Higuchi, W. 1.. Release rates of 
solid drug mixtures dispersed in inert matrices. IV: Binary 
mixture of amphoteric drugs released into reactive media. J. Pharm. 
Sci., 61:1381 (1972). 
283. Goodhart, F. W., McCoy. R. H., and Ninger, F. C., Release of a 
water-soluble drug from a wax matrix timed-release tablet. J. 
Pharm. sei., 63: 1748 (1974). 
284. Choulis, N. H. and Papadopoulos I H., Timed-release tablets containing 
quinine sulfate. J. Pharm. sct., 64: 1033 (1975). 
285. Chien, Y. W., Lambert, H. J., and Lin, T. K., Solution-solubility 
dependency of controlled release of drug from polymer matrix: 
Mathematical analysis. J. Pharm. sct., 64: 1643 (1975). 
286. Desai, S. J., Simonelli, A. P., and Higuchi, W. I  Investigation of 
factors influencing release of solid drug dispersed in inert matrices. 
J. Pharm. set, 54: 1459 (1965). 
287. Desai, S. J  Singh, P., Simonelli. A. P., and Higuchi, W. 1., 
Investigation of factors influencing release of solid drug dispersed 
in inert matrices. II: Quantitation of procedures. J. Pharm. Sci., 
55; 1224 (1966). 
288. Desai, S. J., Singh, P., Simonelli. A. P., and Higuchi, W. 1., 
Investigation of factors influencing release of solid drug dispersed

Sustained Drug Release from Tablets and Particles 301 
in inert matrices. III. Quantitative studies involving the polyethylene 
plastic matrix. J. Pharm. sct., 55: 1230 (1966). 
289. Desai, S. J., Singh, P., Simonelli, A. P., and Higuchi, W. 1., 
Investigation of factors influencing release of solid drug dispersed 
in inert matrices. IV: Some studies involving the polyvinyl 
chloride matrix. J. Pharm. Sci.. 55: 1235 (1966). 
290. Singh. P., Desai. S. J  Simonelli, A. P  and Higuchi, W. I., 
Release rates of solid drug mixtures dispersed in inert matrices. 
I: Noninteracting drug mixtures. J. Pharm, sct., 56:1542 (1967). 
291. Singh, P., Desai, S. J., Simonelli, A. P., and Higuchi, W. I., 
Release rates of solid drug mixtures dispersed in inert matrices. 
II: Mutually interacting drug mixtures. J. Piuirm; set., 56: 1548 
(1967). 
292. Singh, P., Desai, S. J., Simonelli, A. P . and Higuchi, W. I., 
Role of wetting on the rate of drug release from inert matrices. 
J. Pharm, Sci., 57: 217 (1968). 
293. Schwartz, J. B., Simonelli, A. P., and Higuchi, W. I.. Drug release 
from wax matrices. I: Analysis of data with first-order 
kinetics and with the diffusion-controlled model. J. Pharm. Sci., 
57:274 (1968). 
294. Schwartz, J. B., Simonelli, A. P., and Higuchi, W. I., Drug 
release from wax matrices. II: Application of a mixture theory to 
the sulfanilamide-wax system. J. Pharm. sct., 57: 278 (1968). 
295. Levy, G. and Hollister, L. E., Dissolution rate limited absorption in 
man. Factors influencing drug absorption from prolonged-release 
dosage form. J. Pharm. Sci., 54: 1121 (1965). 
296. Nicholson, A. E., Tucker, S. J., and Swintosky, J. V., Sulfaethylthiadiazole. 
VI: Blood and urine concentrations from sustained 
and immediate release tablets. J. Am. Pharm. Aasoc; , Sci. Ed., 49: 
40 (1960). 
297. Kaplan, L. L.. Determination of in vivo and in vitro release of 
theophylline aminoisobutanol in a prolonged-action system. J. Pharm. 
Sci 54:457 (1965). 
298. Laekenbaeher, R. S., Chlortrimeton maleate repeat action tablets in 
the treatment of pruritic dermatoses. Ann. Allergy. 10:765 (1952). 
299. Bancroft, C. M., Tripelenamine hydrochloride and chlorprophenpyridamine 
maleate. A comparison of their efficacies in the treatment 
of hay fever. Ann. Allergy, 15: 297 (1957). 
300. Fuller, H. L. and Kassel, L. E., Sustained-release triethanolamine 
trinitrate biphosphate (Metamine) in angina pectoris. Antibiot. Med., 
3: 322 (1956). 
301. DeRitter, E., Evaluation of nicotinic alcohol Timespan tablets in 
humans by urinary excretion tests. Drug Stand., 28: 33 (1960). 
302. Caas, L. J. and Fredertk , W. S., Clinical evaluation of long-release 
and capsule forms of pentobarbital sodium. Curro Ther. Res., 4: 
263 (1962). 
303. Webster, J. J., Treatment of iron deficiency anemia in patients with 
iron intolerance: Clinical evaluation of a controlled-release form of 
ferrous sulfate. CUr'r. Ther, Res 4: 130 (1962). 
304. Morrison, B. 0  Tolerance to oral hematinic therapy: Controlledrelease 
versus conventional ferrous sulfate. J. Am. Geriatr, Soc., 14: 
757 (1966).

302 Chang and RObinson 
305. Crosland-Taylor, P. and Keeling. D. H A trial of slow-release tablets 
of ferrous sulphate. Curro Ther, Res  7:244 (1965). 
306. Tarpley. E. L Controlled-release potassium supplementation. Curro 
Ther. Res., 16:734 (1974). 
307. 0 'Reagan. T.. Prolonged release aspirin. Drug. Cosmet. Ind., 98: 
35 (April 1966). 
308. Wiseman, E. H. and Federici, N. J., Development of a sustainedrelease 
aspirin tablet. J. Pharm. Sci.. 57: 1535 (1968). 
309. Wiseman. E. H. Plasma salicylate concentrations following chronic 
administration of aspirin as conventional and sustained-release tablets. 
Curro TheY'. Res  11:681 (1969). 
310. Harris, R. and Regalado, R. G., A clinical trial of a sustainedrelease 
aspirin in rheumatoid arthritis. Ann. Ph)!s. Med 9:8 
(1967)  
311. Chandraesekaran. S. K Benson, H., and Urquhart. J., Methods 
to achieve controlled drug delivery: The biomedical engineering 
approach, pp, 557-593. In Sustained and Controlled Release Drug 
Delivery Systems (J. R. Robinson, ed.), Marcel Dekker, New York, 
1978.

5
The Pharmaceutical 
Pilot Plant 
Charles I. Jarowski 
St. John's University, Jamaica, New York 
I. INTRODUCTION 
A. Primary Functions of the Pharmaceutical 
Pilot Plant 
The primary responsibility of the pilot plant staff is to ensure that the 
newly formulated tablets developed by product development personnel will 
prove to be efficiently, economically, and consistently reproducible on a 
production scale. Attention must be given to the cost of manufacture, 
since low production costs provide a competitive advantage. This is 
especially for tablets containing generic drugs. As a consequence, welldesigned 
tablet formulas must be processed intelligently to insure that 
each unit operation is optimized. Thus, final compression conducted at a 
rapid rate is economically advantageous. However, some of this advantage 
will be lost if excessive production times are required and undesirable 
yield losses accrue during the blending, granulating, drying, and compression 
steps. Furthermore, excessive strain On the tablet presses can 
lead to the need for both more frequent press repair and resurfacing of 
the tablet punch faces. 
The manufacturing instructions transferred to the production department 
should be clearly written, readily understood, and unambiguous. 
The widespread use of word processors makes standardization of such procedures 
desirable. Attention should be given to the use of in-house production 
equipment, unless sufficient data has been accumulated to support 
the economic advantage of purchasing new equipment. Alternate manufacturing 
equipment and procedures may also be required for international 
companies intending to manufacture pharmaceutical products at several sites. 
303

304 Jarowski 
The physical properties and specifications for the manufactured tablet 
formulation should match those established earlier by the product formulator, 
the pilot plant staff. and the quality control department. Therefore, 
the tablets manufactured on a production scale should possess the 
proper weight. thickness. and content uniformity. Tablet hardness. disintegration, 
and dissolution rates in simulated gastrointestinal media must 
be consistently attainable to ensure optimal bioavafiability. 
Additional responsibilities for pilot plant personnel include the evaluation 
of new processing equipment and aiding in finding causes and providing 
solutions for problems that occasionally arise during routine tablet 
manufacture. The manufacturer of quality tablets at a rate of 10, 000 per 
minute attests to the competence of tablet technologists. Such achievements 
have been made possible by the interaction of Skilled research, 
process development, and production personnel, Manufacturers of processing 
equipment have also played key roles by supplying excellent apparatus 
for improving unit operations. such as particle size reduction. mixing. 
drying. granulating, compressing. and coating. 
II. SELECTED FACTORS TO BE CONSIDERED 
DURING DEVELOPMENT 
The establishment of ideal formulations and procedures for plant manufacture 
must take into account a variety of factors. 
A. Efficient Flow of Granules 
The high speed of tablet manufacture currently attainable requires that 
the granule flow from hopper to die cavity be unimpeded. To accomplish 
such desired free flow, several parameters need study. First of all, the 
particle size distribution of the granules must be accurately defined. The 
addition of glidants such as talc, starch. and magnesium stearate may be 
indicated for the large-scale manufacture of the tablet formulas developed 
in the laboratory. 
The efficiency of granule flow can be checked in the pilot plant by 
conducting experiments under extended running conditions at high speed. 
Tablets produced for at least 3 to 4 h will possess uniform weight and 
hardness if granule flow has been efficient. Granule flow may be judged 
to be satisfactory and stfll tablet weight and hardness may be unsatisfactory. 
Such deficiencies in many instances can be corrected by increasing 
the concentration of fines. 
B. Ease of Compression, Speed of Manufacture, 
Yield of Finished Tablets 
Tableting equipment, punches, and dies wID require less maintenance if 
tablets are routinely easily compressed. Excessive compressional forces 
applied in the manufacture of tablets wID lead to an increased frequency 
of maintenance and repair. Tablets that are produced under such conditions 
are apt to possess excessive hardness. and are apt to exhibit reduced 
dissolution rates and erratic bioavailability.

The Pharmaceutical Pilot Plant 305 
A high yield of finished tablets and the speed of their manufacture 
are obvious economic advantages that an ideal formulation should ensure. 
C. Content Uniformity 
The use of finely milled ingredients in tablet manufacture is advantageous. 
The oral absorption efficiency of poorly soluble neutral drugs is improved 
as their surface area in the intestinal tract is increased. Granulations 
prepared with such finely milled material and excipients possessing coarser 
particle size may lead to classification problems under high-speed, largescale 
tablet manufacture. Particle size distribution and blending time must 
be well defined during the product development stage to avoid unacceptable 
variation in drug concentration between individual tablets. 
D. Advantage of Accurately Defined Variables 
Process development pharmacists must conduct well-controlled scale-up experiments 
on the tablet formulations developed in the laboratory. Such 
variables as drying time, residual moisture, granule particle size distribution, 
percentage of fines, and compressional force should be accurately 
defined within specified limits. Deleterious effects encountered outside 
these specified limits should also be recorded. Such detailed data developed 
during the pilot stage will become valuable as tableting problems 
arise in future production runs. 
Reworking a production batch of tablets not meeting quality control 
standards has peen complicated by recent rulings by the U. S. Food and 
Drug Administration (FDA). The reason for the poor content uniformity, 
the poor dissolution rate, or some discoloration, for example, must be discovered 
and explained before reworking of such batches can be considered. 
The value of a well-equipped p:ilot plant manned with a skilled staff will. 
become increasingly apparent to managers of a pharmaceutical company 
whose volume and variety of tablets produced is increasing. 
III. TYPES OF ORGANIZATIONAL STRUCTURES 
RESPONSIBLE FOR PILOT OPERATIONS 
The types of organizational structures found in the drug-manufacturing 
industry depends upon a number of factors. In a small company. there 
may not be space allocated for pilot development of tablet formulations. 
The tablet formulator in the product development department may be responsible 
for the ill'st few production batches of tablets. Most l:ikaly he 
or she would also be called upon to aid in the solution of problems encountered 
in future batches. 
In a large organization, a pharmaceutical development team may be responsible 
for the transfer of new tablet formulations to production. A 
well-equipped space for conducting scale-up runs of new tablets will also 
be provided in such an organization. Such a developmental team may report 
administratively to the head of pharmaceutical research and development. 
In other instances. such a group will be a part of the production 
division.

306 Jarowski 
The various types of organizational structures that can exist for 
pharmaceutical pilot development are mentioned below. 
A. Research Pharmacist Responsible for Initial 
Scale-Up and Initial Production Runs 
Figure 1 represents an example of an organizational structure wherein no 
direct responsibility exists administratively for the pilot operation. This 
abbreviated structure is concerned only with administrative responsibility 
for the research and production of tablet dosage forms. The solid lines 
connecting the boxes represent administrative lines of authority and responsibility. 
The broken lines represent lines of communication. 
In such an organizational structure, direct responsibility rests with the 
director of pharmaceutical research and development and the manager of 
solid-dosage form research. The tablet formulators, who report administratively 
to the manager. are responsible for the scale-up and initial 
production runs of their tablet formulations. 
There are advantages that can be cited for such an arrangement. 
Thus, the tablet formulators who know the most about their new tablet are 
directly involved with the manager and section head in the production division. 
who will be responsible for the routine manufacture of their tablet. 
Communicating such information as stability data, physical properties. and 
the reasons for the procedure adopted is best conveyed by the tablet 
formulator, who alone is aware of the variations in formulation that were 
investigated. Several batches of the preferred tablet formula had to be 
Director of pharmaceut1cal 
Research 
III
I 
Manager of Solid 
100- 
Dosage Form Research 
I : '" ....'" ....'" 
Pharmaceutlcal 
".' ----- Research Staff 
Technlcal Dlrector of - Production 
II
I 
". Manager of Tablet and 
Capsule Production 
j
~ 
Sectlon Head ----- 
i
 
Operators 
Figure 1 Abbreviated organizational diagram of a pharmaceutical company 
where no direct responsibility exists administratively for the pilot operation.

The Pnarmaceutical Pilot Plant 307 
prepared for accelerated and long-term stability testing. In addition. 
many clinical batches may also have been prepared by the tablet formuIator-, 
The advantage that accrues to the production division is that individuals 
with the most technical information concerning the new tablet are directly 
involved in the initial production runs of the new formula. The 
tablet formulators from the research division will also gain from such an 
arrangement. They in turn gain valuable experience concerning the types 
of problems that can arise during the large-scale manufacture of their 
tablets. Such experience wD1 serve to improve their competence in developing 
future tablet products. 
There are disadvantages that can be cited for such a working relationship. 
Assigning the research division the responsibility for the first three 
to five production batches means a significant commitment of research time. 
The research pharmacist may strive to develop formulations and procedures 
which are preferred by the production division in order to avoid 
complaints. Thus. for example, resistance to a direct-compression or 
double-compresskm procedure might be encountered. The heavy investment 
in equipment suitable for wet granulation methodology by the production 
division will naturally result in their continuing support for such procedures. 
A person not thoroughly familiar with the production division's equipment, 
materials, ete , , could cause unnecessary expense in urging the 
acquisition of new manufacturing equipment. Furthermore, a product development 
pharmacist is not as familiar with the plant operations as a pilot 
plant person whose job responsibility necessitates knowing the production 
division's personnel and facilities. 
In a small company -where equipment and personnel are limited -the 
tablet formulator can more readily introduce a formula due to the limitations 
of facilities and personnel. In a big company. the pilot laboratory is 
called upon to bridge the gap between the production and research divisions. 
Manufacturing problems can arise with different lots of bulk materials. 
Efficient problem solving will be favored if the troubleshooter is 
familiar with the production division's facilities and has a good working relationship 
with research and production personnel. 
The objective of the research pharmacist is to develop practical tablet 
formulas that cause minimal manufacturing problems. However. he or she 
must not become complacent. A less practical. more expensive procedure 
may produce a tablet exhibiting superior bioavaBabnity. Such a formula 
modification may be difficult to promote within an organization while patent 
protection exists for the drug in the less-efficient tablet. The alert and 
capable tablet formulator will not wait for generic competition to initiate 
such an improvement in oral absorption through the use of a new manufacturing 
procedure. 
Formulations that are manufactured very efficiently can still be improved 
by using less-expensive excipients. Automated procedures can 
significantly reduce manufacturing costs. Such improvements can only be 
made after an investment of time and effort. Frequent interruptions in 
research effort result when the research pharmacist is called upon to 
search for the solution to a problem that has arisen during the manufacture 
of a tablet formulation developed by him or her. Such interruptions are 
unfortunate because they are distracting and disruptive to long-term 
research.

308 Jarowski 
B. Pharmaceutical Pilot Plant Controlled 
by Pharmaceutical Research 
The abbreviated organizational diagram depicting such an administrative 
structure is shown in Figure 2. There are a number of advantages in this 
type of organizational structure. Thus, newly hired research pharmacists 
can include service in the pharmaceutical pilot plant in their orientation 
program. The scheduling of scale-up runs is under the research division's 
control. Clinical supplies of a new drug in a tablet dosage form should be 
controlled by the research division when it is prepared in the pilot plant. 
If any scale-up problems are encountered in the preparation of clinical 
lots, corrective measures, such as dosage formulation modification, can be 
made immediately. Such corrective measures should be made as rapidly as 
possible to ensure that the formulation being clinically evaluated will be 
the one ultimately marketed and that it will prove to be practical to manufacture. 
The pharmaceutical research and development division is dedicated to 
developing dosage forms of new drugs and to search for more economical 
manufacturing procedures and formulations. Thus, it is expected that in a 
pilot plant under research control, new processing equipment, automated 
procedures, and alternate excipients will be actively investigated. Ideally, 
the pharmaceutical pilot plant facility should be located close to the manufacturing 
unit. With such proximity several advantages accrue: 
Technical D1rector of 
Production 
II
I 
Manager of Tablet and 
Capsule Product1on 
,,I
I 
Section Head 1n 
Charge of 
Tablet Production 
I I!
I Operators I 
, 
I 
I 
I 
Director of Pharmaceutical Research 
and Development .. 
 j ,I 
I : I 
Manager of So11d Manager of 
Dosage Form ..~ Pilot 
Research Development 
: : I I I ! I 
Pharmaceutical Pharmacists and 
Research Staff . Engineers 
Figure 2 Abbreviated organizational diagram of a pharmaceutical company 
where direct responsibility for the pilot plant is under the research 
division.

