Larry l augsburger, stephen w hoag pharmaceutical dosage forms tablets, third edition three volume set pharmaceutical dosage forms tablets, third edition volume 2 rational design and formulation

Pharmaceutical Science

Pharmaceutical Dosage Forms: Tablets, Volume Two examines:
s formulation examples for stability, facilitating, and manufacturability
s systematic approaches to design formulation and optimization of dosage forms
s immediate release and modified release tablets
about the editors...
LARRY L. AUGSBURGER is Professor Emeritus, University of Maryland School of Pharmacy,
Baltimore, and a member of the Scientific Advisory Committee, International Pharmaceutical
Excipients Council of the Americas (IPEC). Dr. Augsburger received his Ph.D. in Pharmaceutical
Science from the University of Maryland, Baltimore. The focus of his research covers the design
and optimization of immediate release and extended release oral solid dosage forms, the
instrumentation of automatic capsule filling machines, tablet presses and other pharmaceutical
processing equipment, and the product quality and performance of nutraceuticals (dietary
supplements). Dr. Augsburger has also published over 115 papers and three books, including
Pharmaceutical Excipients Towards the 21st Century published by Informa Healthcare.
STEPHEN W. HOAG is Associate Professor, School of Pharmacy, University of Maryland, Baltimore.
Dr. Hoag received his Ph.D. in Pharmaceutical Science from the University of Minnesota,
Minneapolis. The focus of his research covers Tablet Formulation and Material, Characterization,
Process Analytical Technology (PAT), Near Infrared (NIR) Analysis of Solid Oral Dosage Forms,
Controlled Release Polymer Characterization, Powder Flow, Thermal Analysis of Polymers, Mass
Transfer and Controlled Release Gels. Dr. Hoag has also published over 40 papers, has licensed
four patents, and has written more than five books, including Aqueous Polymeric Coatings for
Pharmaceutical Dosage Forms, Third Edition and Excipient Development for Pharmaceutical,
Biotechnology, and Drug Delivery Systems, both published by Informa Healthcare.
Printed in the United States of America

$+

PHARMACEUTICAL DOSAGE FORMS: TABLETS

New to the Third Edition:
s developments in formulation science and technology
s changes in product regulation
s streamlined manufacturing processes for greater efficiency and productivity

Third Edition

The ultimate goal of drug product development is to design a system that maximizes the
therapeutic potential of the drug substance and facilitates its access to patients. Pharmaceutical
Dosage Forms: Tablets, Third Edition is a comprehensive treatment of the design, formulation,
manufacture, and evaluation of the tablet dosage form. With over 700 illustrations, it guides
pharmaceutical scientists and engineers through difficult and technical procedures in a simple
easy-to-follow format.

Volume 2: Rational Design and Formulation

about the book…

PHARMACEUTICAL
DOSAGE FORMS: TABLETS
Third Edition
Volume 2:

Rational Design
and Formulation

Augsburger r
■
Hoag

Edited by

Larry L. Augsburger
Stephen W. Hoag


Pharmaceutical
Dosage Forms: TABLETS



Pharmaceutical
Dosage Forms: TABLETS
Third Edition
Volume 2:

Rational Design and Formulation

Edited by

Larry L. Augsburger

University of Maryland
Baltimore, Maryland, USA

Stephen W. Hoag

University of Maryland
Baltimore, Maryland, USA

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Pharmaceutical dosage forms. Tablets. – 3rd ed. /
edited by Larry L. Augsburger, Stephen W. Hoag.
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Includes bibliographical references and index.
ISBN-13: 978-0-8493-9014-2 (v. 1 : hardcover : alk. paper)
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1. Tablets (Medicine) 2. Drugs–Dosage forms. I. Augsburger, Larry L. II. Hoag, Stephen W. III.
Title: Tablets.
[DNLM: 1. Tablets–pharmacology. 2. Drug Compounding. 3. Drug Design. 4. Drug
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To my loving wife Jeannie,
the light and laughter in my life.
—Larry L. Augsburger

To my dear wife Cathy and my children Elena
and Nina and those who helped me
so much with my education:
My parents Jo Hoag and my late father
Jim Hoag, Don Hoag, and Edward G. Rippie.
—Stephen W. Hoag



