Pharmaceutical
`Dosage Forms:
`TabletS Volume 1
`
`Expanded
`Second Edition, Revised and
`Edited by Herbert A. Lieberman,
`Leon Ladunan, and Joseph B. Schwartz
`
`COMPRESSION CYCLE
`
`TJ
`rs
`
`U n
`
`n;
`
`EJECT
`
`COMPRESS
`
`ADJUST
`WEIGHT
`
`DIE
`FILL
`
`B
`
`B
`
`MYLAN - EXHIBIT 1030
`
`

`

`PHARMACEUTICAL
`DOSAGE FORMS
`
`Tablets
`SECOND EDITION, REVISED AND EXPANDED
`
`In Three Volumes
`VOLUME 1
`
`EDITED BY
`
`Herbert A. Lieberman
`H H Lieberman Associates, Inc
`Consultant Services
`Livingston, New Jersey
`Leon Lachman
`Lachman Consultant Services
`Westbury, New York
`Joseph B. Schwartz
`Philadelphia College of Pharmacy and Science
`Philadelphia, Pennsylvania
`
`M A R C E L
`
`D E K K E R
`
`MARCEL DEKKER, INC.
`
`NEW YORK • BASEL • HONG KONG
`
`

`

`Library of Congress Cataloging-in~Publication Data
`
`Pharmaceutical dosage forms--tablets / edited by Herbert A. Lieberman,
`Leon Lachman, Joseph B. Schwartz. -- 2nd ed., rev. and expanded,
`p.
`cm.
`Includes index.
`ISBN 0-8247-8044-2 (v. 1 : alk. paper)
`1. Tablets (Medicine) 2. Drugs--Dosage forms. I. Lieberman,
`Herbert A. II. Lachman, Leon. III. Schwartz, Joseph B.
`[DNLM: 1. Dosage Forms. 2. Drugs--administration & dosage. QV
`785 P535]
`RS201.T2P46 1989
`6i5M91--dcl9
`DNLM/DLC
`for Library of Congress
`
`89-1629
`CIP
`
`Copyright © 1989 by MARCEL DEKKER, INC. AH Rights Reserved
`
`Neither this book nor any part may be reproduced or transmitted in
`any form or by any means, electronic or mechanical, including photo­
`copying, microfilming, and recording, or by any information storage
`and retrieval system, without permission in writing from the publisher.
`
`MARCEL DEKKER,INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last digit) :
`10 9 8 7 6
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`

`

`PHARMACEUTICAL
`
`PHARMACEUTICAL
`DOSAGE FORMS
`
`DOSAGE FORMS
`
`

`

`Preface
`
`Several years have passed since the first edition of Pharmaceutical Dosage
`Forms: Tablets was published. During this time, considerable advances
`have been made in the science and technology of tablet formulation, manu­
`facture, and testing. These changes are reflected in this updated, re­
`vised and expanded second edition.
`The tablet dosage form continues to be the most widely used drug de­
`livery system for both over-the-counter and prescription drugs. The term
`tablet encompasses: the usual compressed tablet; the compressed tablet that
`is sugar- or film-coated to provide dissolution in either the stomach or the
`intestine, or partially in the stomach and partially in the intestine; layered
`tablets for gastric and intestinal release; effervescent tablets; sustained-
`release tablets; compressed coated tablets; sublingual and buccal tablets;
`chew able tablets; and medicated lozenges. These various dosage forms are
`described in depth in the three volumes of this series.
`In the first volume, the various types of tablet products are discussed;
`the second volume is concerned with the processes involved in producing
`tablets, their bioavailability and pharmacokinetics; and in the third volume,
`additional processes in tablet production are discussed, as well as sustained
`drug release, stability, kinetics, automation, pilot plant, and quality as­
`surance.
`The first chapter in Volume 1 describes "Preformulation Testing." This
`second edition of the chapter contains an extensive amount of new material
`on substance purity, dissolution, the concept of permeability, and some of
`the pharmaceutical properties of solids.
`In the second chapter, "Tablet
`Formulation and Design," the plan for developing prototype formulas has
`been revised and an approach, using statistical design, is presented.
`There is consideration given to those elements in tablet formulation that are
`of importance to the operation of tablet presses with microprocessor controls.
`There have been so many advances in the technology of wet granula­
`tion and direct compression methods since the first edition that what had
`previously been one chapter has now been expanded into two chapters.
`
`Hi
`
`