The Pharmaceutical Pilot Plant 309 
1. Scale-up runs can be readily observed by members of the production 
and quality control divisions. 
2. Supplies of excipients and drugs. cleared by the quality control 
division. can be drawn from the more spacious areas provided to 
the production division. 
S. Supplies of packaging material will be easily accessible. 
4. Access to engineering department personnel is provided for equipment 
installation. maintenance, and repair. 
5. Subdivision and packaging of clinical supplies will be expidited by 
temporarily borrowing personnel from the production division. 
The principal disadvantage that can arise from such an organizational 
structure is that inadequate time may be provided to solving production 
problems when they arise. The fact that such problems arise unpredictably 
makes it difficult to justify maintaining an adequately staffed 
troubleshooting team in the production division. An experienced pilot 
plant development team is technically trained to solve such problems. Its 
frequent interaction with both research and production personnel provides 
this team with an excellent base of diverse information which is of value in 
troubleshooting. All that would seem to be needed to surmount this possible 
disadvantage is the assignment of priorities by closely cooperating 
heads of production and research. 
C. Pharmaceutical Pilot Plant Controlled 
by the Production Division 
Pilot development of tablet formulations from the research division under 
such an organizational structure would be carried out by personnel reporting 
administratively to the production division. The abbreviated organizational 
diagram depicting this is shown in Figure 3. 
In such an organization, the responsibility of the tablet formulator is 
to establish the practicality of his or her formula and manufacturing procedure 
in pilot plant equipment. Such equipment is most likely to be similar 
to that used in the production division. This similarity is advantageous 
because a successful scale-up in the pilot plant augers well for 
future success in large-scale manufacturing equipment. 
The frequency of direct interaction of the tablet formulator with production 
personnel in the manufacturing area will be reduced under this 
organizational structure. The presence of a pilot plant team will make it 
likely that manufacturing problems will be directed to their own pilot plant 
personnel. High priority can be assigned because the pilot plant is under 
the control of the production division. Thus, any troubleshooting that is 
required will be initiated expeditiously. Having competent individuals in 
the pilot plant will serve to reduce interruptions on the research effort 
by the production division. 
On the other hand, initiation of a developmental project that may require 
pilot plant equipment not representative of production models is 
likely to meet resistance. The pressures of manufacturing a line of products 
on schedule is bound to make the pilot group ever sensitive to production 
priorities. As a consequence, a sustained commitment on the development 
of new manufacturing procedures is likely to be assigned a 
lower priority.

310 Jarowski 
Section Head in 
Charge of 
Tablet Production 
Technical Director of 
Production 
Manager of Tablet and 
Capsule production 
Section Head of 
Pilot Development 
Director of Pharmaceutical . Research 
I 
I
II
 
Manager of Solid Dosage l-- 
Fot1\l Research 
r 
I: 
-' 
Pharmaceuti ca 1 
Research Staff 
1---- 
Figure 3 Abbreviated organizational diagram of a pharmaceutical company 
where direct responsibility for the pilot operation is under the production 
division. 
IV. EDUCATIONAL BACKGROUNDS OF 
PILOT PLANT PERSONNEL 
Pilot plant staff members concerned with the development of tablets should 
understand the functions of the ingredients used, the various unit operations 
involved, and the general methods of preparing tablets. They 
should possess knowledge of the physicochemical factors which could adversely 
affect the bioavailabfiity of the drug component from a tablet 
dosage form. In addition, good communication skills, both oral and 
written, are essential because these individuals must frequently interact 
with members of the pharmaceutical research and production divisions. 
An individual with graduate training in industrial pharmacy is well 
qualified for such a responsibility. Industrial pharmacy core curricula 
and electives usually include the following courses: product formulation 
(lecture and laboratory), manufacturing pharmacy (lecture and laboratory), 
industrial pharmacy. biopharmaceutics. homogeneous systems, pharmaceutical 
engineering. evaluation of pharmaceutical dosage forms, pharmaceutical 
materials, regulatory aspects of drug production and distribution, 
principles of quality assurance, reaction kinetics, and physical chemistry 
of macromolecules. 
Tablet production operations are by no means static. The following 
technological trends attest to anticipated production complexity: (1) preparing 
tablets by continuous processing, (2) aqueous film coating, (3) 
direct compression of tablets, and (4) use of fluid-bed technology in 
granulating powder blends and in coating tablets. The addition of mechanical 
and chemical engineers would be advantageous in the selection of new

The Pharmaceutical Pilot Plant 311 
equipment offerings being considered for such operations as well as in the 
organization of the most economical sequence of unit operations. 
Whatever the technological trend ~ once the goals are defined. the best 
combination of trained personnel can be determined for the pilot plant. 
V. PILOT PLANT DESIGN FOR TABLET 
DEVELOPMENT 
The 1979 amendments of Current Good Manufacturing Practices of the Food 
and Drug Act are fairly comprehensive with respect to the design, maintenance, 
and cleanliness of a production facility used in the manufacture 
of drugs and their various dosage forms. One of the paragraphs of the 
regulations on Current Good Manufacturing Practices reads as follows: 
Buildings shall be maintained in a clean and orderly manner and 
shall be of suitable size. construction and location to facilitate 
adequate cleaning, maintenance and proper operations in the manufacturing, 
processing, packaging, labelling or holdings of a 
drug. 
Thus, a drug shall be deemed to be adulterated if the methods used for 
its manufacture, processing. packaging, or holding are not operated in 
conformity with good manufacturing practice. The above regulations apply 
to the pilot plant area as well, since it serves as the site for the 
preparation of clinical supplies of drugs in various dosage forms. 
The design and construction of the pharmaceutical pilot plant for tablet 
development should incorporate features necessary to facilitate mamtenance 
and cleanliness. If possible, it should be located on the ground 
floor to expedite the delivery and shipment of supplies. Extraneous and 
microbiological contamination must be guarded against by incorporating the 
following features in the pilot plant design: 
1. Fluorescent lighting fixtures should be the ceiling flush type. 
2. The various operating areas should have floor drains to simplify 
cleaning. 
3. The area should be air conditioned and humidity controlled (75F 
and 50% relative humidity). The ability to maintain a much lower 
relative humidity in a confined area may be desired if special 
processing conditions are required, such as the development of 
effervescent tablets. In other areas, only clean but not conditioned 
air is needed, such as in the site where the fluid-bed 
dryer is installed. 
4. High -density concrete floors should be installed in all areas where 
there is heavy traffic or materials handling. 
5. The walls in the processing and packaging areas should be enamel 
cement finish on concrete masonry for ease of maintenance and 
cleanliness. 
6. Equipment in the pharmaceutical pilot plant should be similar to 
that used by the production division in the manufacture of tablets. 
The diversity of equipment on hand should enable the developmental 
team to conduct unit operations in a variety of ways. 
Space should be provided for evaluating new pieces of equipment.

.... 
Qo 
312 
Jarowski 
1.1 7.1 7.5 13.1 13.2 
7.0 13 .0 
1.0 i , Drying Area 
Granulating 
7.9 
1.9 
Blending 
2.8 
8.0 
8.3 8.5 
Coating Cleaning Area 
Area 9.0 [l;J I 9.3 ] 2.7 
Packaging Area 
I 3.1 1 
3.0 
I 3.1 I 
3.2 
4.0 
Conference Room and 
Library 
5.0 6.0 
Manager's Office sec'ty 
Office 
r- 
U 
10.1 10.2 
weigh~ 10.0 - 
Area I 10.3 
Storage Area for Drugs 
and Excipients 
i i ,o 
Quarantine Area 
~ 
12.0 
J 
I 
-I t--------------- 60' 
I,- 
I
Figure 4 Floor plan for tablet development.

The Pharmaceutical Pilot Plant 313 
A typical floor plan is shown in Figure 4; the floor plan reference is 
shown in Table 1. A typical floor plan for a small pilot plant is shown in 
Figure 5, and its reference is shown in Table 2. The variety of equipment 
installed must be narrow because of space limitations. However, efficient 
use of such limited space can be made by borrowing from the production 
division, as needed, portable tablet presses, mills, and coating 
pans. 
Table 1 Floor Plan Reference for the Tablet Development Area (Fig. 4) 
1. 0 Tablet compression room 
1.1 Heavy-duty tablet press for 
dry granulation 
1.2 Rotary tablet press, 54 
stations 
1. 3 Rotary tablet press, 16 
stations 
1. 4 Compression-coating tablet 
press 
1.5 Single-punch tablet press 
1. 6 Tablet deduster 
1. 7 Storage cabinet for the 
punches and dies 
1.8 Bench top with wall cabinets 
Ancillary equipment; balances, 
friabilator, disintegrationtesting 
apparatus, dissolutiontesting 
apparatus. hardness 
tester 
1. 9 Bench top with wall cabinets 
Ancillary supplies: tools, 
vacuum cleaner 
2. 0 Coating area 
2.1 Coating pan. 36-in diameter 
2.2 Coating pan, 30-in diameter 
2.3 Coating pan, 20-in diameter 
2. 4 Perforated coating pan. 
24-in diameter 
2. 5 Polishing pan 
2. 6 Fluidized bed coating 
apparatus 
2. 7 Airless spray equipment 
2. 8 Area for preparing syrups  
solutions, and suspensions 
for sugar or f"11m coating 
2.9 Bench top with wall cabinets 
3. 0 Packaging area 
3. 1 Work tables 
3.2 Storage cabinets containing 
packaging supplies 
4.0 Conference room and library 
5.0 Manager's office 
6.0 Secretarial office 
7.0 Granulating area 
7.1 Comminuting mill 
7. 2 Sigma blade mixer 
7.3 Planetary-type mixer 
7.4 Tornado mill 
7.5 Fluidized bed spray granulator 
7.6 Comminuting equipment 
7. 7 Extructor 
7.8 Chilsonator 
7.9 Bench top with wall cabinets 
8.0 Blending area 
8. 1 V shaped blender with intensifier 
bar, 1 ft 3 capacity 
8.2 V shaped blender with intensifier 
bar, 5 ft3 capacity 
8. 3 V shaped blender with intensifier 
bar, 20 ft3 capacity 
8. 4 Ribbon blender 
8. 5 Lodige blender

314 Jarowski 
Table 1 (Continued) 
9.0 Cleaning area 
9.1 Sink 
9. 2 Ultrasonic cleaner 
9. 3 Bench top with wall cabinets 
10.0 Weighing area 
10.1 Scale 
10.2 Scale 
10.3 Bench top with wall cabinets 
Small scales and balances 
positioned on bench top 
11.0 Storage area for drugs and 
excipients 
12. 0 Quarantine area 
13. 0 Drying area 
13. 1 Tray and truck dryer 
13. 2 Fluidized bed dryer 
13.3 Freeze dryer 
14. 0 Milling area 
14. 1 Hammer mID 
14.2 Ball mID 
14.3 Muller 
14.4 Fluid energy mID (micronizer). 
2 in diameter 
15.0 Spray-drying area 
15.1 Spray-dryer 
1.1 I 3.1 I 
1.2 1.4 3.0 3.2 1.0 Granulating 
Tablet Drying - Compression Milling 3.3 
1.3 n 03.513.6( 
3.4 
I 1.5 I 
3D' 
--- 
I
-' 
u I 4.1 I 
4.0 T:2 
~ 
Weighing 
Quarantine 
storage 
j 
5.0 
6.0 
fl Off~ce 
30 I ~ 
U 
2.1 
2.0 
2.2 Coating r-- 
Area 2.4 
2.3 
I 2.5 I 

... 
Figure 5 Floor plan for a small pilot plant for tablet development.

The Pharmaceutical Pilot Plant 
Table 2 Floor Plan Reference for the Small Pilot Plant (Fig. 5) 
315 
1. 0 Tablet compression room 
1. 1 Tablet press, single-punch 
1.2 Rotary tablet press, 16 
stations 
1.3 Tablet deduster 
1.4 Bench top with wall cabinets 
Ancillary equipment: balances , 
friabilator, disintegrationtesting 
apparatus, dissolutiontesting 
apparatus, hardness 
tester 
1. 5 Bench top with wall cabinets 
Ancillary supplies: tools, 
vacuum cleaner 
2.0 Coating area 
2.1 Polishing pan, 36-in diameter 
2.2 Coating pan, 36-in diameter 
2.3 Airless spray equipment 
2.4 Area for preparing syrups, 
SOlutions, and suspensions for 
sugar or film coating 
2.5 Sink 
3.0 Granulating, drying, and 
milling area 
3.1 Tray and truck dryer 
3. 2 Hobart mixer 
3. 3 Comminuting mill 
3.4 Hammer mill 
3. 5 Fluidized bed dryer 
3. 6 V-shaped blender with intensifier 
bar 
4.0 Weighing area 
4.1 Bench top with wall cabinets 
4.2 Scale 
5.0 Quarantine and storage area 
6.0 Office 
VI. PAPER FLOW BETWEEN RESEARCH, QUALITY 
CONTROL, AND PRODUCTION 
When the tablet formulation has reached the pilot developmentsl stage it 
becomes the responsibility of the tablet formulator to issue clearly written 
instructions for its manufacture. In addition, analytical specifications for 
the ingredients must be thoroughly delineated. Thus, for example, the 
use of micronized drug may be specified. The in-process steps describing 
the milling conditions to be followed must be spelled out. In addition, 
particle size characterization of the micronized material must be included. 
In other instances, the latter characterization would be included as a 
quality control responsibility for purchased micronized bulk drug. The 
tablet formulator is well aware of the need to use micronized material on 
the basis of dissolution studies conducted during the early stages of 
formula development. When bulk drug specifications are being established, 
such information is related to members of the quality control and production 
divisions. A raw material (RM) number is designated for the micronized 
bulk drug along with any physical or chemical information deemed 
significant. Melting point is not only an important indication of the purity 
of a compound, it also serves as an additional checkpoint for the desired 
polymorphic form on a crystslline compound. A stringently low trace 
metal content may be specified in some instances if improved drug stability 
dictates it.

316
Specification Number 
RM 1000 
Specification 
Classification 
Release and Purchase 
Specification 
Effective Date Super8edes 
7/11/80 10/10/79 
Product Description 
ASCorbic Acid, DSP, FCC 
Empirical Formula C6Hg0 6 
Molecular Weight 176.13 
Jarowski 
Page
1 of 1 
Grade 
'l'~let 
Label Claim if Applicable 
Description 
Specific Rotation at 25
0C 
Heavy Metals 
Lead 
Arsenic 
Residue on Ignition 
Assay 
Mesh size 
white, practically odorous, 
crystalline powder with a 
pleasantly tart taste 
+20.5 to 21.SoC 
Maximum 20 ppm 
Maximum 10 ppm 
Maximum 3 ppm 
Maximum 0.1% 
Minimum 99% 
100% through a No. 20 u.s. Std 
sieve 
Maximum 60\ through a No. 80 
sieve 
Maximum 8% through a No. 200 
sieve 
Figure 6 Example of a specification sheet for a bulk vitamin. 
A typical specification sheet for ascorbic acid is shown in Figure 6. 
As there may be several grades or particle sizes of ascorbic acid within 
the company. it is important to remember to specify the desired grade (in 
this example. RM-1000). 
Figures 7 -9 illustrate manufacturing instructions for tablets containing 
50 mg of hydrochlorothiazide. On the first sheet (Fig. 7) are listed the 
ingredients, the amounts per tablet, and the amounts of each required for 
the batch size. At the top of the figure there appears the words "product 
code number." Such a designation will help to avoid confusion by the 
various departments involved in the manufacture and release of the finished 
tablets. There may be hydrochlorothiazide tablet potencies other 
than 50 mg also being manufactured in the company. When a new drug is 
to be marketed in a tablet dosage form. a new product code number is 
assigned and subsequently used. 
There are columns headed by the words "compounded by" and "checked 
by. II When each ingredient is weighed the individual who made the weighing 
puts his or her initials along side the ingredient weight; the observer

Product and Potency Product Code Number 1 Lot Number Page 
Hydrochlorthiazide Tablets, 50 mg 1 of 3 
Batch Size Date Started Date Completed 
5,000,000 
Prepared By Production Approval Quality Control 
Approval 
Numbel Ingredient Grade Grams/Tablet Grarns/Batct !comReunded Checked RM Lot 
Bv II 11 
1 Hydrochlorthiazide ~.S.P. 0.050 250,000 
2 Microcrystalline 
Cellulose (PH 101) N.F. 0.050 250,000 
3 Dicalcium phosphate, dihydratE N.F. 0.099 495,000 
4 Magnesium Stearate N.F. 0.001 5,000 
Total 0.200 1,000,000 
Figure 7 List of ingredients used in manufacturing hydrochlorothiazide tablets (50 mg) as 
they would appear in a set of manufacturing instructions. 
"'3 
;:l" 
tl) 
~;
(') 
~
..... 
5' a
"tl 
1=:1 
Q... 
:g s..... 
Co) .... 
""I

Product and Potency Product Code Numbe~ Lot Number Page 
Hydrochlortniazide Tablets, 50 mg 2 of 3 
Steps Manufacturlng Instructions Compounded Checked 
By By 
1 Pass ltems I, 2 and 3 through a #16 screen using a comminutlng 
mlll to break up any lumps. 
2 Blend the three lngredients in a V shaped blender for 1 hour. 
3 Add the magneslum stearate and contlnue blend~ng for 15 mlnutes. 
4 Subdivlde the blended materlal lnto polyethylene-llned drums. 
SUbmlt representatlve samples to the Quallty Control divlslon to 
determlne lf the blend is homogeneous. 
5 Upon receipt of clearance from Quallty Control, tablet the blend 
wlth 5/16" standard, round concave puncres on the 54 statlon, 
rotary tablet machine. 
6 Submlt representatlve samples of the finished tablets to the 
Quality Control division for final release. 
ee .... 
OJ 
Figure 8 An example of manufacturing instructions for the prepa.ration of tablets. 
~
~
I;Q 
fI>' ....