Foreword

We are delighted to have the privilege of continuing the tradition begun by Herb
Lieberman and Leon Lachman, and later joined by Joseph Schwartz, of providing the
only comprehensive treatment of the design, formulation, manufacture and evaluation of
the tablet dosage form in Pharmaceutical Dosage Forms: Tablets. Today the tablet
continues to be the dosage form of choice. Solid dosage forms constitute about twothirds of all dosage forms, and about half of these are tablets.
Philosophically, we regard the tablet as a drug delivery system. Like any delivery
system, the tablet is more than just a practical way to administer drugs to patients.
Rather, we view the tablet as a system that is designed to meet specific criteria. The most
important design criterion of the tablet is how effectively it gets the drug “delivered” to
the site of action in an active form in sufficient quantity and at the correct rate to meet the

therapeutic objectives (i.e., immediate release or some form of extended or otherwise
modified release). However, the tablet must also meet a number of other design criteria
essential to getting the drug to society and the patient. These include physical and
chemical stability (to assure potency, safety, and consistent drug delivery performance
over the use-life of the product), the ability to be economically mass produced in a
manner that assures the proper amount of drug in each dosage unit and batch produced
(to reduce costs and provide reliable dosing), and, to the extent possible, patient
acceptability (i.e., reasonable size and shape, taste, color, etc. to encourage patient
compliance with the prescribed dosing regimen). Thus, the ultimate goal of drug product
development is to design a system that maximizes the therapeutic potential of the drug
substance and facilitates its access to patients. The fact that the tablet can be uniquely
designed to meet these criteria accounts for its prevalence as the most popular oral solid
dosage form.
Although the majority of tablets are made by compression, intended to be
swallowed whole and designed for immediate release, there are many other tablet forms.
These include, for example, chewable, orally disintegrating, sublingual, effervescent, and
buccal tablets, as well as lozenges or troches. Effervescent tablets are intended to be
taken after first dropping them in water. Some modified release tablets may be designed
to delay release until the tablet has passed the pyloric sphincter (i.e., enteric). Others may
be designed to provide consistent extended or sustained release over an extended period
of time, or for pulsed release, colonic delivery, or to provide a unique release profile for a
specific drug and its therapeutic objective.
Since the last edition of Pharmaceutical Dosage Forms: Tablets in 1990, there have
been numerous developments and enhancements in tablet formulation science and
technology, as well as product regulation. Science and technology developments include
new or updated equipment for manufacture, new excipients, greater understanding of
excipient functionality, nanotechnology, innovations in the design of modified release
v

vi

Foreword

tablets, the use of artificial intelligence in formulation and process development, new
initiatives in real time and on-line process control, and increased use of modeling to
understand and optimize formulation and process parameters. New regulatory initiatives
include the Food and Drug Administration’s SUPAC (scale up and post approval
changes) guidances, its risk-based Pharmaceutical cGMPs for the 21st Century plan, and
its PAT (process analytical technology) guidance. Also significant is the development,
through the International Conference on Harmonization of proposals, for an international
plan for a harmonized quality control system.
Significantly, the development of new regulatory policy and new science and
technology are not mutually exclusive. Rather, they are inextricably linked. The new
regulatory initiatives serve as a stimulus to academia and industry to put formulation
design, development, and manufacture on a more scientific basis which, in turn, makes
possible science-based policies that can provide substantial regulatory relief and greater
flexibility for manufacturers to update and streamline processes for higher efficiency and
productivity. The first SUPAC guidance was issued in 1995 for immediate release oral
solid dosage forms (SUPAC-IR). That guidance was followed in 1997 with SUPAC-MR
which covered scale-up and post approval changes for solid oral modified release dosage
forms. These guidances brought much needed consistency to how the Food and Drug
Administration deals with post approval changes and provided substantial regulatory
relief from unnecessary testing and filing requirements. Major underpinnings of these
two regulatory policies were research programs conducted at the University of Maryland
under a collaborative agreement with the Food and Drug Administration which identified
and linked critical formulation and process variables to bioavailability outcomes in
human subjects. The Food and Drug Administration’s Pharmaceutical cGMPs for the
21st Century plan seeks to merge science-based management with an integrated quality
systems approach and to “create a robust link between process parameters, specifications

and clinical performance”1 The new PAT guidance proposes the use of modern process
analyzers or process analytical chemistry tools to achieve real-time control and quality
assurance during manufacturing.2 The Food and Drug Administration’s draft guidance
on Q8 Pharmaceutical Development3 addresses the suggested contents of the pharmaceutical development section of a regulatory submission in the ICH M4 Common
Technical Document format.
A common thread running through these newer regulatory initiatives is the building
in of product quality and the development of meaningful product specifications based on
a high level of understanding of how formulation and process factors impact product
performance.
Still other developments since 1990 are the advent of the internet as a research and
resource tool and a decline in academic study and teaching in solid dosage forms.
Together, these developments have led to a situation where there is a vast amount of
formulation information widely scattered throughout the literature which is unknown and
difficult for researchers new to the tableting field to organize and use. Therefore, another
objective to this book to integrate a critical, comprehensive summary of this formulation
information with the latest developments in this field.
Thus, the overarching goal of the third edition of Pharmaceutical Dosage Forms:
Tablets is to provide an in-depth treatment of the science and technology of tableting that
1