`

`iv
`
`Preface
`
`"Compressed Tablets by Wet Granulation" has been updated, and a new
`section on unit operations has been added.
`Information on the formulations
`of sustained-release tablets by wet granulation is included in the chapter.
`"Compressed Tablets by Direct Compression," a separate chapter new to
`this edition, contains: a table comparing all aspects of direct compression
`versus wet granulation; an extensive glossary of trade names and manu­
`facturers of tableting excipients; a section on morphology of pharmaceutical
`excipients, including scanning electron photomicrographs; a discussion of
`direct compression of example active ingredients; and a considerably ex­
`panded section on prototype or guide formulations.
`The chapter entitled "Compression-Coated and Layered Tablets" de­
`scribes the current technology for making these types of tablets. The
`chapter "Effervescent Tablets" has been expanded to include fluid-bed
`granulation techniques, updating on stability testing methods, new packag­
`ing materials, and methodologies for checking airtightness of sealed pack­
`ets. The chapter on "Special Tablets" now contains information on long-act­
`ing and controlled-release buccal tablets as well as new sections on vaginal
`and rectal tablets. The chapter "Chewable Tablets" has increased its cov­
`erage to include microencapsulation and spray coating techniques. This
`chapter includes an update of the information concerned with excipients,
`colorants, direct-compression chewable tablets, and current manufacturing
`and product evaluation procedures related to these tablets. "Medicated
`Lozenges," the final chapter in Volume 1, has increased its scope to include
`liquid-center medicated lozenges and chewy-based medicated tsblets.
`Each of the tablet forms discussed requires special formulation procedures.
`Knowing how to make a particular type does not guarantee knowledge of how
`to make another. Since considerable expertise is required for the myriad
`tablet dosage forms, a multlauthored text seemed to be the only way to
`accomplish the editors' goals of providing knowledgeable and complete cov­
`erage of the subject. The editors chose authors to describe particular
`types of tablets on the basis of their experience, training, and high degree
`of knowledge of their subjects.
`The authors were charged with the task of covering their technology in
`a way that would not be merely a review of the literature. Each chapter
`begins by assuming the reader is not very familiar with the subject.
`Gradually, as each chapter develops, the discussion becomes more advanced
`and specific. Following this format, we have intended the text to be a
`teaching source for undergraduate and graduate students as well as ex­
`perienced and inexperienced industrial pharmaceutical scientists. The book
`can also act as a ready reference to all those interested in tablet tech­
`nology. This includes students, product development pharmacists, hospital
`pharmacists, drug patent attorneys, governmental and regulatory scientists,
`quality control personnel, pharmaceutical production personnel, and those
`concerned with production equipment for making tablets.
`The authors are to be commended for the manner in which they cover
`their subjects ss well as for their patience with the editors' comments con­
`cerning their manuscripts. The editors wish to express their special
`thanks to the contributors for the excellence of their works, as well as for
`their continued forbearance with our attempts to achieve our desired level
`of quality for this text. Although there has been a great deal written
`about various types of tablets, it is only in this multivolume treatment
`that this subject is completely described. The acceptability and usefulness
`
`

`

`Preface
`
`v
`
`of these volumes is attributable to the efforts and skills of all of the con­
`tributing authors.
`The topics, format, and choice of authors are the responsibilities of
`the editors. Any multiauthor book has problems of coordination and
`minimizing repetition. Some repetition was purposely retained because,
`in the editors' opinions, it helped the authors to develop their themes and
`because each individual treatment is sufficiently different so as to be val­
`uable as a teaching aid. The editors hope that the labors of the contrib­
`utors and our mutual judgments of subject matter have resulted in an up-to-
`date expanded reference that will facilitate the work of the many people who
`use it.
`
`Herbert A. Lieberman
`Leon Lachman
`Joseph B. Schwartz
`
`