Product and Potency Product Code Number Lot Number Page 
Hydrochlorthia~ide Tablets, 50 mg 3 of 3 
Tablet Specifications 
Weight of Tablet 0.200 g 
Weight Range 0.190 - 0.210 g 
Potency 50 mg!tablet 
Range in Potency 46.25 - 53.75 g !tablet 
Hardness Range 7 - 9 (Strong-Cobb units) 
Dis~ntegration Time Less than 5 minutes (U S P method) 
Disso1utl.on Rate 60% of the labeled potency shall dissolve 
withl.n 30 ml.nutes (U S P method) 
Color of Tablet Whl.te 
Figure 9 An example of a tablet specification form which is attached to the manufacturing 
instructions. 
~
;:,' 
~
~
~
R
~.... .... oa
'l:l 
~o.... 
~
Q;::s .... 
C.:l ..... 
to

320 Jarowski 
of the operation also places his or her initials as a double check on the 
accuracy of the weighing operation. A similar procedure should be followed 
for each step in the compounding operation. Such double checking 
is required by the Food and Drug Administration for all new drug application-
type products. However, even if it were not required. such a 
double-checking procedure should be followed to ensure that there are no 
weighing or compounding errors. 
The lot number of each ingredient used must be recorded. Such recordings 
become of special importance when one is attempting to trace the 
history of a particular batch of tablets. Troubleshooting will be simplified 
in some instances by tracing the source of a raw material. A typical problem 
that may arise can be due to a particular lot number of a substandard 
excipient that could have been inadvertently used. 
On the second sheet of the proposed manufacturing instructions (see 
Fig. 7) the stepwise procedure to be followed is described. The words 
chosen should be readily understood by the variety of individuals who will 
be reading these instructions. Thus, quality control personnel considering 
the establishment of in-process controls and pilot and production operators 
who will be following the procedure for the first time should not be 
confused by cryptic phrases containing technical words not easily understood. 
The tablet formulator should keep in mind that his or her manufacturing 
procedure may also be circulated to foreign manufacturing plants. 
Manufacturing instructions that are clearly written are advantageous because 
they avoid confusion which may lead to errors. 
Figure 9 illustrates a list of specifications for the finished tablets. As 
can be seen in Figures 7-9, spaces for the product code and lot number 
are provided at the top of the form. The three forms become a part of 
the file for the lot number of the batch of tablets prepared. These three 
sheets serve as a historical record. Attachments that are included, for 
example, would be the clearance data from the quality control division and 
a record of the physicians receiving the material for clinical study. 
VII. USE OF THE PILOT PLANT SCALE-UP TO SELECT 
THE OPTIMAL PROCEDURE FOR THE PREPARATION 
OF DEXAMETHASONE TABLETS 
A company was planning to expand its tablet-manufacturing facility. The 
company's tablet products in greatest demand were potent corticoids and 
cardiovascular drugs. These water-insoluble, neutral drugs were to be 
used in concentrations ranging from 0.1 to 5.0 mg per tablet. 
The presence of 0.1 mg of drug in a tablet weighing 200 mg represents 
a drug dilution with tablet excipients of 1: 2000. Maintaining content uniformity 
could be a problem in the routine manufacture of such tablets. In 
addition to content uniformity, the dissolution rates of such water-insoluble 
drugs can be a problem. Such drugs as the corticoids and the cardiac 
glycosides, on occasion, have been recalled by the Food and Drug Administration 
because of a lack of bioequivalency. 
The company's top management requested the pharmaceutical research 
and development department to determine which tablet-manufacturing procedure 
should be adopted for this line of tablet products. Their 0.25-mg 
dexamethasone tablets were considered to be representative of the several 
drugs whose production volume were to be expanded.

The Pharmaceutical PIlot Plant 321 
One of four tablet-manufacturing procedures were to be considered: 
(1) wet granulation; (2) microgranulation , (3) direct compression; and 
(4) double compression. Each of these procedures had been used successfully 
by the pharmaceutical research department in the development of 
the 0.25-mg dexamethasone tablets. The responsibility now rested with 
the pilot plant personnel to scale-up each of the four procedures. The 
basis for selection of the optimal procedure would take into consideration 
the following: (1) simplicity of manufacture; (2) physical properties of 
the finished tablets. (3) content uniformity; (4) dissolution rate of the 
dexamethasone from the tablets; and (5) cost of manufacture. On the 
basis of the procedure selected decisions could be made about new equipment 
purchases for the expanded manufacturing facility. The tablet 
formulations are listed in Table 3 [1-3]. 
Dexamethasone was chosen as the drug in this study because it is a 
water-insoluble. neutral compound whose bioavailability can be adversely 
Table 3 Formulations of Experimental Dexamethasone Granules and 
Tabletsa 
Ingredients Wet Micro- Direct 
(mg/tablet) granulation granulation compression Slugging 
Dexamethasone 0.25 0.25 0.25 0.25 
Starch. dry 10.00 11.00 15.00 11.00 
Acacia. powdered 2.60 3.00 3.00 3.00 
Lactose 130.75 130.25 126.75 
Lactose. direct 127.75 
compresaionv 
Starchc 
1.00 
Acacia. powderedc 0.40 
Purified water 18.60 8.00 
Starch, dryd 
4.00 4.00 4.00 
Magnesium stearate 1. 00 1. 00 2.00 1.00 
Talcum, powdered 0.50 2.00 3.00 
Magnesium 
e 1.00 stearate 
Total 150.00 150.00 150.00 150.00 
aBatch size for each method was 10; 000 tablets. 
bDirectly compressible lactose. 
"used as starch Iacacia paste. 
d
Added to the dry granules. 
eAdded for the final. compression. 
Source: From Refs. 1-3.

322 Jarowski 
affected by a poor tablet formulation. In each procedure the micronized 
dexamethasone was mixed with the excipients by using a geometric dilution 
procedure in a V-shaped blender of 3 kg capacity. The four procedures 
followed are summarized below. 
A. Wet Granulation 
Homogeneous blends of the dexamethasone and excipients were granulated 
with starch/acacia in a planetary mixer. The wet mass was passed through 
an oscillating granulator equipped with a No. 8 screen and oven dried 
overnight at 45C. After dry screening through a No. 16 screen, the 
granulations were blended with the remaining dry starch, lubricated, 
and compressed. 
B. Microgranulation 
Microgranulates were prepared by a procedure first described by de Jong 
[4)  An advantage cited for this procedure is that a blend of finely powdered 
drug and excipients can be converted into compressible granules 
with only minor changes in particle size. Thus, micro granulation is differentiated 
from conventional wet granulation by the absence of large agglomerates. 
A relatively small quantity of granulating liquid is used in the 
process of forming microgranulates. As a consequence, the blended powder 
particles become coated by a thin fUm of binder which reduces interparticular 
attraction and yields a free-flowing powder which can be compressed 
to form a tablet. Hydrophobic powders coated in such a manner 
are rendered less hydrophobic, and thus more readily dispersible in water. 
Since such microgranulations are devoid of large agglomerates, powder 
blends granulated in this manner exhibit excellent content uniformity. 
rapid dissolution. and excellent bioavailability. 
In the preparation of dexamethasone microgranulates a homogeneous 
blend of micronized drug, powdered acacia, starch, and lactose was placed 
in a planetary mixer and uniformly moistened with a minimal quantity of 
purified water. The uniform distribution of water is a critical step. Failure 
to distribute the water uniformly will mean that portions of the blend 
will have been inadequately granulated. As a result excessive capping 
will result during the compression stage. The addition of excessive water 
during the granulating step will result in the formation of macrogranules. 
The uniformly moistened granules were passed through a No. 16 sieve 
and tray dried at 45C overnight. The dried granules were passed through 
a No. 16 sieve. Additional starch and magnesium stearate were added to 
the sieved microgranules and the blend was compressed into tablets. 
C Double Compression 
Slugs were made using a heavy-duty press with t-In diameter punches. 
The slugs were granulated through an oscillating granulator fitted with a 
No. 16 sieve. Additional lubricant was added to the granules and, after 
additional blending, the granules were compressed into tablets.

The Pharmaceutical Pilot Plant 
D. Direct Compression 
323 
The dexamethasone, binder, disintegrant, and anhydrous lactose were 
blended by geometric dilution. The homogeneous blend was lubricated and 
compressed. 
The granules prepared by the three granulation procedures and the 
directly compressible blend were compressed on a 16-station tablet machine 
in which only 4 stations were used. Flat punches measuring 5/16 in in 
diameter were employed. Particle size analyses were performed on samples 
of the powder blend before granulation, after granulation, and after compaction 
and disintegration by using a nest of sieves and an electromagnetic 
sieving machine. The particle size distribution of the granules after 
compaction and disintegration was determined by the method of Khan and 
Rhodes [5]. 
These authors prepared compacts by means of a hydraulic press. To 
effect disintegration of the compacts without agitation, which might cause 
granule fracture, a particularly effective disintegrant was included in the 
compacts. In the case of compacts prepared from insoluble materials, such 
as dicslcium phosphate, distilled water was used as the disintegration 
vehicle; for other systems appropriately saturated solutions were used. 
Particle size determinations of the disintegrated compacts were made using 
a particle size counter or an air-jet sieve. 
The dexamethasone tablets were allowed to disintegrate into particles 
and granules by soaking them in absolute ethanol saturated with the drug. 
Aqueous media were avoided because of the presence of water-soluble 
lactose. The particles and granules were separated by filtration and dried 
at 40C for 16 h. The dried particles and granules were then gently 
brushed through a 16-mesh screen. The screened particles and granules 
were then subjected to a particle size analysis using a nest of sieves and 
an electromagnetic sieving machine. 
Representation of Particle Size Distribution Data 
In Table 4 are shown the weight percentages and cumulative weight percentages 
of particles on each of the sieves for the following: (1) the 
dexamethasone powder blend, (2) dried granules prepared by wet granulation 
before compaction, and (3) dried granules after compaction and 
disintegration. 
Inspection of the data in Table 4 reveals that 100% of the particles in 
the dexamethasone powder blend have a particle size of less than 251 um, 
since all the particles passed through the GO-mesh sieve. Approximately 
50% of the material should have diameters of less than 152 um and greater 
than 75 um, This follows, since 13% of the material was collected on the 
120-mesh sieve and 43% was collected on the 200-mesh sieve. The aperture 
for the 100-mesh sieve is 152 um and the aperture for the 200-mesh 
sieve is 75 urn, 
A method of representing the particle size data to obtain a rough estimate 
of the average diameter is to plot the cumulative percentage over or 
under a particular size versus particle size. This is shown in Figure 10, 
using the cumulative percentage oversize for the data in Table 4. 
As an example, the points on the dexamethasone powder blend curve 
were generated as follows. All of the particles of the dexamethasone


600 
>; 
::r 
(ll 30 
~
~
~
(') 
(\) 
l:: .... 
[
"tl 
~
0.... 
::g s.... 
Equivalent Sieve Mesh Numbers (ASTM) 
80 60 50 40 
I I J' I I I I ,~ ~!_ I I I 100 l:J ~I"i 'II"'''' .,~.... ........ _~ 
o 
... .J:: en 
~ 50 
Q) .e 60 ... ..!!! 
:J 
E 70 
8
Q) 
N 80 
.~ 
~ 
090 
Figure 10 Cumulative frequency plot of the data in Table 4. (0) dexamethasone powder blend, 
(11) dried granules prepared by wet granulation before compaction, (D) dried granules after compaction 
and disintegration. (From Refs. 1-3.) ~
~

326 Jarowski 
powder blend passed through the 60-mesh sieve, therefore 0% are greater 
than 251 um (sieve aperture diameter). Only 1% of the particles that 
passed through the 60-mesh sieve were retained on the SO-mesh sieve. 
Hence, only 1% of the particles are greater than 1'18 um, Of the particles 
that passed through the SO-mesh sieve, 8% were retained on the 100-mesh 
sieve. As a consequence, 9% of the particles have diameters greater than 
152 um (1 plus 8%). The remaining points on the dexamethasone powder 
blend curve as well as the curves for the dried granules before compaction 
and after compaction and disintegration were plotted in a similar 
fashion. 
The curves shown in Figure 10 can be used to estimate the average 
particle size of the particles. This is determined by drawing a line parallel 
to the abscissa which meets the ordinate at the 50% point. Perpendicular 
lines are drawn at the points where the horizontal line intersects 
each curve. The average particle size diameter is read on the abscissa. 
A rough estimate of the average diameter of the particles can be obtained 
from the sigmoid curves in Figure 10. A perpendicular to the 
abscissa is drawn from the point where the 50% point on the ordinate 
meets the curves. By this method, the dexamethasone powder blend has 
an average diameter of 84 urn, The dried granules obtained after wet 
granulation have an average diameter of 339 um, the dried granules obtained 
after compaction and disintegration have an average diameter of 
237 um, 
Extrapolation of data from sigmoidal curves as shown in Figure 10 is 
not recommended. A linear relationship is preferred for greater accuracy. 
When the weight of particles lying within a certain size range is plotted 
against the size range or average particle size a frequency-distribution 
curve is obtained. Such plots are valuable because they give a visible 
representation of the particle size distribution. Thus, it is apparent from 
a frequency-distribution curve which particle size occurs most frequently 
within the sample. Hence, it is desirable to determine if the data will 
yield a normal frequency-distribution curve. 
A normal frequency-distribution curve is symmetrical around the mean. 
The standard deviation is an indication of the distribution about the mean. 
In a normal frequency-distribution curve, 68% of the particles lie 1 
standard deviation from the mean, 95.5% of the particles lie within the 
mean 2 standard deviations, and 99. 7% lie within the mean 3 standard 
deviations. 
Unfortunately, a normal frequency-distribution curve is not commonly 
found in pharmaceutical powders. Pharmaceutical powders tend to have an 
unsymmetrical, or skewed. distribution. However, when the data are 
plotted as frequency versus the logarithm of the particle diameter, then 
frequently a typical bell-shaped curve is obtained. A size distribution 
fitting thu? pattern is referred to as a log-normal distribution. 
A log-normal distribution has several properties of interest. When the 
logarithm of the particle diameter is plotted against the cumulative percentage 
frequency on a probability scale a linear relationship is observed. 
Selected data from Table 4 is plotted in this manner as shown in Figure 
1l. 
On the basis of the linear relationship of the data shown in Figure 11, 
one can determine the geometric mean diameters and the slopes of the 
lines. The geometric mean diameter is the logarithm of the particle size 
equivalent to 50% of the weight of the sample on the probability scale.

The Pharmaceutical Pilot Plant 327 
9 
o <:) 0 00 00 
"'" LJ'1 \D r- ee "'0 
..-l 
ooM 
Particle Size CJ,tm) 
o
o.., o 0 0 00 o 0 0 00 
." Ifl \ll r-. CXI 
Figure 11 A plot of oversize cumulative weight percentage versus particle 
size. (0) dexamethasone powder blend. (6.) dried granules prepared by 
wet granulation. (0) dried granules after compaction and disintegration. 
(From Refs. 1-3.) 
The values for the geometric mean diameters as shown in Figure 11 are 
(1) 88 um for the dexamethasone powder blend. (2) 322 um for the dried 
granules prepared by wet granulation. and (3) 250 um for the dried granule 
granules obtained after compaction and disintegration. 
The slopes of the lines are given by the geometric standard deviations. 
which are the quotients of anyone of the following ratios: 
84% undersize 
geometric mean diameter 
geometric mean diameter 
84% oversize 
16% oversize 
geometric mean diameter 
geometric mean diameter 
16% undersize 
Knowing the two parameters. slope and geometric mean diameter. one can 
determine the particle size distribution at various fractional weights of the 
sample from the graph and reconstruct a log-normal distribution curve. 
Mention should be made of the origin of the numbers 84 and 16%. In a

328 Jarowski 
normal or log-normal distribution curve, 68% of the particles will lie less 
than one standard deviation away from the mean or geometric mean diameter. 
To put it another way, 34% of the particles will be larger than the 
mean or geometric mean (34 + 50 = 84) and 34% of the particles will be 
smaller than the mean or geometric mean (50 - 34 = 16). 
In Figure 11, the ordinate data are spaced logarithmically. Equally 
good linear data are obtained if semilog plots are used; that is, one plots 
oversize cumulative weight percentage versus the logarithm of the particle 
size. A comparison of the average particle size of granules obtained from 
log-probability and semilog plots is shown in Table 5. In the table, the 
average particle size data tabulated attest to the close agreement of the 
two procedures. Semilog plots were adopted for the presentation of all 
particle size data (Figs. 12-15). The average particle diameters determined 
from the figures are summarized in Table 6. 
Slugging produced the widest particle size distribution and the largest 
average particle diameter (Fig. 14). Forty percent of the weight of the 
sample had particle diameters greater than 596 um. Furthermore, only 
91% of the sample was collected on the nest of sieves, and thus 9% of the 
sample possessed particle diameters less than 44 um, The original dexamethasone 
powder blend was completely collected on sieves ranging from 
80 to 325 mesh. After compaction and disintegration, the granules with 
the largest particle diameter amounted to only 7%. Fifteen percent of the 
sample after compaction and disintegration passed through the 325-mesh 
screen. Such data are indicative of size reduction occurring during the 
two compressional stages. Such size reduction was not found to be 
deleterious, since the granulations prepared by slugging yielded satisfactory 
tablets. If the concentration of particles with diameters less than 
44 um had exceeded 25 to 30%, irregular granule flow and capped tablets 
cotUd have been obtained. 
Table 5 A Comparison of Average Particle Sizes of 
Granules Prepared by Three Granulating Methods and 
a Direct-Compression Powder Blenda 
Average particle size 
(um) 
Log probability Semilog 
Granulating method plot plot 
Wet granulation 322 315 
Microgranulation 100 100 
Slugging 410 400 
Direct compression 122 120 
aTh e average particle sizes were obtained from log 
probab:ility and semilog plots.

The Pharmaceutical PUot Plant 329 
Table 6 Average Particle Diameters of Dexamethasone Powder Blends and 
Granules Prepared by Wet Granulation, Microgranulation, and Slugginga 
Average particular diameter (11m) 
Wet Micro- Direct 
Processing stage granulation granulation Slugging compression 
Powder blend 88 88 88 120 
Granules 315 100 400 
Disintegrated 235 90 120 120 
tablets 
aAlso included are dried granules obtained after compaction and disintegration 
and tablets prepared by direct compression. 
lOo-r_------------------., 
Particle Size l#.tml 
Figure 12 Effect of wet granulation on the particle size distribution of a 
dexamethasone powder blend before and after compaction and disintegration. 
( 0) dexamethasone powder blend, (A) dried granules before compaction, 
(D) dried granules after compaction and disintegration. (From 
Refs. 1-3.)