J. Woodcock, “Quality by Design: A Way Forward,” September 17, 2003.

2

/>
3

/>

Foreword

vii

acknowledges its traditional, historical database but focuses on modern scientific,
technological, and regulatory developments. The common theme of this new edition is
DESIGN. That is, tablets are delivery systems that are engineered to meet specific design
criteria and that product quality must be built in and is also by design.
No effort of this magnitude and scope could have been accomplished without the
commitment of a large number of distinguished experts. We are extremely grateful for
their hard work, dedication and patience in helping us complete this new edition.
Larry L. Augsburger
Stephen W. Hoag



Preface

The ultimate goal of drug product development is to design a system that maximizes the
therapeutic potential of the drug substance and facilitates its access to patients. Volume 2
addresses this goal with a series of chapters that are replete with practical illustrations and
formulation examples.
A tablet may be viewed as a delivery system that must be designed to meet four
specific criteria: first the drug must be “delivered” to the site of action in an active form
in sufficient quantity and at the correct rate to meet the therapeutic objectives, second, the
product must be physically and chemically stable to assure potency, safety, and consistent
drug delivery performance over the use-life of the product, third, the tablet must be
capable of being economically mass-produced in a manner that assures reliable dosing,
and fourth, to the extent possible, the product must be patient acceptable. Accomplishing
these tasks can be a substantial challenge. Formulation scientists are often confronted
with a broad array of formulation and process variables that can interact in complex ways.

The chapters on preformulation testing, drug product stability, and unit processes
presented in Volume 1 provide an essential background for the rational development of
dosage forms.
Volume 2 begins with a discussion of mass transport from solid dosage forms and
discusses many of the implications of formulation and process variables on bioavailability. Since one of the major challenges in modern oral solid dosage form development
is poor drug solubility, Chapter 2 discusses at length strategies for addressing this
problem in tablet formulations.
The days of the “trial-and-error” approach to formulation development are over, as
pharmaceutical scientists adopt systematic approaches for the design, formulation and
optimization of dosage forms. Such systematic approaches are discussed in Chapters 3
and 4, which address experimental design and the use of artificial intelligence. An
understanding of biopharmaceutic principles, coupled with such powerful softwaredriven optimization and decision-making tools, can give pharmaceutical scientists the
ability to make logical and deliberate formulation design decisions.
In the ensuing chapters, where the formulation of tablets is addressed, attention is
focused in large part on excipients which are generally included in tablet formulations to
cause the desired drug delivery performance, provide product stability, facilitate
manufacturability, and contribute to aesthetics. Chapters 5–8 provide a comprehensive
discussion of excipient functionality, selection, and proper use in conventional immediate
release tablet formulations. That discussion is extended in Chapters 9–13 to include such
specialized formulations as orally disintegrating tablets, lozenges, vitamin and mineral
tablets, veterinary tablets, botanical tablets, and others.
The next part of the book examines the design of oral modified release formulations. The major focus in the design and optimization of modified release formulations
ix


x

Preface

is the development of systems that exhibit well-defined controlled release delivery.

Chapters 14–16 address the formulation of matrix and osmotic systems. Chapter 17
addresses the technology of tableting of multiparticulate modified release systems. Each
release mechanism provides a different set of variables to consider: “critical” variables
that affect drug release, and “non-critical” variables that have little or no effect on drug
release rate, but are important to the delivery system in other respects.
Larry L. Augsburger
Stephen W. Hoag


Contents

Dedication iii
Foreword v
Preface ix
Contributors xiii

1. Mass Transfer from Solid Oral Dosage Forms
J. A. Wesselingh and H.W. Frijlink

1

2. Approaches for Improving Bioavailability of Poorly Soluble Drugs 51
Navnit H. Shah, Wantanee Phuapradit, Yu-E Zhang, Harpreet Sandhu, Lin Zhang,
and A. Wassen Malick
3. Aims and Objectives and of Experimental Design and Optimization in
Formulation and Process Development 105
Fridrun Podczeck
4. Knowledge-based Systems and Other AI Applications for Tableting
Yun Peng and Larry L. Augsburger