`

`Contents
`
`Preface
`Contributors
`Contents of Pharmaceutical Dosage Forms:
`Volumes 2 and 3
`Contents of Pharmaceutical Dosage Forms: Parenteral Medications,
`Volumes 1 and 2
`Contents of Pharmaceutical Dosage Forms: Disperse Systems,
`Volumes J and 2
`
`Tablets, Second Edition
`
`iii
`xi
`
`xiii
`
`xv
`
`XXX
`
`Chapter 1. Preformulation Testing
`Deodatt A. Wadke, Abu T. M. Serajuddin, and
`Harold Jacobson
`I.
`Introduction
`II. Organoleptic Properties
`III. Purity
`IV. Particle Size, Shape, and Surface Area
`V. Solubility
`VI. Dissolution
`VII. Parameters Affecting Absorption
`VIII. Crystal Properties and Polymorphism
`IX. Stability
`X. Miscellaneous Properties
`XI. Examples of Preformulation Studies
`References
`
`Chapter 2.
`
`11.
`III.
`
`Tablet Formulation and Design
`Garnet E. Peck, George J. Baley, Vincent E. McCurdy,
`and Gilbert S. Banker
`Introduction
`Preformulation Studies
`A Systematic and Modern Approach to
`Tablet Product Design
`Tablet Components and Additives
`Regulatory Requirements for Excipients in
`the United States
`References
`
`IV.
`V.
`
`VI.
`
`1
`
`1
`2
`3
`5
`12
`18
`24
`34
`42
`53
`57
`69
`
`75
`
`75
`77
`
`79
`88
`
`121
`128
`
`vii
`
`

`

`via
`
`Contents
`
`Chapter 3. Compressed Tablets by Wet Granulation
`Fred J. Bandelin
`Properties of Tablets
`Formulation of Tablets
`Tablet Manufacture
`Granulation
`Excipients and Formulation
`Multilayer Tablets
`Prolonged Release Tablets
`Manufacturing Problems
`References
`
`II.
`III.
`IV.
`V.
`VI.
`VII.
`VIII.
`
`131
`
`132
`133
`135
`148
`151
`179
`181
`188
`190
`
`195
`
`195
`
`197
`198
`203
`214
`220
`225
`
`227
`228
`229
`243
`245
`
`247
`
`247
`260
`273
`274
`278
`284
`
`285
`
`285
`286
`294
`300
`302
`
`II.
`
`Chapter 4. Compressed Tablets by Direct Compression
`Ralph F. Shangraw
`Introduction and History
`Advantages and Disadvantages of the Wet
`Granulation Process
`The Direct-Compression Process
`Direct-Compression Filler Binders
`Factors in Formulation Development
`Morphology of Direct-Compression Fillers
`Coprocessed Active Ingredients
`Modification and Integration of Direct-
`Compression and Granulation Processes
`Future of Direct-Compression Tableting
`Formulations for Direct Compression
`Glossary of Trade Names and Manufacturers
`References
`
`III.
`IV.
`V.
`VI.
`VII.
`VIII.
`
`IX.
`
`Chapter 5. Compression-Coated and Layer Tablets
`William C. Gunsel and Robert G. Ousel
`Compression Coating
`Formulations (Compression Coating)
`Inlay Tablets
`Layer Tablets
`Formulations (Layer)
`References
`
`II.
`III.
`IV.
`V.
`
`Chapter 6. Effervescent Tablets
`Raymond Mohrle
`I.
`Introduction
`II. Raw Materials
`III. Processing
`IV. Manufacturing Operations
`V. Tablet Evaluation
`
`