330 larowski 
o 0 0 
o 0 0 0 
U"\ \0 r-- aJ 
oo
"" 
oo 
,., o 0 00 00 
ll'I \D r--a:I 0'10 
r-I 
o.&--... ......TIr--r-'-,---,r----T-r--r--H 
o... 
Particle Size (101m) 
Figure 13 Effect of microgranulation on the particle size distribution of a 
dexamethasone powder blend before and after compaction and disintegration. 
(0) dexamethasone powder blend, (A) dried granules before compaction, 
(0) dried granules after compaction and disintegration. (From 
Refs. 1-3.) 
Microgranulation brought about the least change in particle size distribution 
(see Fig. 13)  The slopes of the three lines are similar. The 
amounts of material passing through the 325 mesh screen were 0% (dexamethasone 
powder blend), 2% (before compaction), and 10% (after compaction 
and disintegration). Such increases in fine particles are not 
significant. 
Granules prepared by wet granulation were much larger than the 
original powder blend (see Fig. 12). Ninety-five percent of the sample 
was collected on 30- to 120-mesh sieves. Only 5% of the sample passed 
through the 325-mesh sieve. After compaction and disintegration a significant 
size reduction occurred. The 200-mesh sieve collected 21% of 
the granules and the 325-mesh sieve retained 10% of the sample. Prior to 
compaction and disintegration none of the granules had been retained by 
either of these sieves. 
Direct compression produced the least change in particle size before 
and after compaction and disintegration (see Fig. 15). The slopes of the 
two lines are practically identical. Ninety-seven percent of the particles

The Pharmaceutical Pilot Plant 331 
100------------------------- 
o a 0 00 
o 0 0 00 
qo "" \0 r--oo 
o
<:> 
M 
oo
"'I 
o a 0 00 00 
~ Lf> \0 r- 00 "'0
r-l 
O-l--.....-...-._ ......-...-z;.........--r--.......-r--r-"""Y'"T 
80 
10 
90 
70 !
~ 60 
l1. 
~
en 50 
~
~ 40 
~
~
(5 30 
l!l 
~ 20 
o 
Particle Size (p:mJ 
Figure 14 Effect of slugging on the particle size distribution of a dexamethasone 
powder blend before and after compaction and disintegration. 
(0) dexamethasone powder blend, (6) granules prepared by slugging, 
(0) dried granules after compaction and disintegration. (From Refs. 1-3.) 
in the directly compressible blend were collected on 50- to 325-mesh sieves, 
whereas 92% of the particles after compaction and disintegration were collected 
on such sieves. The fines which were collected in the receiver 
(3 and 8%, respectively) are of concern in this instance, since micronized 
dexamethasone accounts for only 0.16% of the sample weight. As a consequence, 
classification and poor content uniformity might be anticipated. 
None of the original dexamethasone powder blend passed through the 
325-mesh sieve. Hence, compressed tablets prepared from granules obtained 
by the three granulating procedures could be expected to exhibit 
differences in content uniformity and weight uniformity. 
Dexamethasone Homogeneity in the 
Granules and Tablets 
The relative homogeneity of dexamethasone in the granules prepared by 
the four procedures is shown in Table 7. Microgranulation produced the 
best dispersion of dexamethasone. The fine granule size most likely accounts 
for the homogeneity of drug distribution in the microgranulate.

332
70 
i... c 60 80- .. a. 
i. 50 
"ij 
3: 
.~ 40 
~ 
~ 30 <3 ..hi '2 20 ..> 
0 
10
0 
0 0 00 r--m 0 0 0 00  li'l \0 1"-00 
Particle Size (pm) 
Jarowski 
Figure 15 Effect of direct compression on the particle size distribution 
of a dexamethasone powder blend before and after compaction and disintegration. 
(0) direct compression powder blend, (0) dried granules 
after compaction and disintegration. (From Refs. 1-3.) 
Table 7 Homogeneity of Dexamethasone Distribution in Granules 
Prepared by Four Different Methods 
Average Maximum Minimum Coefficient 
content content content of variation 
Granulating method (mg) (mg) (mg) (%) 
Wet granulation 0.240 0.265 0.222 5.97 
Microgranulation 0.251 0.253 0.247 0.99 
Direct compression 0.249 0.267 0.238 3.90 
Slugging 0.247 0.252 0.243 1.43 
Source: From Refs. 1-3.

The Pharmaceutical Pilot Plant 333 
On the other hand ~ wet granulation exhibited the poorest homogeneity. 
This is attributable to the larger particle size and the wider distribution 
of particle size of the granules before and after compaction. The slugging 
method was found to be the second best granulating procedure for producing 
homogeneous granules. In the slugging method, dexamethasone 
was dispersed in powdered lactose in a suitable blender. After the addition 
of a portion of the starch and acacia the blend was lubricated with 
magnesium stearate and slugged under high pressure. Unlike wet granuIation 
, the slugging method did not call for SO many processing steps, 
such as wetting ~ wet screening, drying, dry screening~ lUbricating ~ and 
compressing. Moreover, bonding of drug excipient had occurred during 
the slugging operation. Subsequent granulation did not result in segregation 
of dexamethasone because of such bonding. Thus, the homogeneity 
of drug distribution in granules is not only dependent on granule size 
distribution and/or drug particle size, but also is dependent on the granu1ation 
method. The coefficient of variation is also high for the blend prepared 
for direct compression. This is attributable to the great difference 
in particle size between the active ingredient and the exeipienta. The 
dexamethasone was micronized (size range 1-5 llm); the directly compressible 
lactose had an average particle diameter of 120 um. 
Control charts for the weight variations of dexamethasone tablets are 
shown in Figures 16-19. The control chart is a useful measure for 
process control. It is based on standard deviation or range (R). 
Each of the circled .20ints in Figures 16-19 represent the average 
weight of five tablets (X) taken at s-mtn intervals up to 40 min. Thus, a 
total of 40 tablets were individually weighed. The highest and lowest 
weight of each time interval Jlre also shown in the four figures. The 
average for the 40 tablets (jC) is represented by the solid horizontal line. 
The horizontal broken lines above and below the solid line represent 3 
standard deviations from the mean. For a normal curve distribution of 
Time (minutes) 
5 10 15 20 25 30 35 40 
158 
157 
156 
155 
t1' 154 
! 153 ., 
152 .c: 
t1' .... lSI III 
~ 150 
149 
148 
147 
146 
x - A R 2 
Figure 16 Control chart for the weight variation of dexamethasone tablets 
prepared by the wet granulation method. (From Refs. 1-3. )

334 
T1me (minutes) 
157 
156 
155 
D'> 
E 154 
+I 153 
~ 152 .J.._--I-~~~:::::~~:::::::~~:::::=G~~~--~,4:""+X 
~ 151 
150 
149 
Jarowski 
Figure 17 Control chart for the weight variation of dexamethasone tablets 
prepared by microgranulation. (From Refs. 1-3.) 
weights. this means that 99.73% of the tablets in the batch will weigh 
within the range represented by the upper and lower limits; for a skewed 
curve distribution. 95% or more of the tablets wID weigh within the upper 
and lower limits represented by the horizontal broken lines. 
The standard deviation is used as the measure of spread for almost all 
industrial frequency distributions. It is the root mean square deviation of 
Time (minutes) 
162 
161 
160 
159 
158 
~ 157 
tl' 
,5 156 
+I 155 
~
~ 154 &153 
152 
151 
150 
149 
148 
5 10 15 20 25 30 35 40 
Figure 18 Control chart for the weight variation of dexamethasone tablets 
prepared by slugging. (From Refs. 1-3.)

The Pharmaceutical Pilot Plant 335 
40 35 
T~me (m~nutes) 
15 20 2S 30 10 5 161 
160 
159 
159 
157 
156 
155 
lS4'1-_--:I:-------~I11""""---_1't_---~tt_X 
153 
152 
~ 151 !' 150 
-4.1 149 
-, 14 9 
rot &147 
146 
145 
144 
143 
142 
141 
140 
139 
Figure 19 Control chart for the weight variation of dexamethasone tablets 
prepared by the wet granulation method. (From Refs. 1-3. ) 
the readings in a series from their average. The sample standard deviation 
is obtained by extracting the square root of the sums of the squares 
of the series from the average, divided by the number of readings. This 
is represented symbolically as follows: j -2 -2 -2 Standard = (Xl - X) + (X2 - X) + (X 3 - X) + 
deviation n 
... + (X - X)2 
n 
X :: value of each reading n
X :: average value of the series 
n :: number of readings 
The standard deviation of the data presented in Figure 16 is calculated 
as follows: X, the average weight for the 40 tablets = 152.4 mg

336 Jarowski 
Time (min) 
5 10 15 
(X - X) (X - ib 2 
(X - X) (X - JC)2 (X - X) (X - Jb 2 
+2.8 7.84 -0.4 0.16 +2.8 7.84 
+1.6 2.56 +3.3 10.89 -1.6 2.56 
+3.2 10.24 +0.1 0.01 -2.6 6.76 
+1.2 1.44 -2.1 4.41 -3.1 9.61 
+0.4 0.16 +0.2 0.04 -0.2 0.04 
Time (min) 
20 25 30 
(X - X) (X - Jb 
2 
(X - ,b (X - X) 2 (X - X) ex - X) 2 
-2.4 5.76 +2.8 7.84 -0.2 0.04 
-1.8 3.24 -4.5 20.25 +5.1 26.01 
-2.3 5.29 -1.2 1.44 -1.0 1.00 
-2.6 6.76 +0.6 0.36 -1.0 1.00 
-1.5 2.25 +3.6 12.96 +1.0 1.00 
Time (min) 
35 40 
eX - X) (X - 5(2) (X - X) (X - 5(2) 
-1.2 1.44 +0.1 0.01 
+3.1 9.61 +4.2 17.64 
-2.9 8.41 -2.8 7.84 
+1.6 2.56 -1.8 3.24 
-3.0 9.00 +2.6 6.76 
S d d d . t' / 226.27 tan ar evia IOn = 40 = .; 5.657 = 2.38 
Standard deviation of 
the sample average 
standard deviation of the lot = 
In 
= 2. 38 = 2.38 =: 1. 06 
15 2.24 
Three standard deviations of the sample average = 3 x 1.06 =: 3. 18

The Pharmaceutical Pilot Plant 337 
From the calculations shown, the upper line of the control chart (see 
Fig. 16) is set at 152.4 = 3.18 = 155.58; the lower line of the control 
chart is set at 152.4+ 3.18= 149.22. 
Obviously, it would be tedious to gather a series of samples of small 
size, determine the values for central tendency and spread for each of 
these samples, and then go through the laborious calculations that are involved. 
However. statisticians have simplified the calculations by preparing 
a table of constants (Table 8) [6]. 
Through the use of the following equation the control limits can be 
cslculated much more easily (R = average of the range values): 
Upper broken line (Fig. 16) == X + A2R 
Lower broken line (Fig. 16) =X - A2R 
Thus. for samples consisting of five units at each time interval the 
value for A2 has been calculated to be 0.577 (see Table 8). Substitution 
of the factor into the above equations is shown at the bottom of Figure 16. 
Note the close agreement of the limit values derived by either method of 
calculation, 
Table 8 Factors for Computing 
Control Limits When Range is Used 
as a Measure of Spread 
Number of 
observations 
in sample 
(n) 
Factor for 
control limits 
(A
2) 
2 1.880 
3 1.023 
4 0.729 
5 0.577 
6 0.483 
7 0.419 
8 0.373 
9 0.337 
10 0.308 
11 0.285 
12 0.266 
13 0.249 
14 0.235 
15 0.223 
Source: From Refs. 1-3.

338 Jarowski 
Examination of Figures 16-19 reveals that the tablets prepared by the 
microgranulation procedure were most uniform in weight (Fig. 17). This 
conclusion can be drawn from the following considerations: (1) the average 
range value. 3. 85. is the smallest for the four granulation procedures; 
(2) the average value for the five tablets at each time interval always fell 
between the upper and lower limits; and (3) the weight spread between 
the 40 tablets was least for the microgranulation procedure (156.6 - 150 = 
6.6 mg). 
An interesting correlation can be seen between the average range values 
R from the four control charts (see Figs. 16-19) and the average 
particle size of the granules used in preparing the tablets (see Table 5). 
On the basis of the data in Table 5. one can conclude that the lower the 
average particle size of the granules the lower the average range value. 
Thus. the four granulating procedures rank in the following order with 
respect to increase in average particle size and R value: micro granulation  
1001-1, 3.85mg; direct compress., 120 u . 3.9mg; wet gran .. 31511, 
5.35 mg : and slugging. 400 u . 6.6 mg. Thus weight variation is a function 
of the average particle size of the granules. 
Content uniformity was determined for the tablets prepared by the four 
manufacturing procedures. Assay data collected on 40 tablets were treated 
in a fashion similar to that shown in Figure 16. Control charts for content 
variation of dexamethasone tablets are shown in Figures 20- 23. Each 
point on these figures represents the average spectrophotometric absorbance 
(at 239 nm) for five tablets individually assayed at 5-min intervals up to 
40 min. 
Microgranulation and slugging can be seen to be the best procedures 
for preparing dexamethasone tablets possessing good content uniformity 
(see Figs. 21 and 22). Their average range values of 0.017 and 0.016. 
respectively, were much lower than those values for the wet granulation 
and direct-compression procedures. 
Confirmation of these conclusions was derived from assays performed 
on 50 individual tablets selected at random from each batch of tablets. 
The coefficients of variation (standard deviation/average) were significantly 
lower for tablets prepared by the micro granulation and slugging procedures 
(Table 9). 
Table 9 Coefficient of Content Variation for Dexamethasone Tablets 
Prepared by the Four Manufacturing Proceduresa 
Number 
Manufacturing of Average Standard 
procedure assays absorbance deviation 
Wet granulation 50 0.430 0.0248 
Microgranulation 50 0.452 0.0092 
Direct compression 50 0.450 0.0182 
Slugging 50 0.455 0.0129 
aContents expressed in terms of absorbance. 
Source: From Refs. 1-3. 
Coefficient 
of variation 
(%) 
5.77 
2.04 
4.04 
2.84

The Pharmaceutical Pilot Plant 339 
5 10 15 20 25 30 35 40 
41 
tl 
I:: 
III . 435 s 430+.-------+------+-----++---t-X 
~ 425 
+J 420 
I:: 
~ 415 
g 410 
o 
405 
400 
395 
390 
385 
380 
375 
370 
Figure 20 Control chart for the content variation of dexamethasone tablets 
prepared by the wet granulation method. (From Refs. 1-3.) 
Time (ml.nutes) 
5 10 15 20 25 30 35 40 
47 
QI 47 
l) 
I:: 46 III X A}l .Q 46 + 
~
0
1/1 45 
~ 45 X 
+J 44 I:: A2R Q.I 44 - 
+J 
J:: 
0 43 u 
43 
Figure 21 Control chart for the content variation of dexamethasone tablets 
prepared by microgranulation. (From Refs. 1-3.)

340 
Tlme (mlnuteS) 
Jarowski 
5 10 15 20 25 30 35 40 
QJ 
Uc 
.3 
+ A2R "" 0
III 
~ X 
.j.J 
C
QJ - Ai .j.J c0
u 
Figure 22 Control chart for the content variation of dexamethasone tablets 
prepared by slugging. (From Refs. 1-3.) 
Tlme (minutes) 
5 10 15 20 25 30 35 40 
48 
48 
475 
47 
46 
~B 46 
~ 45 
~ 4SO+----....l~~:::::~-----.....-_t-~~--;_ X 
III 
~ 445 
44 
~ 43 
 
, -, "- .- _"--'11" ...-,~-. --_. .. 
-.~ 
, ~ 
~_." .# ~. ;. "- --.-" <, ~'-"~' 
- 
~ - , " TABLET ~ TABLET 
_.-. ..... _- -... ~--- .... "". ./"'" -, PRESS ....- _..- _...... ._--.... PRESS "lit"<,, 4- - .....~- ...... -- ... ./ 
Figure 16 Air handling in compression area. 
PACKAGING. Some tablet-filling machines are designed with a selfcontained 
vacuum system that returns the air, filtered through an absolute 
filter, back to the packaging area. There should also be some provisions 
made at the cottoning stations. If the filling machine being used does not 
have an air-filtering system, dust pcikups of approximately 300 cfm 
should be provided at the hopper station and 50 CFM at the bottle chute. 
C. Humidity/Temperature Controls 
From the standpoint of both product protection and employee comfort, 
careful consideration must be given to humidity and/or temperature controls. 
Unless otherwise indicated, conditions of 45% RH and 70F are 
generally adequate for critical manufacturing areas such as compression 
and coating. Comfort conditioning should be provided for weighing,

400 Connolly. Beretler, and Coffin-Beacn 
granulation, compression. and packaging operations. However. temperature 
controls should be such that little or no variation will be caused by 
external ambient temperatures. Thus, comfortable working conditions are 
achieved and there should be no impact on characteristics of in-process 
materials, such as granulation. raw materials. etc. Warehousing operations 
should have some adequate type of ventilation, particularly in areas 
of high storage. either pallet racks or pallet-to-pallet-type storage. The 
ventilation could be provided by large roof fans to circulate air. In addition, 
some form of supplemental air heating. such as hot-air blowers. 
should be provided fol' cold areas. such as shipping or receiving docks. 
D. Water Systems 
Although water systems are not covered to any great extent in the CGMPs, 
CGMP regulation 211.48 states that the supply of potable water in a plumbing 
system must be free of defects that could contribute contamination to 
any drug product [6]. Thus, an effective water system is a necessity. 
In recent years, various techniques have been developed for producing 
the high-quality water required in ever-increasing quantities in pharmaceutical 
manufacturing operations. These include ion-exchange treatment. 
reverse osmosis. distillation, electrodialysis. and ultrafiltration. In fact. 
the United States Pharmacopeia (USP) XXI defines purified water, USP. 
as water obtained by these processes or other suitable processes. Unfortunately, 
there is no single optimum system for producing high-purity 
water. and selection of the final system(s) is dependent on such factors 
as raw-water quality. intent of use. flow rate, cost. etc. [1]. 
In the pharmaceutical industry, the classes of water normally encountered 
are well water. potable water. USP (which complies with Public 
Health Service Drinking Water Standards), purified water. USP, and specially 
purified grades of water. such as water for injection. USP. or FDA 
water for cleaning and initial rinse in parenteral areas (as defined in the 
CGMPs for large-volume parenterals). For purposes of this chapter. only 
the first three classes will be addressed because these are the classifications 
encountered in processing for solid- and semisolid-dosage forms. 
Well Water 
Well water, as the title indicates, is water drawn directly from a well. 
The water may not be either chemically or microbiologically pure because it 
is untreated. Therefore. the use of well water should be restricted to 
nonmanufacturing operations. such as lawn sprinklers. fire protection systerns, 
utilities, and the like. 
Potable Water 
Potable water, USP, is city water or private well water that has usually 
been subjected to some form of microbiological treatment. such as chlorination. 
to meet the United States Public Health Service Standard with respect 
to microbiological purity. Potable water is fit for drinking. and is 
generally used in processing operations for cleaning and sanitation purposes. 
Periodic monitoring of use points should be conducted to ensure 
adequate residual chlorine levels and the absence of microbial contamina