137

5. Direct Compression and the Role of Filler-binders 173
Brian A. C. Carlin
6. Disintegrants in Tableting
R. Christian Moreton

217

7. Lubricants, Glidants and Antiadherents
N. Anthony Armstrong

251

8. Surfactants and Colors in Tablets 269
Paul W. S. Heng and Celine V. Liew
9. Orally Disintegrating Tablets and Related Tablet Formulations
Huijeong Ashley Hahm and Larry L. Augsburger

293

10. Formulation Challenges: Multiple Vitamin and Mineral Dosage Forms
Joy A. Joseph
11. Botanicals and Their Formulation into Oral Solid Dosage Forms
Susan H. Kopelman, Ping Jin and Larry L. Augsburger
12. Formulation of Specialty Tablets for Slow Oral Dissolution
Loyd V. Allen, Jr.

313

333

361

xi


xii

Contents

13. Formulation and Design of Veterinary Tablets 383
Raafat Fahmy, Douglas Danielson, and Marilyn Martinez
14. Swellable and Rigid Matrices: Controlled Release Matrices with Cellulose
Ethers 433
Paolo Colombo, Patrizia Santi, Ju¨rgen Siepmann, Gaia Colombo,
Fabio Sonvico, Alessandra Rossi, and Orazio Luca Strusi
15. Carrageenans in Solid Dosage Form Design
Katharina M. Picker-Freyer

469

16. Osmotic Systems 493
Nipun Davar, Brian Barclay and Suneel Gupta
17. Tableting of Multiparticulate Modified Release Systems
Juan J. Torrado and Larry L. Augsburger
Index

533

509


Contributors

Loyd V. Allen, Jr.
Oklahoma, U.S.A.

University of Oklahoma College of Pharmacy, Oklahoma City,

N. Anthony Armstrong Formerly at the Welsh School of Pharmacy, Cardiff
University, Cardiff, U.K.
Larry L. Augsburger
Maryland, U.S.A.
Brian Barclay

School of Pharmacy, University of Maryland, Baltimore,

ALZA Corporation, Mountain View, California, U.S.A.

Brian A. C. Carlin
New Jersey, U.S.A.

Pharmaceutical R & D, FMC BioPolymer, Princeton,

Gaia Colombo
Ferrara, Italy

Dipartimento di Scienze Farmaceutiche, Universita` di Ferrara,

Paolo Colombo
Parma, Italy

Dipartimento Farmaceutico, Universita` degli Studi di Parma,

Douglas Danielson
Nipun Davar

Perrigo Pharmaceutical Company, Allegan, Michigan, U.S.A.

Transcept Pharmaceuticals, Inc., Point Richmond, California, U.S.A.

Raafat Fahmy Center for Veterinary Medicine, Office of New Drug Evaluation,
Food and Drug Administration, Rockville, Maryland, U.S.A.
H. W. Frijlink Department of Pharmaceutical Technology and Biopharmacy,
University of Groningen, Groningen, The Netherlands
Suneel Gupta

ALZA Corporation, Mountain View, California, U.S.A.

Huijeong Ashley Hahm Office of Generic Drugs, U.S. Food and Drug Administration,
Rockville. Maryland, U.S.A.
Paul W. S. Heng Department of Pharmacy, Faculty of Science, National University
of Singapore, Singapore
Ping Jin

U.S. Pharmacopeia, Rockville, Maryland, U.S.A.

Joy A. Joseph

Joys Quality Management Systems, Los Angeles, California, U.S.A.

Susan H. Kopelman

Shire Pharmaceuticals, Inc., Wayne, Pennsylvania, U.S.A.

Celine V. Liew Department of Pharmacy, Faculty of Science, National University of
Singapore, Singapore
xiii


xiv

Contributors

A. Wassen Malick Pharmaceutical and Analytical Resarch and Development,
Hoffman-La Roche, Nutley, New Jersey, U.S.A.
Marilyn Martinez Center for Veterinary Medicine, Office of New Drug Evaluation,
Food and Drug Administration, Rockville, Maryland, U.S.A.
R. Christian Moreton
Yun Peng

FinnBrit Consulting, Waltham, Massachusetts, U.S.A.

School of Pharmacy, University of Maryland, Baltimore, Maryland, U.S.A.

Wantanee Phuapradit Pharmaceutical and Analytical Research and Development,
Hoffman-LaRoche, Nutley, New Jersey, U.S.A.
Katharina M. Picker-Freyer Department of Pharmaceutical Technology and
Biopharmacy, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg,

Halle (Saale), Germany
Fridrun Podczeck Department of Mechanical Engineering, University College
London, Torrington Place, London, U.K.
Dipartimento Farmaceutico, Universita` degli Studi di Parma,

Alessandra Rossi
Parma, Italy

Harpreet Sandhu Pharmaceutical and Analytical Research and Development,
Hoffman-LaRoche, Nutley, New Jersey, U.S.A.
Patrizia Santi
Parma, Italy

Dipartimento Farmaceutico, Universita` degli Studi di Parma,

Navnit H. Shah Pharmaceutical and Analytical Research and Development, HoffmanLaRoche, Nutley, New Jersey, U.S.A.
College of Pharmacy, University of Lille, Lille, France

Jurgen Siepmann
Fabio Sonvico
Parma, Italy

Dipartimento Farmaceutico, Universita` degli Studi di Parma,

Orazio Luca Strusi
Parma, Italy
Juan J. Torrado
Madrid, Spain

Dipartimento Farmaceutico, Universita` degli Studi di Parma,

School of Pharmacy, University Complutense of Madrid,

J. A. Wesselingh Department of Chemical Engineering, University of Groningen,
Groningen, The Netherlands
Lin Zhang Pharmaceutical and Analytical Research and Development, HoffmanLaRoche, Nutley,New Jersey, U.S.A.
Yu-E Zhang Pharmaceutical and Analytical Research and Development, HoffmanLaRoche, Nutley, New Jersey, U.S.A.


1

Mass Transfer from Solid Oral
Dosage Forms
J. A. Wesselingh
Department of Chemical Engineering, University of Groningen, Groningen,
The Netherlands

H. W. Frijlink
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen,
Groningen, The Netherlands

INTRODUCTION
This chapter will show how dosage forms release their content and how you can influence
where and how quickly the drug is released.
For a patient, the use of a tablet or capsule is a simple act of mass transfer:
unpacking and following the instructions, which usually implies swallowing the tablet or
capsule. However, there is a lot of technology behind this as you will see in our first
example.

Example 1: Using NexiumÒ 20

Figure 1 shows a photograph of some tablets and also a magnification of their cross
section. The tablets have the trade name NexiumÒ 20; they are produced by AstraZeneca
(London, U.K). The instructions tell that they contain a “proton pump inhibitor”: a drug
that reduces the secretion of protons (acid) by the parietal cells in the wall of the stomach.
The tablet is said to contain coated granules containing the drug esomeprazol. The
coating is to protect the granules against acid in the stomach.
The tablet is to be swallowed with water—and not to be chewed. If you have
problems in swallowing the tablet, then you can first let it disintegrate into granules in a
glass of water before swallowing. The usual dosage is one tablet per day, which is to be
taken in at the same time every day. A tablet is said to contain 20 mg of the drug.
However, each tablet has a mass of 410 mg. What does the rest of the tablet consist of?
The instructions contain a list of ingredients which we have grouped according to their
purpose in Table 1.
When you are reading the following paragraphs, keep the following questions in mind:
1.
2.

Where is the drug released in the body?
What are the reasons for the instructions?
1


2

Wesselingh and Frijlink

FIGURE 1 Nexium 20 tablets.

3.
4.

What is the purpose of the different groups of ingredients?
Could you make a sketch of the construction of the tablets?
We discuss these points at the end of this section.

Drug in the Body
Most drugs are administered in the form of tablets or capsules that are taken orally
(“swallowed”) (1). The amount of drug is in the range of micrograms to several hundred
milligrams. The aim is to get the drug in the right place in the body, with a concentration
that is neither too high nor low, so within a “therapeutic window”. Sometimes a more or
less constant drug level is required; in other cases a short burst of drug is better. What
happens largely depends on what the body does with the drug (a subject known as
“pharmacokinetics”).
Orally taken drugs can enter the body in several places:
n
n
n

via the membranes of the mouth (“buccal” or “sublingual” administration);
via the membranes of the stomach;
via the membranes of the intestines.