Tablet Production 
tion. If necessary t additional chlorine should be added to the water 
supply as it enters the plant, or a suitable flushing program should be 
implemented to ensure adequate chlorine levels at point of use. 
401 
Purified Water 
Purified watert USP, is usually prepared from water that meets the potable 
water standard. Purified water is treated to attain specified levels of 
chemical purity and it is the type of water used in most pharmaceutical 
processing operations. Bowever, this class of water is not without problems 
in that the requirements of no chlorides presents special concerns 
from a microbial contamination standpoint. 
Purified water. USP. generally is produced by deionization or distillatton 
, although reverse osmosis or ultrafiltration systems might be utilized 
if the required chemical purity could be achieved. As a starting point in 
these processes, water softening or activated carbon filtration frequently 
is employed as a pretreatment process to remove calcium and magnesium 
ions or chlorine and organic materials. Ion exchange and demineralization 
through deionization is a very common method of obtaining the purified 
water, USP t used in the pharmaceutical industry. 
Water-Treatment Equipment 
Deionization equipment should be sized to ensure frequent regeneration and 
a recirculating system should be installed on the unit that approaches the 
rated flow of the deionization unit. Procedures should be written to ensure 
that all water-treatment equipment is properly operated. monitored. 
maintained. and sanitized on a regular basis. 
WATER FILTRATION. Water filtration generally is approached on the 
basis of two major considerations: prefiltering to prevent large particulates 
from entering the system and microfiltering to remove bacteria. Prefilters 
are generally the replaceable cartridge type with porosities ranging as 
high as 25 u, Microfiltering is usually accomplished with a O.2-11 absolute 
filters, which will remove most bacteria. 
A proliferation of filters within the system should be avoided, since 
what might be implemented as a protective measure could readily develop 
into a problem wherein retained bacteria are given the opportunity to 
multiply. In any system employing filters for the control of bacteria t the 
filters and all of the downstream piping must be effectively sanitized on a 
regular basis. There should be procedures written for filter inspection, 
replacement, integrity testing, and monitoring on a scheduled basis. 
SAN ITIZATION PROCEDURES. Sanitization is best accomplished 
through several methods. After periods of low usage of water, the system 
should be flushed. with a supply of water that has residual chlorine. 
Periodic hyperchlorination also is recommended. Effective microbial control 
can be maintained by storing water at 80C. However, this approach 
is expensive and presents some hazards to personnel and material. Ultraviolet 
radiation may be used. but it has limited application because of the 
many factors which can reduce its effectiveness. written instructions 
should be developed for sanitization procedures for water-treatment equipment 
on a regular, prescribed basis.

402 Connolly. Berstler. and Coffin-Beach 
E. Plant Pest Control 
The CGMP regulation 211. 56a states that 
Any building used in the manufacture, processing, packing, or 
holding of a drug product shall be maintained in a clean and sanitary 
condition. Any such building shall be free of infestation by 
rodents, birds, insects, and other vermin (other than laboratory 
animals). Trash and organic waste matter shall be held and disposed 
of in a timely and sanitary manner [6]. 
A pest-control program should be developed that will ensure the integrity 
and quality of products produced and comply with existing legislation. 
The program should be written to include a general statement of 
purpose and the company position. Effectiveness of the program should be 
assured by defining the plant individual with overall responsibility for the 
program and how the responsibility will be carried out. The training and 
experience requirements of the extermination staff should be delineated, 
whether they be in-house or SUbcontracted personnel. Assistance in supporting 
the program may be gained from other plant personnel by their 
pointing out problem areas. 
The program should be issued to Une management personnel and 
periodically updated in order to keep the program current. The program 
should contain a list of approved pesticides to be used in the plant. Individual 
sheets should be prepared for each specific item of use [5]. 
Basic information should be spelled out as follows: 
1. Trade name of the pesticide 
2. Classification 
3. Type of action 
4. Chemical name and concentration of active ingredient 
5. Effective for: 
6. To be used for: 
7. Area of usage 
8. Mode and frequency of application 
9. Toxicities and any specific toxic symptoms, if known 
10. Status of government approval 
11. Specific restrictions and cautions 
The development of sheets as indicated above will serve a twofold purpose. 
First, the sheets can be SUbjected to approval by the plant safety 
organization to determine if the materials comply with the Occupational 
Safety and Health Administration (OSHA) requirements and the requirements 
of other state or local agencies. Second, the sheets would also 
facilitate compliance with CGMP regulation 211. 56c, which states the 
following: 
There shall be written procedures for use of suitable rodenticides J 
insecticides, fungicides, fumigating agents. and cleaning and 
sanitizing agents. Such written procedures shall be designed to 
prevent the contamination of equipment, components, drug products 
containers, closures, packaging, labeling materials, or drug 
products and shall be followed. Rodenticides, insecticides, and

Tablet Production 
fungicides shall not be used unless registered and used in accordance 
with the Federal Insecticide, Fungicide, and Rodenticide Act 
(7 U.S.C. 135) [6]. 
403 
Written records of regularly scheduled inspections and preventive treatments 
should be maintained. Emergency or special service! should be documented 
specifying the type of problem encountered, the service rendered, 
effectiveness of the treatment, and any follow-up that might be required. 
The program should also specify when production interruptions might 
be necessary, either due to the presence of a specific pest or to avoid 
possible contamination during the treatment to exterminate a pest. 
All manufacturing areas should be constructed using nonporous materials 
on the walls and floors. Any protrusions such as pipes and electrical 
boxes should be minimized. Space should be allocated carefully to 
provide sufficient rooms for aU operations. There should be adequate 
lighting and the areas should be remote from any openings to the outside. 
Care should be taken that adequate training in understanding CGMPs be 
given to all personnel. Outside contractors must also be trained and understand 
CGMPs before embarking on any construction or remodeling efforts 
having to do with pharmaceutical manufacturing. 
VI. EQUIPMENT SELECTiON 
A. Granulation 
There are a multitude of equipment manufacturers, each with a specific advantage. 
But, more importantly, the initial formulations corning from the 
scale-up laboratory should be done in equipment that most closely mimics 
the final processing equipment that will be used in production. The success 
or failure of a manufacturing process depends on the time and effort 
put into the formulation design and equipment selection. 
Selection of equipment for dry blending. dry granulation, or wet 
granulation is a process that must start at the time the formulation is first 
conceptualized. There are numerous types and designs for each processing 
technique. 
Dry Blending 
The first choice for dry mixing is in tumble-type blenders, and here, as 
elsewhere in this section, an effort will be made to identify the more commonly 
used designs and some of the manufacturers of that equipment. 
This information is intended as a guide and is not proported to be a complete 
listing. Figure 17 shows some configurations of a double-cone blender, 
both straight and offset. 
Figure 18 illustrates both the conventional twin-shell or Vee blender, 
and the newer cross-flow or short-leg Vee blender. Double-cone and 
twin-cone blenders are supplied by Gemeo, J. H. Day Corp  and Patterson 
Kelly Co., among others. 
The important considerations to take into account when developing a 
formulation for these type mixers are deagglomeration of the raw materials 
prior to charging the blender, not exceeding the rated capacities which is 
approximately 60% of the total capacity. particle size uniformity, dry and 
humid conditions, reducing vibration. and avoiding over mixing.

404 Connolly, Berstler, and Coffin-Beach 
(a) (b) 
Figure 17 (a) Double-cone blender, (b) slant-cone blender. 
Ribbon blenders of the type shown in Figure 19 may also be used for 
dry blending. However, care must be exercised here when formulating 
tow-dosage products. Dead spots such as discharge ports must be cleared 
and the materials recycled. Samples must be taken from multiple locations 
when validating this process. Some ribbon blender suppliers are Marion 
Mixers, Ine; , J. H. Day Corp., Charles Ross & Son Co., and S. Howes 
Co., among others. 
(a) (b) 
Figure 18 (a) Vee blender, (b) short-leg vee blender.

Tablet Production 
Figure 19 Ribbon blender. 
405 
Dry Granulation 
Dry granulation is becoming more popular as equipment improvements continue 
to accelerate. Moisture-sensitive actives and some heat-sensitive 
actives can now be prepared as efficiently as less sensitive products. A 
combination of roll compaction and sizing coupled with improved cleanabllity 
of the equipment have encouraged formulators to look at this method more 
closely than in the past. 
Figure 20 shows a typical design for roll compaction. Again, equipment 
manufacturers have realized the importance of being able to precisely 
control feed rates, compaction force, and particle size, and have 
carefully addressed these parameters when scaling from lab equipment to 
production equipment. Some roll compaction equipment suppliers are 
Vector Corp., Fit zpatrick Corp., Alexanderwerke, and Bepex, among 
others. 
Wet Granulation 
The wet-granulation technique is benefiting from improved processing 
equipment. High-shear granulating equipment is being developed and improved 
upon. Equipment manufacturers are studying changeover times, 
clean up, end point measurement, ease of discharge. and many more points 
to improve quality and productivity. Granulator/dryer combinations are 
also becoming more available. Fluid-bed drying, microwave drying J and 
vacuum-drying equipment are rapidly replacing the traditional tray 
dryers. 
B. Compression 
Introduction of the high-speed, computer-controlled tablet press has had a 
profound impact on the industry. With capacities of over 800,000 doses/hr. 
presses no longer need to be dedicated to a single product. Many products 
may be manufactured on one machine to utilize excess capacity and to 
justify the high costs. Depending on the manufacturing strategies of a 
particular company, different criteria would be used to select their equipment. 
Large production rate capacities become important as the batch size

406 Connolly. Berstler, and Coffin-Beach 
Figure 20 Roll compactor. (Courtesy of Alexanderwerke.) 
increases and the number of different products decreases. Cleanability 
and change-over time become important as the batch size decreases and 
the number of products increases. Some manufacturers claim as little as 
4 h for a complete changeover to a different product. 
Theory of Computer-Controlled Presses 
If every particle and granule were the same size and shape. and if every 
die cavity were filled with exactly the same amount, and if every punch 
Were exactly the same, etc.. the compression force for each tablet produced 
would be identical from die cavity-to-die cavity, from revolution -torevolution, 
and from the beginning to the end of a batch. Unfortunately. 
the particle size distribution may vary slightly from die cavity-to-die 
cavity, from revolution-to-revolutton , and from the beginning to the end 
of a batch. Therein lies one of the sources of variation of weight and 
hardness from tablet-to-tablet.

Tablet Production 407 
Consider two identical die cavities, A and B. A is filled with small 
particles, whereas B is filled with larger particles. While both die cavities 
are filled, the weight of the powder in A is heavier than the weight of 
the powder in B. The compression force will be larger for A than for B 
as they pass under the same compression rollers. Obviously, the tablet 
resulting from A will be heavier than the tablet resulting from B. The 
compression forces can therefore be directly correlated to tablet weights. 
The basic assumption used by all computer controlling systems is that 
all significant variations in compression forces are resultant from the actial 
weight of the material being compressed, hence tablet weight. The 
target tablet weight can be correlated to a target compression force that is 
determined during the setup operation. This target compression force can 
then be used to control the compression operation. 
During the prestart operation, a target compression force will be determined. 
As the press begins production, it will warm up and its operating 
condition will change. As the punches warm, they will elongate 
slightly. As the electronic components warm. their signals may vary 
slightly. The sum of the press's varying operating conditions is a drift 
in the compression force/target weight correlation. 
Until recently, it was up t9 ~ the operator to verify that the target compression 
force correlated to the target tablet. If this was found not to be 
the case, an adjustment needed to be made before compression could continue. 
With the Introduction of tablet measurement/feedback systems. 
control is taken a step further and the loop is closed. Compression forces 
are periodically referenced to actual produced tablet measurements. All 
necessary adjustments, including weight and hardness adjustments, are 
then performed automatically and the compression force/tablet weight correlation 
is adjusted automatically as necessary. 
Instrumentation Strategies 
There are currently two basic strategies used by the many tablet manufacturers 
to computer-control their presses. The first is to set up the 
press to produce tablets with the desired weight. hardness, thickness, friability. 
etc. The next step is to convert the compression force signal to a 
reference value. This reference value corresponds to the target tablet, and 
is usually displayed as an average per revolution of each station's actual 
compression force. This reference value must be established at the start 
up for each batch and is then used to control the tablet weights. When 
the average force value drifts from the reference value and reaches an 
adjustment value, a signal is sent to the weight-control motor to adjust the 
filling depth appropriately. Some manufacturers provide for the duration 
of the weight-control signal to be set so that the adjustment brings the 
force value back to the reference value. Compression forces of individual 
stations are measured, and if their force values are within a set reject 
range, the tablet is accepted as a good tablet. If the force value is outside 
the reject range, the tablet is rejected as an out-of-spec tablet. 
The second strategy, which most tablet manufacturers are using or 
moving toward, is the use of internal calibrations so that actual compression 
forces are measured and displayed. The benefits include a simplfied 
computer setup and a standard/common base by which batches of the same 
product can be compared for compression characteristics and statistical 
analysis. The adjustment range settings and the reject range settings

408 Connolly. Berstler, and Coffin-Beach 
initiate the same responses as they do in the first strategy. The difference 
is that they are set and displayed as actual compression forces. 
Rejection Strategies 
The rejection mechanisms are also of two basic strategies. pneumatic reject 
and mechanical reject. The pneumatic reject relies on a timed burst 
of air to direct a bad tablet to a reject chute. The disadvantages with a 
dusty product are clogging of the jets and inducing airborne dust particles. 
Also, depending on the speed of the press, up to six or more 
tablets may be rejected for each bad tablet. The advantages are no 
moving parts and the timing is fixed and not varied owing to table speed 
changes. 
The mechanical reject is usually a gate or arm that swings out to divert 
the bad tablet to the reject chute. The timing is critical and must 
be set correctly. As the table speed changes, the timing may need to be 
changed. Also, tablets of different sizes and shapes will require different 
timings and gate settings. Abrasive dusts can interfere with proper rejection 
by causing sluggishness. On the other hand, mechanical mechanisms 
can be set to reject only one tablet, regardless of speed. 
Induced Die Feeder (IDF) Strategies 
Another distinguishing feature of high-speed machines is the induced die 
feeder (IDF). The IDF is basically a mechanism to ensure adequate and 
uniform filling of the die cavities as they pass the feeder at high speeds. 
It uses a combination of paddles which pushes or plows the powder over 
the dies. Virtually every combination of paddle placement and blade configuration 
is represented by some manufacturer. Different IDF configurations 
and speeds may induce different compression characteristics of the 
same material. Because the IDF agitates the powder, and its speed can 
be varied, some additional mixing may be considered to occur in the feeder 
for some formulations. This can sometimes become a source of problems 
rather than a solution. 
Power Delivery Systems 
Some manufacturers offer a powder feed controller which maintains a constant 
level of powder that feeds the IDF. The effects of the sudden increase 
of weight by adding a scoop full of powder to a hopper can be 
seen very clearly on computer monitoring/controlling devices that have 
graphical displays. These effects are eliminated by the powder feed controller, 
and help to create more uniform products by eliminating the 
powder level variable. 
Future Trends 
Most press manufacturers currently have on the market presses and controlling 
systems which provide a complete loop for controlling all of the 
tablet parameters. Tablet sampling and checking systems take a sample of 
tablets at specified intervals, automatically perform weight, hardness, and 
thickness measurements, perform statistical calculations, and feedback the 
appropriate signals to the press to adjust the weight and/or hardness. 
These signals include readjusting the target compression force and the

ol:lo. o
co 
~an~:fdcturer Elizabeth Kilian Kikusui Korsch Manesty Stokes 
Hata 
:-1odel AP-38-SC T300 Libra Pharmdpress e xov apr ss s -15 Stokes 454 
336 
Station :'-:0. 38 32 36 36 .,I5 .,I5 
Output/Hr: I 
i ~1ax (:,.1) 160 2-10 216 216 - 222 270 
I ~in(Yl) 34.6 9.6 21.6 71.3 5J 96 
:vrain Comp 9 80 kX 8 8 6.5 6 
Pre Comp 3.5 28 k~ 8 2 - 2 
Computerized: I ~lonitoring y Y y Y Y Y 
I 
Control by y y y y y y 
Porce 
Control by y Y Y y y :;: 
I weight 
Figure 21 General comparison of currently available tablet presses.

410 Connolly, Berstler, and Coffin-Beach 
window of limits. The target compression force is therefore being constantly 
verified against actual tablet parameters. 
Some manufacturers currently offer systems where all of a product's 
parameters are stored on a disk and the operator loads the information 
in a computer. The computer will tell the press where the initial settings 
are, produce some tablets for automatic testing. make any necessary adjustments 
until the tablets are at target, and then begin production. Figure 
21 is a general comparison of some of the tablet presses currently 
available and is not all inclusive. 
VII. PERSONNEL 
A. Training 
operators 
This group includes the mixmg and granulating operators and the compression 
operators. The training of the mixing and granulation operators 
should include the following: 
1. Cleaning procedures 
2. Familiarization with and ability to identify the codes and names of 
the raw materials being used in the product being mixed 
3. Proper label control and reconciliation 
4. Handling, usage, and operation of equipment in area 
5. Proper handling of raw materials in each operation 
6. Importance of precise mixing times and geometric dilutions 
7. Proper labeling and handling of mixed materials 
8. Quality assurance and validation procedures 
9. Training to observe and look for foreign matter in the raw 
materials 
10. Product reconciliation 
11. Ability to check mathematics required by the formula 
The training of the compression operators should include the following: 
1. Cleaning procedures 
2. Ability to identify and distinguish from quarantine and released 
materials 
3. Proper label control and reconciliation 
4. Handling, usage, and operation of equipment in the area 
5. Proper handling and hopper loading of mixed material 
6. Proper handling of bulk tablets produced 
7. Quality assurance and validation procedures 
8. Training to observe and look for foreign matter in the mixed material 
and bulk tablets 
9. Product reconciliation 
10. Ability to check mathematics required by the formula 
Mechanics 
Mechanics have specialized training in addition to the same training as the 
operators. During their setup operation, mechanics operate the machine

Tablet Production 411 
and, also during periods where there are no setups to be performed, they 
may be asked to operate a machine. The training of mechanics, in addition 
to operator training, should therefore include the following: 
1. Cleaning procedures for tooling and machinery 
2. Breakdown and setup of machinery 
3. Complete operation of the machines 
4. Proper handling of the tooling 
5. Theory behind computer-controlled tablet presses 
6. Setup and control of computerized units 
7. Maintenance and repair of machinery 
8. Troubleshooting of machinery 
Supervisors 
Supervisors need to have the necessary training and background to lead 
and direct their operators and mechanics. They must have an intimate 
knowledge and preferably some hands-on experience of the operators' and 
mechanics' jobs. In addition, supervisors must also possess the supervisory 
skills necessary to maintain the high standards demanded by the 
pharmaceutical industry. 
In addition to the job-specific responsibilities outlined above, all manufacturing 
employees must be versed and trained in CGMPs and in the appropriate 
standard operating procedures (SOPs) governing their area. 
VIII. ROLE OF MANUFACTURING 
A. Marketing Support 
Marketing is usually the only organizational link to the customer, and any 
feedback on the sales impact of quality and delivery COmes through as 
marketing requests. Also, the direction that applied R&D takes should be 
driven by the marketing function. Marketing should encourage the development 
of products that would generate the highest potential revenues 
with the greatest margin. Each product developed or produced should fit 
into an overall marketing plan. Without insight to the marketing plan, the 
R&D and Production Departments might question the wisdom of their directions, 
creating unnecessary, undesirable boundaries between departments. 
The importance of marking to an organization is obvious. However, 
the importance of accurate, timely information from marketing to various 
other departments cannot be stressed enough. The role of manufacturing, 
therefore, is to support the marketing function. Successful support might 
be defined by improving quality, reducing manufacturing lead times, lowering 
costs, and hastening manufacturing response to changing demands. 
The role of all other departments in the organization is to support, in one 
way or another, manufacturing [7]. 
B. The Production Plan 
A finished goods requirements plan should drive the master production 
schedule, which provides a detailed action plan from placing purchase 
orders to final packaging schedules.