TABLE 1 Ingredients in Nexium Tablets
Ingredients (grouped)
Esomeprazol
Sucrose/starch granules
Microcrystalline cellulose
Hydroxypropylcellulose, hypromellose,
Methacrylic acid/ethylacrylate copolymer, polysorbate 80
Synthetic paraffin, triethyl citrate, macrogol 6000

Polysorbate 80
Iron oxide (E172), titanium dioxide (E171)
Crospovidone
Glycerol monostearate, magnesium stearate, sodium stearyl fumarate
Talc


Mass Transfer from Solid Oral Dosage Forms

3

For many drugs the first part of the small intestines, the “duodenum”, is the site of
absorption. The time a drug stays in the throat is too small to allow for much uptake. The wall
of the stomach is not very permeable, so this route is not used by many drugs. In the large
intestine (the “colon”) much of the water content of food has already been absorbed in the
body, and the remaining luminal content is too viscous to allow much transport into the body.
Where, when, and how quickly the drug is absorbed not only depends on the drug
properties, but also on how the user applies it. Whether the tablet is kept in the mouth or
swallowed immediately. It depends on what the stomach does with the drug: a meal can
retard a tablet for several hours, but not small particles or dissolved drug. Where the drug
is absorbed of course also depends strongly on the physico–chemical properties of the
drug and the composition and structure of the tablet or capsule (the “dosage form”).
Once the drug has been absorbed in the body, it is transported further by blood. The
circulation time of blood is a matter of minutes, so the drug is rapidly distributed. How
the concentration at a certain site develops, depends on a number of things:
n
n
n
n
n

how quickly the drug is released by the tablet or capsule;
how quickly it passes the membrane of the intestines;
whether the drug is excluded from certain parts of the body (or the opposite: that it is
preferentially accumulated in certain parts);
how quickly the drug is metabolized in the body;
how quickly the drug is excreted from the body.

Many drugs are excluded (more or less) from certain parts of the body by internal
barriers. A well-known one is the barrier that protects the brain. Drugs can also be
adsorbeda, for example, on white blood cells (lymphocytes). This can affect the profile of
the drug concentration. The body is continually metabolizing substances that are entering
it (usually enzymatically). This happens in the intestines and liver, but some drugs can
also be degraded by the highly acidic liquid in the stomach. Drugs are also excreted,
mainly via the liver and kidney. All these processes depend on the patient and on the
patient’s condition, so they are highly variable.
This chapter deals with mechanisms that determine the rate of release of the drug from a
tablet or capsule, and how the release rate can be predicted and controlled. However, one
should realize that all the phenomena described above play a role in determining how the
concentration of a drug in the body changes in time. We will investigate their interplay and
how they affect drug concentrations in the body in the “Systems and Balances” section.
Dosage Forms
Common types of tablet are:
n
n

a

plain tablets
coated tablets

You may not have noticed, but we need two related and similar words. They are confusing. The
two words are:
1.
2.

absorption: transfer of a substance to a liquid, or to some system;
adsorption: transfer of a substance to a surface or interface.

Unfortunately, the term absorption is also used for the uptake of drug from the site of administration
into the blood circulation.


4
n
n
n

Wesselingh and Frijlink

matrix tablets (non-swelling)
matrix tablets (swelling)
effervescent tablets.

Figure 2 gives a schematic cross section of the different types and an indication of
how they work.
Plain Tablets
Plain tablets consist of the drug substance (the active material) and a number of auxiliary
materials or “excipients”. There are many kinds of excipients:
n

n
n
n
n
n
n

fillers (lactose monohydrate, mannitol, microcrystalline cellulose, di-basic calcium
phosphateb);
binders (methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrollidone,
pregelatinized starch);
lubricants (magnesium stearate, sodium stearyl fumarate, glyceryl tri-behenate, stearic acid);
disintegrants (sodium starch glycolate, croscarmellose sodium, crospovidone);
glidants or powder flow improvers (colloidal silicon dioxide, talc);
colorants (ferric oxide red, ferric oxide yellow);
flavoring agents (mint, lemon, cherry).
Finally a whole series of stabilizers:

n
n
n

anti-oxidants (ascorbic acid, potassium metabisulfite, a-tocopherol);
complexing agents (disodium edetate);
buffers (citric acid/sodium citrate, phosphate);

We will encounter a few more excipients in other tablets.
Tablets must have a volume of a few hundred microliters: smaller ones cannot be
handled easily and larger ones cannot be swallowed. If the volume of drug to be applied is
less than this amount, then this will be compensated by a filler—an inert solid added to

increase the volume. Drug particles are then dispersed between filler particles. Most drugs

FIGURE 2 The different kinds of tablets.

b

We have only given a few common examples or each kind of excipient.


Mass Transfer from Solid Oral Dosage Forms

5

cannot be tableted in their pure form: they yield tablets that are too weak, or that wear too
easily. This can be overcome by using a binder: a material that bridges the contacts
between the drug particles. Fillers are often also good binders: these are the filler–binders.
The solid particles in tablets are often quite abrasive. Also they may stick to metal
surfaces, and this can give great problems in tableting machines. The solution is to add a
lubricant. Unfortunately most lubricants also reduce the internal binding in the tablet, and
the wettability of the pores in the tablet.
If no measures are taken tablets often dissolve very slowly. The rate of dissolution
can be greatly increased by including a disintegrant: strongly swelling polymer particles
that push the drug and filler particles apart when they are contacted with water. This
effect is similar to that of the effervescent tablets that we discuss further on. Disintegrants
can also improve transport of water into the tablet.
Coated Tablets
There are several reasons for coating a tablet:
n
n
n

n
n

to apply a color (for identification);
to mask the taste or smell of the drug;
to avoid dusting of the tablet;
to retard release till the drug is in the intestines (to protect it from the gastric
environment);
to control the release rate of the drug.

For the first three applications, the coating only has to work until the tablet is
swallowed. This can be achieved with a number of materials. Typical examples are
cellulose–esters (such as hydroxypropyl methylcellulose or methylcellulose) and polyvinylpyrrolidone. Next to the polymers, formulations used for the coating of tablets
contain materials such as plasticizers (to enhance film formation), anti tacking agents
(e.g., talc), and colorants (e.g., iron oxides).
Some drugs are degraded by the acid conditions in the stomach, so they have to be
protected by a coating till they are in the intestines. It is more difficult to achieve this.
The time a tablet stays in the stomach can vary between minutes and hours and cannot
be accurately predicted. So time-activated systems are of little use. The most successful
systems use a coating with a polymer with weak acid groups fixed to the polymer
backbone. Under acid conditions these groups are not ionized, and the polymer is dense
and impermeable. However, when the tablet enters the duodenum, the pH increases, and
the weak acids dissociate. The polymer swells and becomes much more permeable
(Fig. 3). This then allows a (slow) release of the tablet contents. Examples of such

FIGURE 3 Swelling of a polymer with
weak acid groups.


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Wesselingh and Frijlink

polymers are poly(methacrylic acid, ethyl acrylate) 1:1, poly(methacrylic acid, methyl
methacrylate) 1:2, hydroxypropyl, methylcellulose, phthalate, and cellulose acetate
phthalate.
Some drugs have to be released slowly after administration, either to reduce the
frequency of dosing, or because high plasma concentrations give problems. One way to
do this is by using a coating that it is permeable for the drug, but does not dissolve. This
kind of design allows some special release characteristics, as we discuss in the section
“Motion in Mixtures”
Polymers used for slow release coatings are ethylcellulose, poly(ethyl acrylate),
and poly(methyl methacrylate). The release is often further slowed down by the application of lipophilic plasticizers like dibutyl sebacate or acetyl tributyl citrate.
Matrix Tablets (Non-Swelling)
In these tablets the drug is embedded in a poorly soluble matrix (such as ethylcellulose or
a poly(methacrylate). This can be either a polymer or a structure of filler–binder particles.
It is essential that the structure is permeable, so that water can enter. The drug is released
by “leaching”: it has to diffuse through the pores in the tablet that have been emptied by
dissolution.
There are two important limiting cases:
1.
2.

the matrix dissolves much more slowly than the drug (or not at all);
the matrix dissolves or erodes a little more slowly than the drug.

In the first case the release begins with a high rate and then decreases continuously
as the diffusion distance increases. In the second case there is an initial release burst, but
then the rate becomes more or less constant. (It still decreases slowly because the surface
of the particle decreases.)

Matrix Tablets (Swelling)
The matrix in these tablets is a polymer. The drug is immobilized in the dry polymer.
When the polymer gets in contact with water, it swells, and the drug can move through
the swollen material.
The penetration of water often proceeds with a sharp front. The motion of the front
can be governed by two different mechanisms:
1.
2.

by the transport of water through the swollen polymer, or
by the rate at which the polymer can swell.