412 Connolly. Beretler, and Coffin-Beach 
The master schedule is the operations statement for production and related 
activities. It is a positive commitment to perform certain activities 
within the required time span. In the packaging area, the master schedule 
states that the Packaging Department will package X amount of a put-up 
during week N on day Y. In order to fulfill this commitment, the Quality 
Control Department must release the bulk during week N-l. For quality 
control to meet its commitment, the Manufacturing Department must have 
the bulk produced in time for the former to perform its functions. In 
order for the Manufacturing Department to produce the product, approved 
materials must be available X number of weeks before the manufacturing is 
to be completed. the number of weeks being dependent on the manufacturing 
cycle time (including dispensing time). Having approved material 
available to manufacturing requires that quality control perform their 
analysis in the stated time span for quality control lead time. For this to 
happen the material must be received as sCheduled. The Purchasing Department 
must, therefore. place the order X weeks before the material is 
to be received, where X is the vendor lead time. Purchasing must also 
follow up with the blender to assure the material will be received on time. 
If the material is rejected, purchasing must issue a replacement order. In 
order for purchasing to issue the order on time, production planning must 
requisition the material at least 1 week before the order is to be placed. 
Given the large number of components and materials involved in pharmaceutical 
production operations, the task of manually performing the above 
"time-phasing" routine would be virtually impossible. This time phasing of 
the production, quality control, and purchasing processes is one of the 
functions performed by materials requirement planning (MRP). 
C. Material s Requ irement Plan 
Materials requirement planning starts with the master schedule. Using the 
bill of materials, lead time, capacities, and other product-related database 
information, together with information on inventory, open production orders, 
and open purchase orders, the materials requirement planning system will 
determine the quantity of materials and the date they are needed for each 
phase of the production process. The logic used in making the determination 
is basically the same as that described under the master SChedule. 
The master schedule states which put-ups are scheduled to be packaged 
during the weekly time periods. By applying the bills of material for the 
put-ups to the quantities to be packaged, the system can determine the 
quantities of packaging components and bulk that are needed. Working 
within the established lead times, the system will show a demand for the 
items in the correct time segment. In turn, the system will plan replacement 
orders to maintain specified levels of inventory. The planned order 
will be shown as being available in the time frame needed and will be 
placed "on order" by considering the purchasing, production, and quality 
control lead times. The procedure is carried out for each phase of production 
and the release of a planned order at one level generates requirements 
at the next level. For example, if finished products were assigned 
to 0 level code, items used to produce finished stock would be assigned a 
1, products used to produce bulk would be assigned a 2. and so on until 
the purchased materials are reached.

Tablet Production 413 
The MRP lends itself well to computerization and can perform other 
functions, such as alerting management to items with excessive inventory. 
It can suggest corrective actions (such as delaying or canceling open 
orders) and can predict inventory levels and investments for each time 
period in the planning horizon [2]. 
D. Production Scheduling 
All of the elements previously described could be categorized as planning 
elements. From the planning phase one must move into the execution 
phase, with the transition being supplied by the master schedule. 
The development of a production schedule is of prime importance because 
this is the basic means for monitoring production activities. Progress 
can be Checked and results reported based on the production or planning 
period. The production planning schedule forms a basis for decision 
making during the production cycle. Production scheduling is one of the 
most detailed and demanding tasks in the organization. 
Scheduling may be performed in an adequate manner either manually or 
mechanically, depending on the size and scope of the organization. Any 
scheduling system requires basic input data from the production plan consisting 
of What?, When?, and How many? Regardless of the circumstances, 
monitoring production activities with the production schedule becomes the 
key to successful fulfillment of the production plan. This is the method by 
which control is exercised over the production operation. A proper schedule 
can optimize production and inventory costs by proper sequencing of 
order quantities and time phasing. No matter how small the organization. 
the development of a sound production schedule is a tool which cannot be 
neglected. The production schedule is the cement which creates the 
foundation for an effective production organization that can meet sales 
demands. 
IX. INDUSTRY OUTLOOK 
The advances over the next decade in equipment, design, instrumentation. 
and process control techniques will certainly be significant. The nature 
of these advancements are difficult to predict. Certainly, computer-integrated 
manufacturing will come into its own in the pharmaceutical manufacturing 
industry as a whole and most assuredly in tablet production. 
Statistical process-control techniques will become widespread throughout 
the industry. Numerous data-collection devices and computer systems are 
currently available and in use as a means of implementing statistical process 
control. Computer-controlled tablet presses and automated material 
handling devices are available that virtually remove the operator from the 
need to control the operation. 
The general state of the industry is that there exists many islands of 
automation. The challenge for the future is to first integrate these 
islands with a computer network so that process data can be easily collected, 
and so that the inventory position and scheduling can be optimized 
on a real-time basis. The second challenge is that of validation of these 
systems to the complete satisfaction of the individual manufacturers and of 
the U.S. Food and Drug Administration.

414 Connolly, Berstler, and Coffin-Beach 
The authors stated in the introduction to this chapter that "our-s is an 
evolving technology-based science that requires canstant attention. II With 
this in mind, the professionals of our industry must stay abreast of current 
practices and recognize the emerging trends. Only in this way, will 
the industry continue to be profitable and provide an important service in 
an increasingly competitive world market. 
APPENDIX: LIST OF SUPPLIERS 
A C Compacting Presses 
North Brunswick, New Jersey 
Aeromatic, Inc. 
Towaco, New Jersey 
Alexanderwerke 
Remscheid, West Germany 
Bepex Corp. 
3 Crossroads of Commerce 
Rolling Meadows, illinois 
Charles Ross & Son Co. 
Hauppauge, New York 
Diosna 
Osnabruck, West Germany 
Elizabeth Hata Int., Inc. 
North Huntingdon, Pennsylvania 
Fitzpatrick Corp. 
Elmhurst, illinois 
Fluid Air, Inc. 
Napersville, illinois 
Gemco (The General Machine Co. 
of N.J.) 
Middlesex, New Jersey 
Glatt Air Techniques, Inc. 
Ramsey, New Jersey 
Glen Mills, Inc. 
Maywood, New Jersey 
Gral- Collette 
Northbrook, illinois 
H. C. Davis Sons Mfg. Co., Inc. 
Bonner Springs, Kansas 
Hollan d-McKinley 
Malvern, Pennsylvania 
Indupol Filtration Assoe , , Inc. 
Cresskill, New Jersey (Torit) 
Inppec , Inc. 
Milford, Connecticut (Kilian) 
J. H. Day Corp. 
Cincinnati, Ohio 
Jaygo, Inc. 
Mahwah, New Jersey 
Kemutec, Inc. 
Bristol, Pennsylvania 
Korsch Tableting, Inc. 
Somerset, New Jersey 
Lightnin Mixing Equipment Co. 
Rochester, New York 
Littleford Bros., Inc. 
Florence, Kentucky 
Mane sty , Thomas Engineering, Inc. 
Hoffman Estates, Illinois 
Marion Mixers, Inc. 
Marion, Iowa 
Micropul 
Summit, New Jersey 
Millipore Corp. 
Bedford, Massachusetts 
Mocon (Modern Controls, Inc.) 
Minneapolis, Minnesota

Tablet Production 
Natoli Engineering 
Chesterfield, Missouri 
Patterson-Kelly Co. 
East Stroudsburg, Pennsylvania 
Raymond Automation Co , , Inc. 
Norwalk, Connecticut 
S. Howes Co  Inc. 
Silver Creek, New York 
Scientific Instruments & 
Technology Corp. 
Piscataway. New Jersey 
Stokes-Merrill 
Warminster, Pennsylvania 
SUGGESTED READINGS 
Thomas Engineering. Inc. 
Hoffman Estates, Illinois 
United Chemical Machinery 
Supply, Inc. 
Toms River. New Jersey 
(Kikusui) 
Urschel Laboratories, Inc. 
Valparaiso, Indiana 
Vector Corp. 
Marion, Iowa 
415 
Alessi. P. Operational MRP vs , Integrated MRP, P 811M with APIC S 
News, June 1986. 
Anton, C. J. and Malmborg, C. J. The Integration of Inventory 
Modeling and MRP Processing: A Case Study. Production and 
Inventory Management, 2nd Quarter, 1985. 
Ballou, Ronald H. Estimating and auditing aggregate inventory 
levels at multiple stocking points. J. Operations Management 
1(3): 143-154 (Feb. 1981). 
Bryson, W. L. Profit-Oriented Inventory Management. APICS 
22nd Annual Conference Proceedings, 1979. pp , 88-91. 
The Competitive Status of the U. S. Pharmaceutical Industry. 
National Academy Press, Washington, D.C., 1983. 
Hadley, G. and Whitin, T. M. Analysis of Inventory Systems. 
Prentice-Hall, New York. 1963. 
Lotenschtein, S. Just-in-Time in the MRP II Environment, P &1M 
Review with APICS News, Feb. 1986. 
Mehta, N. How to Handle Safety Stock in an MRP System. Production 
and Inventory Management, 3rd Quarter. 1980. 
Ott, E. T. Process Quality Control. McGraw-Hill. New York, 
1975. 
REFERENCES 
1. Artiss , D. H. and Klink, A. E. Good Manufacturing Practices 
for Water: Methods of ManUfacturing, Testing Requirements 
and Intended Use. AIChE 70th Annual Meeting, New York, 
Nov. 1977. 
2. Berry, W. L., Whybark, D. C., and Vollmann, T. E. Manufacturing 
Planning and Control Systems. Irwin. Homewood, 
Illinois , 1984.

416 Connolly, Berstler, and Coffin-Beach 
3. Boucher. T. O. and Elsayed, E. A. Analysis and Control of Production 
Systems. Prentice-Hall, New York, 1985. 
4. Guideline on General Principles of Process Validation. U S. Food 
and Drug Administration, Washington. D.C., May 1984. 
5. Guidelines for Plant Pest Control Program. PMA. Washington, D.C., 
Jan. 1975. 
6. Hitchings. W. S.. IV, Tuckerman, M. M., and Willig, S. H. Good 
Manufacturing Practices for Pharmaceuticals. Marcel Dekker, Ine , , 
New York, 1982. 
7. Hutt , M. D. and Speh, T. W. Industrial Marketing Management. 
Dryden Press. Chicago. 198!. 
8. Peterson, R. and Silver, E. A. Decision Systems for Inventory 
Management and Production Planning. Wiley, New York, 1985. 
9. Pharmaceutical Process Validation. Marcel Dekker. New York, 1984. 
10. Tableting Specification Manual, IPT Standard Specifications for 
Tableting Tools. Academy of Pharmaceutical Sciences and American 
Pharmaceutical Association, 1981. 
11. The Theory and Practice of Industrial Pharmacy. Lea & Febiger, 
Philadelphia, 1976.

7
The Essentials of 
Process Validation 
Robert A. Nash 
St. John's University, Jamaica, New York 
I. INTRODUCTION 
The U. S. Food and Drug Administration (FDA) in its most recently proposed 
guidelines has offered the following definition for process validation 
[1] :
Process validation is a documented program which provides a high 
degree of assurance that a specific process (such as the manufacture 
of pharmaceutical solid dosage forms) will consistently produce 
a product meeting its predetermined specifications and quality 
attributes. 
According to the FDA. assurance of product quality is derived from 
careful (and systemic) attention to a number of (important) factors, including: 
selection of quality (components) and materials. adequate product 
and process design. and (statistical) control of the process through 
in-process and end-product testing. 
Thus it is through careful design and validation of both the process 
and its control systems that a high degree of confidence can be established 
that all individual manufactured units of a given batch or succession 
of batches that meet specification will be acceptable. 
According to FDA's Current Good Manufacturing Practices (21CFR 
211.110) 
Control procedures shall be established to monitor output and to 
validate performance of the manufacturing processes that may be 
responsible for causing variability in the characteristics of inprocess 
material and the drug product. Such control procedures 
417

418 
shall include, but are not limited to the following, where appropriate 
[2J: 
1. Tablet or capsule weight variation 
2. Disintegration time 
3. Adequacy of mixing to assure uniformity and homogeneity 
4. Dissolution time and rate 
5. Clarity, completeness, or pH of solutions 
Nash 
The first four items listed above are directly related to the manufacture 
and validation of solid dosage forms. Items 1 and 3 are normally associated 
with variability in the manufacturing process, while items 2 and 4 are 
usually influenced by the selection of the ingredients in the product formulation. 
With respect to content uniformity and unit potency control (item 3) 
adequacy of mixing to assure uniformity and homogeneity is considered to 
be a high-priority concern. 
Conventional quality control procedures for finished product testing 
encompass three basic steps: 
1. Establishment of specifications and performance characteristics 
2. Selection of appropriate methodology, equipment, and instrumentation 
to ensure that testing of the product meets specification 
3. Testing of the final drug product, using validated analytical and 
test methods in order to insure that finished product meets 
specifications. 
With the emergence of the pharmaceutical process validation concept, the 
following four additional steps have been added 
4. Qualification and validation of the processing facility and its 
equipment 
5. Qualification and validation of the manufactUring process through 
appropriate means 
6. Auditing, monitoring, sampling, or challenging the key steps in 
the process for conformance to specifications 
7. Requalification and revalidation when there is a significant change 
in either the product or its manufacturing process [3J 
II. TOTAL APPROACH TO PHARMACEUTICAL 
PROCESS VALIDATION 
It has been said that there is no specific basis for requiring a separate 
set of process validation guidelines since the essentials of process validation 
are embodied within the purpose and scope of the present Current 
Good Manufacturing Practices (CGMPs) regulations [21. With this in mind. 
the entire CGMP document. from subpart B through subpart M. may be 
viewed as being a set of principles applicable to the overall process of 
manufacturing, i.e., solid dosage forms or other drug products and thus 
may be subjected, SUbpart by subpart, to the application of the principles 
of qualification, validation, control, as well as requalification and revalidation. 
where appropriate. Although not a specific requirement of current

The Essentials of Process Validation 419 
regulations. such as comprehensive validation approach with respect to 
each subpart of the CGMP document has been adopted by many drug 
firms. 
A checklist of validation and control documentation with respect to 
CGMPs is provided in Table 1. With the exception of subpart M (sterilization), 
the rest of the CGMPs are directly applicable to the manufacture of 
solid dosage forms. 
Table 1 Checklist of Validation and Control Documentation 
Subpart 
A
B
C
D
E
F
G
H
I
J
K
L 
Section of CGMP 
Introduction 
Organization and 
personnel 
Buildings and 
facilities 
Equipment 
Control of raw materials, 
in-process 
material, product 
Production and 
process controls 
Packaging and 
labeling controls 
Holding and distribution 
Laboratory controls 
Records and reports 
Returned and salvaged 
drug product 
Air and water 
quality 
Validation and control 
documentation 
Establishment of QA & PV functions 
Establishment and facility installation 
and qualification [4.5) 
Plant and facility installation and 
qualification (4,5) 
Maintenance and sanitation [6] 
Microbial and pest control [7) 
Installation and qualification cleaning 
methods [8] 
Incoming components (9] 
Manufacturing non-sterile products 
[10] 
Process control systems [l1J 
(instrumentation and computers) 
Depyrogenation, sterile packaging, 
filling, and closing [12.13] 
Facilities [14] 
Analytical methods [15] 
Computer systems [16J 
Batch reprocessing [17] 
Water treatment and steam systems 
air, heat, and vacuum handling 
[18 - 20]

420 
Table 1 
Subpart 
M 
(Continued) 
Section of CaMP 
Sterilization 
Validation and control 
documentation 
LVPs [21,22] 
Autoclaves and process 
Parametrics [23 - 25] 
Aseptic facilities r26J 
Devices [27] 
Sterilizing filters [28,29] 
Nash 
Table 2 Process Validation Matrix or Checklist of Activities to be 
Considered 
Personnel 
(manpower) 
(people systems) 
Parts 
(components. inprocess. 
finished 

product) 
Process 
(machines) 
(buildings, facilities. 
equipment. support 
systems) 
Procedures 
(methods) 
(manufacturing and 
control. documentation. 
records)

The Essentials of Process Validation 421 
The CGMPs may also be viewed as consisting of the following four essential 
elements: 
1. Personnel. The people system and manpower required to carry 
out the various tasks within the manufacturing and control 
functions. 
2. Parts. The raw materials and components used in connection with 
the manufacture and packaging of the drug product as well as the 
materials used in association with its control. 
3. Process. The buildings. facilities. equipment. instrumentation. 
and support systems (heat. air. vacuum. water, and lighting) used 
in connection with the manufacturing process and its control. 
4. Procedure. The paperwork, documentation, and records used in 
connection with the manufacturing process and its control. 
Thus the four elements of CaMPs listed above may be combined with 
the four elements of pharmaceutical process validation (Le . qualification, 
validation. control, and revalidation) to form a 4 x 4 matrix with respect 
to all the activities that may be considered in connection with the manufacture 
and control of each drug product. An example of such a process 
validation matrix provides a simple checklist of activities to be considered 
in connection with the general principles of process validation (Table 2). 
III. ORGANIZING FOR VALIDATION 
The mission of quality assurance in most pharmaceutical companies today 
has grown in importance with the advent of process validation. The 
process validation concept, which started as a subject noun (validation) in 
Table 3 Specific Responsibilities of Each Organizational Structure within 
the Scope of Process Validation 
Engineering 
Development 
Manufacturing 
Quality 
assurance 
Source: Ref. 31. 
Install, qualify , and certify plant. facilities. equipment 
, and support systems. 
Design, optimize, and qualify manufacturing process 
within design limits, specifications, and /or req uirements. 
In other words, the establishment of process 
capability information. 
Operate and maintain plant, facilities I equipment, support 
system s , and the specific manufacturing process 
within its design limits, specifications, and/or requirements. 
Establish approvable validation protocols and conduct 
process validation by monitoring. sampling, testing. 
challenging. and/or auditing the specific manufacturing 
process for compliance with design limits, specifications, 
and lor requirements.