In the first case we start with a fast release, but the rate goes down as the water has
to travel further into the tablet (this is the most common situation). In the second case, the
rate is more or less constant until the front approaches the center of the tablet.
Examples of the polymers that are used in these matrix tablets are: methylcellulose,
hydroxypropyl, methylcellulose, polyvinylpyrrolidone, or sodium alginate. Next to the
polymers, materials that affect the release rate through changing the solubility of the drug
(e.g., buffers) or through changing the viscosity of the swollen polymer (e.g., mannitol)
can be used.
Effervescent Tablets
We have already encountered the use of swelling polymer particles to disintegrate a
tablet. There is another way of doing this: by including chemicals that form a gas when


Mass Transfer from Solid Oral Dosage Forms

7

contacted with water. A common combination is soda with a weak acid such as citric acid

(HA). These react to give carbon dioxide:
Na2 CO3 þ 2HAÀ!2NaA þ CO2 "
If the tablet is not well designed it may happen that the gas blocks the pores. This
retards the entry of water and can suppress disintegration.
Example 1: Discussion
As you will understand, manufacturers will not tell you all their secrets. So also we had to
guess a few things on Nexium tablets.
The tablet is built up in several steps (Fig. 4). The core is formed by granules of
sucrose and starch, on which the drug esomeprazol is layered using a binder. These
granules are surrounded by a coating that is impermeable in acid conditions, so that the
drug is not released in the stomach. The granules are held together in a tablet by a
filler–binder. This part probably also contains the disintegrant, which accelerates the
disintegration of the tablet once the coating has dissolved. Finally the tablet is covered by
a water-soluble coating, colored pink with iron oxide and titanium dioxide.
The reasoning behind the instructions will be clear. There should be no chewing as
this would damage the internal acid resistant coating. However, patients with swallowing
problems can first dissolve the external coating and binder, before swallowing the much
smaller granules.
Table 2 shows what we think is the purpose of the different ingredients.

MATERIAL PROPERTIES
Before we look at how drugs are released, we first consider the materials involved and
their properties. There are three main groups:
1.
2.
3.

the solvent—usually an aqueous body fluid,
“solids” such as the tablet or the membranes of the body;
solutes—materials dissolved in the solid or solvent.

In addition, we spend a few words on the interfaces between liquids and solids. We
finish this section looking at how components distribute over the different materials at
equilibrium.
Liquids
The bulk of the liquid in our body is aqueous. Even so, we look briefly at few other
solvents to introduce the concept of polarity. Figure 5 shows four solvents and their
energy of vaporization per volume.

FIGURE 4 The construction of Nexium tablets.


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Wesselingh and Frijlink

TABLE 2 Purpose of the Ingredients
Ingredients (grouped)

Purpose

Esomeprazol
Sucrose/starch granules
Microcrystalline cellulose
Hydroxypropylcellulose, hypromellose,
Methacrylic acid/ethylacrylate copolymer,
Synthetic paraffin, triethyl citrate, macrogol 6000
Polysorbate 80
Iron oxide (E172), titanium dioxide (E171)
Crospovidone

Glycerol monostearate, magnesium stearate, sodium stearyl fumarate
Talc

The drug
Core for the granules
Filler–binder
Binders
Acid resistant coating
Plasticizers
Surfactant
Colorants
Disintegrant
Lubricants
Anti-tacking agent

Heptane is an apolar molecule: it has no electrical poles. Water, on the other side, is
a very polar molecule: the two protons are positive and the oxygen atom is negative.
Ethanol is less polar than water, but still quite polar. The aromatics (such as toluene) are
less polar again, but not completely apolar. This is because double bond electrons can be
slightly polarized by other charged molecules.
Polar molecules bind more strongly than similar apolar molecules. This is because
the charges cause hydrogen bonding between the molecules. This is clear from the
energies of vaporization per volume. That of heptane is low; that of water high.
Liquids with similar polarities mix with each other. Water and ethanol are miscible;
so are ethanol and toluene. However, water and toluene hardly mix: they form two
separate liquid phases. Water and heptane dissolve even less in each other: there are no
hydrogen bonds between the two, so water tends to cluster.
Many of the materials used for constructing tablets decompose before they vaporize,
so their polarity cannot be determined directly. This is done by comparing their solubilities
in different solvents. You can often get a rough idea just by looking at the number of –OH,

¼O and –NH2 groups in a molecule. If these dominate, the molecule is polar. On the
other hand, if –CH, –CH2 and –CH3 groups dominate, the molecule will be apolar.
Solids
Most of the solids involved in drug release are permeable: they allow solutes and solvents
to pass. There are two main groups of solids:

FIGURE 5 Polarity of four solvents.