Table 4 Validation Progress Gantt Chart 
Qualification stage Validation stage 
II:>. 
1>.:1 
1>.:1 
Key elements Design stage Installation Operational Prospective Concurrent 
(Batch records and 
validation documentation) 
Scale-up phase - 
(process optimization 
and pilot production) 
Facilities and equipment 
Process and product 
Engineering phase .. Manufacturing 
~(Validation 
/Pro'ocolSl 
Developmental phase --(
formula definition 
and stability testing) 
start-up 
QA and manufactUring phase 
(full production) 
--- _ .. --_.._----- . 
Time line for new product introduction 
~
Qrn 
;::r

The Essentials of Process Validation 423 
the late 1970s, has been turned into an action verb (to validate) by the 
quality assuance function of many drug companies. Quality Assurance was 
initially organized as a logical response to the need to assure that CGMPs 
were being complied with. Therefore, it is not surprising that process 
validation became the vehicle through which quality assurance now carries 
out its commitment to CGMPs [301. 
The specifics of how a dedicated group, team, or committee is organized 
in order to conduct process validation assignments is beyond the 
scope of this chapter. It is clear, however, that the following responsibilities 
must be carried out and that the organizational structures best 
equipped to handle each assignment is presented in Table 3. 
The concept of divided validation responsibilities can be used for the 
purpose of constructing a validation progress time chart (Table 4). Such 
a chart is capable of examining the logical sequence of key events or milestones 
(both parallel and series) that take place during the time course of 
new product introduction and is similar to a Gantt chart constructed by 
Chapman [32J. 
In Table 4, facilities and equipment are the responsibility of Engineering 
and Manufacturing, while process and product are the responsibility of 
the product and process development function(s). The engineering and 
development functions in conjunction with quality assurance come together 
to prepare the validation protocols during the qualification stage of product 
and process development. 
IV. PROCESS VALIDATION -ORDER 
OF pRIORITY 
Because of resource limitation, it is not always possible to validate an entire 
company's product line at once. With the obvious exception that a 
company's most profitable products should be given a higher priority, it is 
advisable to draw up a list of product categories that are to be validated. 
The following order of importance or priority with respect to validation 
is suggested to the reader: 
Sterile Products and Their Processes 
1. Large-volume parenterals (L VPs) 
2. Small-volume parenterals (SVPs) 
3. Ophthalmics and other sterile products 
Nonsteriie Products and Their Processes 
4. Low-dose/high-potency tablets and capsules 
5. Drugs with stability problems 
6. Other tablets and capsules 
7. Oral liquids and topicals 
V. PILOT-SCALE-UP AND PROCESS VALIDATION 
The following operations are normally carried out by the development function 
prior to the preparation of the first pilot-production batch. The development 
activities are listed as follows:

424 Nash 
1. Formulation design I selection, and optimization 
2. Preparation of the first pilot-laboratory batch 
3. Conduct initial accelerated stability testing 
4. If the formulation is deemed stable I preparation of additional 
pilot-laboratory batches of the drug product for expanded nonclinical 
and/or clinical use 
The pilot program is defined as the scale-up operations conducted subsequent 
to the product and its process leaving the development laboratory 
and prior to its acceptance by the full-production manufacturing unit. 
For the pilot program to be successful, elements of process validation 
(i.e., product and process qualification studies) must be included and completed 
during the developmental or pilot-laboratory phase of the work. 
Thus product and process scale- up should proceed in graduated steps 
with elements of process validation (such as qualification) incorporated at 
each stage of the piloting program [33J. 
1. Laboratory Batch. The first step in the scale-up process is the 
selection of a suitable preliminary formula for more critical study and testing 
based upon certain agreed-upon initial design criteria, requirements 
and lor specifications. The work is performed in the development laboratory. 
The formula selected is designated as the (lX) laboratory batch. 
The size of the (1X) laboratory batch is usually 3 - 5 kg of a solid or semisolid, 
3 - 5 liters of a liquid or 3000 to 5000 units of a tablet or capsule. 
2. Laboratory -Pilot Batch. After the OX) laboratory batch is determined 
to be both physically and chemically stable based upon accelerated. 
elevated temperature testing (1. e.. 1 month at 45C or 3 months at 
38C or 38C/80% RH). the next step in the scale-up process is the preparation 
of the (lOX) laboratory -pilot batch. The (lOX) laboratory -pilot 
batch represents the first replicated scale-up of the designated formula. 
The size of the laboratory -pilot batch is usually 30 - 50 kg. 30 - 50 liters 
or 30,000 to 50.000 units. 
It is usually prepared in small-size. pilot equipment within a designated 
CGMP approved area of the development laboratory. The number 
and actual size of the laboratory -pilot batches may vary in response to 
one or more of the following factors: 
a. Equipment availability 
b. Active drug substance availability 
c. Cost of raw materials 
d. Inventory requirements for clinical and nonclinical studies 
Process qualification or process capability studies are usually started in 
this important second stage of the pilot program. Such qualification or 
capability studies consist of process ranging, process characterization, 
and process optimization as a prerequisite to the more formal validation 
program that follows later in the piloting sequence. 
3. Pilot Production. The pilot-production phase may be carried out 
either as a shared responsibility between the development laboratories and 
its appropriate manufacturing counterpart -or as a process demonstration 
by a separate, designated pilot-plant or process-development function. 
The two organizational piloting options are presented separately in Figure 
1. The creation of a separate pilot-plant or process-development unit

The Essentials of Process Validation 425 
PRODUCTION PILOT 
PLANT _I~I- DEVELOPMENT 
LABORATORY 
JOINT PILOT OPERATION 
Pilot Batch 
PRODUCTION DEVELOPMENT 
LABORATORY 
~ Reque.t ';1 
" Pilot Batch /' --------Completion 
Report 
Figure 1 Main piloting options. (top) Separate pilot plant functionsengineering 
concept. (bottom) Joint pilot operation. 
has been favored in recent years for it is ideally suited to carry out 
process qualification and/or validation assignments in a timely manner. 
On the other hand, the joint pilot-operation option provides direct communication 
between the development laboratory and pharmaceutical production.
The objective of the pilot-production batch is to scale the product and 
process by another order of magnitude OOOx) to, for example, 300-500 
kg, 300-500 liters, or 300,000-500,000 dosage-form units (tablets or 
capsules) in size. For most drug products this represents a full production 
batch in standard production equipment. If required, pharmaceutical 
production is capable of scaling the product and process to even larger 
batch sizes should the product require expanded production output. If 
the batch size changes significantly (say to 500x or 1000 x) additional 
validation studies would be required. 
Usually large production batch scale-up is undertaken only after product 
introduction. Again, the actual size of the pilot-production (lOOx) 
batch may vary due to equipment and raw material availability. The need 
for additional pilot-production batches ultimately depends upon the successful 
completion of a first pilot batch and its process validation program. 
Usually three successfully completed pilot-production batches are 
required for validation purposes. 
In summary, process capability studies start in the development laboratories 
and/or during product and process development continue in welldefined 
stages until the process is validated in the pilot plant and/or 
pharmaceutical production. 
An approximate timetable for new product development and its pilot 
scale-up program is suggested in Table 5.

426 Nash 
Table 5 Approximate Timetable for New Product Development and Pilot 
Scale-Up Trials 
Event 
Formula selection and development 
Assay methods development and formula optimization 
Stability in standard packaging 3-month read-out (Ix size) 
Pilot-laboratory batches (lOx size) 
Preparation and release of clinical supplies (lOx size) and 
establishment of process qualification 
Additional stability testing in approved packaging 
6 -8-month read-out (1x size) 
3-month read-out (lOx size) 
Validation protocols and pilot batch request 
Pilot-production batches (lOOx size) 
Additional stability testing in approved packaging 
9 -12-month read-out (Ix size) 
6 -8-month read-out (lOx size) 
3-month read-out (lOOx size) 
Interim approved technical product manual with approximately 
12-months stability (Ix size) 
Totals 
VI. PROCESS CAPABILITY DESIGN 
AND TESTING 
Calendar 
months 
2-4 
2-4 
3-4 
1-3 
1-4 
3-4 
1-3 
1-3 
3-4 
1-3 
18-36 
Process validation trials are never designed to fail. Process validation 
failures> however, are often attributable to an incomplete picture of the 
manufacturing process being evaluated. Upon closer examination of the 
problem, often failures appear to be directly related to an incomplete 
understanding of the process's capability or that the process qualification 
trials were not properly defined for the job to be done. 
Process capability is defined as studies that are carried out to determine 
the critical process parameters or operating variables that influence 
process output and the range of numerical data for each of the critical 
process parameters that result in acceptable process output. 
Thus. the objectives of process capability design and testing may be 
listed as follows: 
1. To determine the number and relative importance of the critical 
parameters in a process that affect the quality of process output 
2. To show that the numerical data generated for each critical 
parameter are within at least statistical quality control limits (i , e. ,

The Essentials of Process Validation 
3 standard deviations and that there is no drift or assignable 
cause of variation in the process data 
427 
If the capability of a process is properly delineated, the process should 
consistently stay within the defined limits of its critical process parameters 
and product characteristics [34J. 
Process qualification, on the other hand, represents the actual studies 
or trials conducted to show that all systems, subsystems, or unit operations 
of a manufacturing process perform as intended. Furthermore, that 
all critical process parameters operate within their assigned control limits 
and that such studies and trials, which form the basis of process capability 
design and testing, are verifiable and certifiable through appropriate 
documentation. Process qualffleation is often referred to as Operational 
or Performance Qualification. 
The manufacturing process is briefly defined as the ways and means 
used to convert raw materials into a finished product. The ways and 
means also include: people, equipment, facilities, and support systems 
that are required in order to operate the process in a planned and an 
effectively managed way. Therefore, let us assume that all people, equipment, 
facilities, and support system s that are required to run the process 
qualification trials have been themselves qualified and validated beforehand. 
The steps and the sequence of events required in order to perform 
process capability design and testing are outlined in Table 6. 
Using the basic process for the manufacture of a simple tablet dosage 
form, we will attempt here to highlight some of the important elements of 
the process capability and qualification sequence. 
1. Basic information is obtained from the (Ix) size laboratory 
batch. 
a. Quantitative formula is scaled to (lOx) size batch and rationale for 
inert ingredient selection provided. 
b. Critical specifications, test methods, and acceptance criteria for 
each raw material used in the formula are provided. 
c. List of proposed specifications, test methods, and acceptance criteria 
for the finished dosage form are provided. 
d. Interim stability report on (Lx) size laboratory batch is provided. 
e. Detailed operating instructions for preparing the (lOX) size batch 
are provided. 
2. Preparation of a simple flow diagram of the process should be provided. 
A good flow diagram should show all the unit operations in a 
logical sequence, the major pieces of equipment to be used, and the 
stages or operations at which the various ingredients are added. The 
flow diagram, shown in Figure 2, outlines the sequence of unit operations 
used to prepare a typical tablet dosage form by the wet granulation 
method. In Figure 3, the enclosed large rectangular modules represent 
the various unit operations in the manufacturing process. The arrows 
represent transfers of material into and out of each unit operation. Each 
large rectangular module or box indicates the particular unit operation, 
the major piece of processing equipment employed, and the facility in 
which the operation takes place. The sequential arrangement of unit

428 Nash 
Table 6 Protocol for Process Capability Design and Testing 
Objective of piloting 
program 
Types of process 
Typical processes 
Definition of process 
Definition of process 
output 
Definition of test 
methods 
Analysis of process 
Review and analysis of 
data 
Pilot batch trials 
Pilot batch replication 
Need for process capability 
redefinition 
Process capability of 
evaluated process 
Final report and 
recommendations 
Process capability design and testing 
Batch. intermittent. continuous 
Chemical, pharmaceutical, filling, and packaging 
Flow diagram. equipment/materials in-process, 
finished product 
Potency. yield, physical parameters 
Methods, equipment. calibration traceability, 
precision, accuracy 
Definition of process variables, influence 
matrix, fractional factorial analysis 
Data plot (x -y plots, histogram, control 
chart) time sequence, sources of variation 
Define stable/extended runs, define sample 
and testing, remove sources of variation 
Different shifts and days, different materials , 
different facilities and equipment 
Data analysis, modification of influence matrix. 
reclassification of variables 
Stability and variability of process output, conformance 
to defined specifications, economic 
limits of process 
Recommended SOP, limits on process adjustments. 
recommended specifications 
operations should be analogous to the major sequential steps in the operating 
instructions of the manufacturing process. 
3. Using the flow chart (Fig. 2) as a guide , a list of process or control 
variables are next drawn up for each unit operation or step in the 
process. A test parameter or response to be objectively measured is then 
assigned to each process variable. The control parameters (Le  process 
variables plus their test parameters) for the manufacture of compressed 
tablets by the wet granulation method are shown in Table 7. According to 
the data presented in Table 7. there are six unit operations or processing 
steps, with from two to five process variables for each unit operation and, 
with the exception of tablet compression (finished tablet analysis), one 
key test parameter for each of the processing steps. Please note that the 
first unit operation, I, e . the weighing of active and inert ingredients, 
was eliminated from Table 7. Weighing operations are a general consideration 
in all manufacturing processes. Balances and measuring devices are 
normally qualified and validated separately on a routine basis as required 
by CGMP's guidelines.

WEIGH ACTIVE &: FILLERS 
Drums RmS 
U 
PREBLEND POWDERS 
Vertical MIxer Rm 10 
~ 
GRANULATE BLEND tI. 
t.:l 
'"

438 Nash 
3. The overall design does not balance to zero because there is a 
constant +2 for each process variable. Since there are, this is due to the 
fact that in our design eight -13s in trial No. 1 and eight +15s in trial 
No. 8 were created. 
The advantage of the fractional factorial experimental design is that. 
using No. 8 qualifleation trial, eight important process variables were 
tested at both their lower and upper control limits. In addition. three 
processing steps [dry milling. lubricant addition (blending). and tablet 
compression] were all shown to be critical with respect to a measured response, 
namely tablet hardness. Since tablet hardness also influences 
tablet dissolution, this second outcome was also indirectly evaluated by the 
experimental design chosen. 
Using a larger fractional factorial experimental design, 12 or even 16 
process variables could be tested by expanding the qualification trials to 
say 12 or 16 pilot runs. But in practice, eight pilot-laboratory batches 
is most likely the maximum number that is reasonable to produce for this 
purpose. Those unit operations that were found. by fractional factorial 
experimental design, to be critical with respect to process capability design 
and testing (size reduction, blending. and tablet compression) could 
then be subjected to more extensive investigation during the laboratory 
stage of product and/or process development. 
C. Optimization Techniques 
Optimization techniques are used to find either the best possible quantitative 
formula for a product or the best possible set of experimental conditions 
(input values) that are needed to run the process. Optimization 
techniques may be employed in the laboratory state to develop the most 
stable, least sensitive formula. or in the qualification and Validation stages 
of scale-up in order to develop the most stable. least variable process 
within its proven acceptable range(s) of operation, Chapman's so-called 
PAR principle [39] 
Optimization techniques may be classified as Parametric Statistical 
Methods and Nonparametric Search Methods. 
Parametric Statistical Methods 
Parametric Statistical Methods, usually employed for optimization, are 
full-factorial designs [40]. half-factorial designs [41]. simplex design [42]. 
and Lagrangian multiple-regression analysis [43]. Parametric methods are 
best suited for formula optimization in the early stages of product development. 
The application of constraint analysis. which was described previously. 
is used to simplify the testing protocol and the analysis of experimental 
results. 
The steps involved in the parametric optimization procedure for pharmaceutical 
systems have been fully described by Schwartz [44]. The 
optimization technique consists of the following' essential operations: 
1. Selection of a suitable experimental design 
2. Selection of variables (independent Xs and dependent Ys) to be 
tested

The Essentials of Process Validation 439 
Table 13 Results of a Three-Components Simplex Design for Tablet 
Hardness 
Transformed Average 
Excipient components proportions tablet 
hardness 
Run no. Xl X2 X3 Xl X2 X
3 
(SCU) 
I 55 10 10 1 0 0 6.1 
2 10 55 10 0 1 0 7.5 
3 10 10 55 0 0 1 5.3 
4 32.5 32.5 10 0.5 0.5 0 6.6 
5 32.5 10 32.5 0.5 0 0.5 6.4 
6 10 32.5 32.5 0 0.5 0.5 6.9 
7 25 25 25 0.33 0.33 0.25 7.3 
8 32.5 21.25 21. 25 0.5 0.25 0.25 7.2 
3. Performance of a set of statistically designed experiments (I.e., 
23 or 32 factorials) 
4. Measurement of responses (dependent variables) 
5. Development of a predictor, polynomial equation based upon statistical 
and regression analysis of the generated experimental data 
6. Development of a set of optimized requirements for the formula 
based upon mathematical and graphical analysis of the data generated 
According to Bolton, one of the most useful methods of defining optimal 
regions of formulation characteristics is based upon the application 
of simplex matrix design [45]. For example, formulations may be constructed, 
using constraint analysis. so that the total amount of excipients 
(Xs) to be added to the powder mix is never more than 75 mg of a total 
tablet weight of 300 mg. A brief outline of the simplex technique, used in 
connection with this example is shown in Table 13. 
In the transformations shown in Table 13, the highest excipient concentration. 
55 mg, is assigned a value of one and the lowest excipient 
concentration, 10 mg, equals 0 is assigned a value of zero. Coefficients 
for X10 X2. and X3 in the following polynomial equation are the hardness 
values from run Nos. 1, 2, and 3. Simple equations for calculating coefficients 
for the following terms: xr X2. Xl X3, X2 X3. and Xl X2 X3 
are given in the reference [45]. 
where

440 
Example (run no. 8): 
Nash 
y =6.1 (0.5) + 7.5 (0.25) + 5.3 (0.25) - 0.8 (0.125) + 2.8 (0.125) 
+ 2 (O~0625) + 15 (0.03125) 
Y =3.05 + 1.875 + 1.325 - 0.1 + 0.35 + 0.125 + 0.47 =7.1 
The best tablet hardness (7.4 value SCU) containing all three excipients 
is obtained at Xl =0.25, X2 = 0.5. and X3 = 0.25. where Xl = 18.75 mg. 
X2 =37.5 mg. and X3 = 18.75 mg. 
Nonparametric Search Methods 
Nonparametric Search Methods are relatively simple techniques used to finetune 
or optimize a process by varying the critical process parameters that 
were found during the qUalification and validation stages of process development. 
The procedure is so constrained that no process variable is 
ever permitted to exceed its lower or upper control limit. In searching a 
given process. it is assumed that there is optimum peak (set of experimental 
conditions or inputs) where the process operates most efficiently. 
There are two basic search methods that are used for this purpose. The 
first method is called evolutionary operation (EVOP) and a second method 
is called random evolutionary operation (REVOP). The difference between 
the two methods, EVOP and REVOP. is not objectivity but simplicity of the 
experimental design chosen. 
Process Improvement Through EVOP 
The process variables whose perturbation or slight change might lead to 
improvement in process performance are usually identified during the qualification 
trials where the operational and control limits for the process 
have been developed. Next. initial perturbation steps away from the present 
operational inputs are selected for each of the critical process variables. 
These steps must be sufficiently small so that no input goes beyond the 
control limits of the process and no output goes out of product and process 
specification. In the traditional box EVOP design [46] a simple two-factor. 
two-level design is created about the present condition or input values (see 
Fig. 4). 
Analysis of the data presented in Figure 4 shows that the path of 
steepest ascent to improve tablet hardness is in the direction of run No. 1 
to run No.4, which is a change of +3 seu in tablet hardness. A second 
two-factor, two-level box is constructed about run No.4 where one corner 
of the box is the original condition, run No.1. Following the same procedure, 
a series of from 8 to 24 runs, using the path of steepest ascent, 
is usually required to ascertain the optimum input values for tablet hardness 
and rapid tablet dissolution. 
By using a simplex EVOP design [47] where connecting triangles are 
created from 2 additional experimental conditions, it is possible to complete 
the optimization search in fewer trial runs than Box EVOP (see 
Fig. 5). 
Process Improvement Through REVOP 
Random evolutionary operation (REVOP) is a comparatively little-used 
method for process and product optimization [48 J The technique.

The Essentials of Process Validation 441 
~ 3000 .... 
ai 
El 2500 G2
0~
r:: 2000 
0 -; 
1ft i 1500 
0c 
6 9 13 15 18 21 
Blend Time (min.) Xs 
Figure 4 Optimization by box Evolutionary Operation. Tablet hardness 
(SeU shown in parenthesis). Optimum conditions (2000 lbs and 6 min). 
developed by F. E. Satterthwaite, employs a random direction of movement 
under constraint analysis to discover a probable pathway of ascent 
to peak process performance. If the linear direction chosen is not promising. 
the direction is reversed and the opposite pathway is chosen in an 
effort to improve performance. Movement continues along the new path in 
direction previously established, as long as the results are positive. 
Movement will then proceed at right angles when progress ceases on the 
previously chosen pathway. Peak performance is almost always achieved 
in less than 20 trials runs (see Fig. 6). 
In summary, process capability studies and qualification trials should 
be underaken during the first stage of pilot scale-up, i.e . with the preparation 
of the pilot-laboratory batch (lOx) size). The objective of such 
~ 3000 -~
2500 G~
~
~ 2000 
1e 1500 rc 
0 3 6 9 13 15 18 21 
Blend Time (min.) x, 
Figure 5 Optimization by simplex evolutionary operation. Tablet hardness 
(SeU) shown in parenthesis.

442 Nash 
.< 3000 ~(20) out of specs --.. ~(18J ~(l5) @ 
2500 ~
~ 
(10) ~ ~ 
2000 -P. 
Q) 
~ 
2 
198J~   50"C 
1.96 
1.94 
 192 
lii ... 
C 1.90 
CD u
c: 8'88 
Cl 
.3 1.86 
184 
182 
180 
178 
3 6 9 12 
TIme 10Months 
Figure 2 Percent of alkaloid remaining' as a function of time for a first -order reaction. 
::r:: 
~
;:s 
;:s 
~

Stab ility Kinetics 
Table 1 Percent of Alkaloida in Tablet Formulation 
Time (months) 
Temperature 
(OC) 3 6 9 12 
50 98.92 97.83 96.70 95.72 
60 96.16 92.47 88.92 85.51 
70 88.41 98.16 69.10 61. 09 
aInitial 100%. 
463 
As log Co is a constant I then a plot of log (drug concentration) against 
time will produce a straight line whose slope is equal to -K /2.303. 
The constant, K. is the reaction velocity constant or specific reaction 
rate, which expresses the fraction of material that reacts in a given unit 
of time expressed in reciprocal seconds, minutes, or hours. For example, 
let K = 0.01 h -1; then the rate at which the drug is de grading is 1%h -1. 
The half-life equation is 
t =0.693 
1/2 K 
and the shelf-life equation is 
t = 0.105 
90 K 
Example: A first-order rate of hydrolysis degradation of an alkaloid at 
1 mg per tablet manufactured by aqueous wet granulation technique is 
shown in Table 1, which. if graphically plotted I should give a straight 
line as shown in Figure 2. 
C. Pseudo-First-Order Reaction 
(8) 
(9) 
When the reaction rate depends on the concentration of two reactants or a 
bimolecular reaction that is made to act like a first -order reaction. then it 
is called pseudo-first -order reaction. for example, when one reactant is 
present in greater quantity than the other or when the first is kept at a 
constant concentration in relation to the second. Under these circumstances, 
one reactant appears to control the rate of reaction even though 
two reactants are present because the concentration of the second reactant 
does not change significantly during the degradation. An example 
of such a reaction is the degradation of sodium hypochlorite tablets in 
aqueous solution, which is highly pH dependent and follows a pseudo-firstorder 
reaction because the hydroxyl ion concentration is high compared to 
the concentration of the carboxylic ion.

464 Hanna 
VI. KINETIC STUDIES 
Solid-dosage forms that are tablets and capsules constitute a large majority 
of pharmaceutical products. However. few kinetic studies and studies on 
rates of drug degradation in solid state have been published. Drug solid 
degradation in absence of excipients and moisture generally follows a 
nucleation chemical reaction rate which may approximate a first-order reaction 
rate. In the presence of moisture and excipients, the reaction rate 
could be either zero-. first-. or pseudo-first-order. It should be noted 
that there is little difference in degradation rates estimated by the zeroor 
first-order reactions when less than 15% degradation has occurred. 
When the amount of degradation found is in excess of 15% the order of the 
reaction which accounts for the degradation should be established. 
Stability study at room temperature is the surest method of determining 
the actual shelf life of a product. Unfortunately, it is difficult to make an 
accurate expiration date prediction until 2 or 3 years of data are generated, 
a situation which can be further complicated by the frequent need 
for tablet formulation changes that would require additional long shelf-life 
study at actual shelf-life conditions. 
The principles of chemical kinetics for the evaluation of drug stability 
are based on the fact that reaction rates are expected to be proportional to 
the number of collisions per unit time. Since this number increases with 
the increase of temperature, it is necessary to evaluate the temperature dependency 
of the reaction. Experimentally, the reaction rate constant is observed 
to have an exponential dependence on temperature as expressed by 
the Arrhenius equation: 
or 
K ::: A (-Ha/RT) (10) 
or 
log K =log A 
lIH 
2.303RT (11) 
K1 Ha (1 1 ) 
log K2 = 2. 303R T 2 - T1 (12) 
where K = specific rate of degradation 
-1 -1 
R = gas constant (1.987 cal deg mol ) 
A =frequency factor (constant) 
T ::: absolute temperature (tOe + 273.16e) 
Ha = activation energy of the chemical reaction 
A plot of log K against lIT will produce a straight line whose slope is 
equal to -lIHa/R (2.303), and is known as an Arrhenius plot (Fig-. 3). 
The reSUlting line obtained at higher temperatures is extrapolated to obtain

Stab ility Kinetics 
4.0 
3.0 
1.0 
465 
o 30
50 
335 35 
II
lIT X 103 
II
25 o 
4.0 
Figure 3 Arrhenius plot of log K against reciprocal of absolute temperature. 
room temperatures and K 25 is generally used to obtain a measure of the 
stability of the drug under ordinary shelf conditions at room temperature; 
however, any other desired temperature can be equally obtained. 
From Figure 3, log K25 is 2 and K25 will be 100 months or 8.3 years 
under shelf conditions at room temperature (25C) if the original points at 
60, 70, and 80C in the Arrhenius plot were calculated from monthly stability 
points. Activation energy can also be calculated from an Arrhenius 
plot by using the slope of the line which is equivalent to -Ha/2.303R. 
From Figure 3, the slope of the line is - 3. 5 x 103. Then 
3 Ha 
-3.5 x 10 = 2.303 x 1.987

466 
and 
Ha =(-3.5 x 103)(2.303)(1.987) 
= 16.0 kcal/mOI- 1 
Hanna 
Arrhenius projection enables predictions to be made that are based on 
accelerated data in such a way that any change in the relationship between 
the degradation at different temperatures will be detected and estimated. 
For example, using equation 10 for the prediction of a tablet product expiration 
date at shelf storage (25C) from accelerated stability study at 
40C and activation energy of 10 keal Zmol ; 
K =A(-Ha/RT1) 
40 
and 
K = A (-Ha/RT2) 
25 
then
K 40 A (-Ha/RT1) 
K
25 
:: A(-Ha/RT 2) 
-1 
Assuming that Ha = 10 kcal/mol ,then T1 = 273.15 + 40 = 313.15 and 
T 2 
= 273.15+ 25= 298.15. 
K
40 
A-10,000/1,987(313.15) 
K 
25 
= A- 10, OOO/ 1. 98 7( 298 . 15) 
=2.24465 
Shelf stability at 25C = 12 x 2.245 = 26.94 months. Tablet product 
with 10 kcal/mol- 1 activation energy of the chemical reaction and stable at 
40C for 12 months will have an expiration date at shelf life (25C) of 
27 months. 
When reactant molecules, e. g., A + B, in a tablet formulation proceeds 
to products, e. g., C + D, the energy of the system must change higher 
than that of the initial reactant and is defined as the activation energy 
(Ha) (Fig. 4). 
The usual range for activation energies for tablet formulation decomposition 
is about 10-20 kcal/mor 1, except if diffusion or photolysis is rate 
determining. Then the rate is about 2 to 3 kcal Zmolr L, which rarely occurs 
in tablet degradation. For reactions in which the heat activation energies 
range is more than 50 kcal Zmolr l , the rate of degradation is not of any 
practical significance at the temperature of shelf-life storage of tablet 
formulations. For tablets with activation energy values higher than

Stability Kinetics 
30 
20 
~
"0 
E <, 
(;j 
0 
~ H..=10 K cal/mol 
>. r Cl 
~ I Q) 
c: 
w t 10 
A+B 
Reactants - Products 
A+B -C+D 
Extent of Reaction 
Figure q Activation energy. 
C+D 
467 
20 kCal/mol- 1, the error in shelf-life prediction will be on the conservative 
side. For example, using equation 10, for a tablet product with 20 kcall 
mol- 1 activation energy and stable at 40C for 3 months: 
K 40 A(-Ha/RT1) 
K25 =A(-Ha/RT2) 
A- 20,000/1. 987(313.15) 
= ~~~~~......,..,,....,..,,~---:-::-:- 
A- 20.00011. 987( 298.15) 
A-32.14250 
=~--:-::"--- 
A-33.75960 
= 5.03847

468 Hanna 
Shelf stability at 25C =3 x 5.03847 =15 months. For this tablet 
product we will predict an expiration date of 15 months at shelf-life storage. 
If in reality the activation energy of the chemical reaction of these tablet 
product was on the higher side, that is, 25 kcal/mol- 1 instead of the previously 
assumed 20 kcal/mol- l, then using equation 10 
K40 A- 25,OOO/I.987(313.15) 
K 25 = A- 25,OOO/1.097(298.15) 
= 7.54867 
and the predicted shelf stability at 25C will be 3 x 7.54867 = 22.5 months. 
which indicates that our original prediction of 15 months expiration date was 
on the conservative side. On the other hand. if the real activation energy of 
the chemical reaction was on the lower side, that is. 15 kcal/mor- 1 rather 
than the originally assumed 20 kcal Imol- 1 then by using equation 10 
K40 A-15.000/1. 987(313.15) 
--= 
K 25 A-15.000/1. 987(298.15) 
=3.36296 
and the predicted shelf stability at 25C will be 3 x 3.36296 =10 months. 
which indicates that our original prediction of 15 months expiration date was 
a risky prediction. 
To USe the Arrhenius equation. three stability storage temperatures 
are obviously the minimum as the more additional temperatures are used the 
more the accuracy of extrapolation is enhanced. 
Table 2 gives an example of the application of the Arrhenius equation 
to predict the stability of tablet product Z, Lot No. XI containing active 
ingredient A. 
1. Determine the potency of active A in the tablet product at appropriate 
intervals of time when held at three temperatures. 50. 60, and 70C. 
as shown in Table 2. make two plots to determine if the degradation reaction 
is zero- or first-order. 
2. First. plot potency (y) against time (t) in weeks for the three temperatures 
on normal graph paper, as shown in Figure 5. Then plot log 
potency (log y) against time (t) in weeks for the three temperatures on 
semilogarithmic graph paper as shown in Figure 6.

Stability Kinetics 469 
110 
100 
90 
80 
70 
<:( 60 
~ 
ti 
<:( 
~ 50 
~ 
8!. 
40 
30 
20 
10
o 5 10 15 2030 40 50 60 
Weeks (I) 
90 120 
Figure 5 Zero-order plot for Active A Tablet Z Lot No. X. 
3. Draw a straight line of best fit through the five points in both 
graphs. Select the plot in which the line most closely fits the determined 
points, including the original potency determined at zero time. which should 
agree with the potency estimated by extending the degradation lines back 
to zero time. In this example, these two conditions are met by the first 
plot figure (y versus t or a zero-order reaction). 
4. Determine for each of the three temperatures the slope of the 
degradation rates (KO) in units of y (in case of first-order reaction Kl 
in units of log y) by selecting two points lying on the line to determine 
the slopes for each of the three temperatures. as shown in Table 3. The 
slope of a line is defined as change in y divided by the change in x, 
5. Plot the log values of KO on semilogarithmic graph paper against 
the reciprocal of absolute temperature as shown in Figure 7.

470 
Table 3 KO Values for Active 
A in Tablets Z Lot No. X 
Temperature 
(OC) KO 
50 -0.53 
60 -2.5 
70 -4.28 
Hanna 
6. Draw a straight line of best fit through the three points and extrapolate 
it to the lower temperatures. 
7. Estimate the rate of degradation at the desired temperature. If 
this is 25C, then the KO from the graph is 0.33. 
8. Calculate the expiration data (tx) from equation 13. 
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Stability Kinetics 491 
25 45" 37 
0.1.._ ...._ ..._ ... .._ ...__.. 
90 SO' 70 60 
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Fiqure 11 Accelerated stability plot. 
value versus liT are above 75 kcal , but one or more is below 17 kcal or a 
minimum of t90 was achieved after at least 52 weeks at 30C, then the label 
storage condition of store at controlled room temperature is used. If t90 
value versus liT is lower than 25 kcaI and above 45 kcal , or a minimum of 
t90 was achieved after at least 4 weeks at 40C and 1 week at 50C. then 
the label storage condition of store below 30C is used. Other label storage 
conditions. like protect from freezing or protect from light, should be used 
as necessary. 
G. Stability During Shipment 
Appropriate labeling conditions derived from suitable stability studies must 
be described to assure proper protection of tablet products during shipment. 
Periods of time that a tablet product may be exposed to extreme 
high or low temperature should be determined and appropriate label recommendations 
are used accordingly. e. g . may be adversely affected by exposure 
to 50C more than 3 weeks.

492 Hanna 
XIII. COMPUTER APPLICATION 
Computer programs are an efficient means of assisting in the design of stability 
studies, especially complex models, and the interpretation of data. 
A typical computer program can provide an efficient control of sample 
storage at given conditions, control inventory. schedule test intervals t 
sample at schedule inter-vals , test requirements and analytical procedure 
for each sample, determine manpower required for sample testing, review 
data, evaluate statistical data, highlight out-of-limits results, maximize research 
and development capabilities, interpret data, plot results, estimate 
shelf life, prepare reports for regulatory submission or commitments and 
product stability trend analysis. Implementation of computer use in stability 
programs will allow efficient statistical evaluation of the kinetic data, 
handling of complex administrative functions t organization of voluminous 
amounts of data, and reduce the potential for human errors. Several stability 
computer programs are commercially available from pharmaceutical as 
well as specialized computer companies. Example for such computer forms 
and stability reports are presented in Figures 12 and 13. Stability data 
listed in these two figures are filled according to the instructions per the 
coding letter mentioned beneath each requirement as follows: 
a = Computer transaction code 
b = Product list number 
c =Product lot number 
d = Assay type: chemical or biological, etc. 
e =Assay name 
f =Date of assay as per the stability protocol 
g = Time of the stability point 
h = Number of assay code as per the written stability-indicating assay 
monograph 
i = Number of monograph code as per the written stability-indicating 
assay monograph 
j = %RH 
k =Temperature in c 
I =Other atability conditions, e. g ., light 
m = Date assay was performed 
n =Chemist or technician name/or initial who performed the assay 
o =Number of tests performed 
p =All results of assay performed 
q =Average assay results 
r =Previous assay results reported 
s = Units the assay is to be run by, e. g., average tablet weight 
(ATW) 
t =Number of samples analyzed 
u = Total time for stability study as per the stability protocol 
v = Product release limit 
w = In-house or action limit 
y = Name of supervisor who check
ed and approved the analysis 
z =Date of supervisor approval

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