`

`Contents
`
`VI. Effervescent Stability
`VII. Effervescent Formulations
`VIII. References
`
`Chapter 7. Special Tablets
`James W. Conine and Michael J. Pikal
`I. Drug Absorption Through the Oral Mucosa
`II. Molded Sublingual Tablets
`III. Special Problems with Molded Nitroglycerin
`Tablets
`IV. Compressed Sublingual Tablets
`V. Buccal Tablets
`VI. Vaginal Tablets
`VII. Rectal Tablets
`VIII. Dispensing Tablets
`IX. Tablets for Miscellaneous Uses
`References
`
`Chapter 8. Chew able Tablets
`Robert W. Mendes, Aloysius O. Anaebonam, and
`Jahan B. Daruwala
`I.
`Introduction
`II. Formulation Factors
`III. Formulation Techniques
`IV. Excipients
`V. Flavoring
`VI. Colorants
`VII. Manufacturing
`VIII. Evaluation of Chewable Tablets
`IX. Summary
`References
`
`Chapter 9. Medicated Lozenges
`David Peters
`Hard Candy Lozenges
`I.
`Processing
`II.
`Formulations (Hard Candy Lozenges)
`III.
`Center-Filled Hard Candy Lozenges
`IV.
`y r
`Formulations (Center Filled Lozenges)
`VI.
`Packaging
`Chewy or Caramel Base Medicated Tablets
`VII.
`Formulations (Chewy Based Confections)
`VIU.
`Compressed Tablet Lozenges
`IX.
`Manufacturing: Compression Sequence
`X.
`Typical Formulations (Compressed-Tablet
`XI.
`Lozenges)
`
`ix
`
`304
`320
`326
`
`329
`
`329
`334
`
`340
`354
`356
`359
`360
`362
`363
`364
`
`367
`
`367
`368
`371
`382
`387
`392
`396
`406
`415
`415
`
`419
`
`419
`445
`497
`501
`509
`511
`520
`541
`543
`558
`
`565
`
`

`

`x
`
`Index
`
`XII. Quality Control Procedures
`References
`Suggested Reading
`
`Contents
`
`567
`576
`580
`
`583
`
`

`

`Contributors
`
`Section Head, Pharmaceutical Development,
`Aloysius 0. Anaebonam
`Fisons Corporation, Rochester, New York
`
`George J. Baley Vice President, Manufacturing and Distribution, The
`Upjohn Company, Inc., Kalamazoo, Michigan
`
`Fred J. Bandelln Consultant, Schering-Plough Corporation, and Assistant
`Professor, Department of Pharmaceutics, University of Tennessee, Memphis,
`Tennessee
`
`Dean, College of Pharmacy, University of Minnesota
`Gilbert S. Banker
`Health Sciences Center, Minneapolis, Minnesota
`
`James W. Conine
`Research Scientist, Lilly Research Laboratories,
`Eli Lilly and Company, Indianapolis, Indiana, Retired
`
`Manager, Macturing Planning and Sourcing, Medical
`Jahan B. Daruwala
`Products Department, E. I. du Pont de Nemours & Company, Wilmington,
`Delaware
`
`Robert G. Dusei Associate, Lachman Consultant Services, Inc.
`Westbury, New York
`
`William C. Gunsel
`
`Ciba-Geigy Corporation, Summit, New Jersey, Retired
`
`Director, Regulatory Affairs, E. R. Squibb & Sons,
`Harold Jacobson
`New Brunswick, New Jersey
`
`Vincent E. McCurdy Scientist, Drug Delivery R&D-Drug Products
`The Upjohn Company, Kalamazoo, Michigan
`
`xi
`
`

`

`xii
`
`Contributors
`
`Professor and Chairman, Pharmaceutics and Industrial
`Robert W. Mendes
`Pharmacy, Massachusetts College of Pharmacy and Allied Health Sciences,
`Boston, Massachusetts
`
`Section Director, OTC Pharmaceutical Development,
`Raymond Mohrfe
`Consumer Products R&D Division, Warner-Lambert Company, Morris Plains,
`New Jersey
`
`Professor of Industrial Pharmacy and Director of the
`Garnet E. Peck
`Industrial Pharmacy Laboratory, Purdue University, West Lafayette,
`Indiana
`
`Senior Research Associate, Consumer Products
`David Peters*
`Development, Warner-Lambert Company, Morris Plains, New Jersey
`
`Senior Research Scientist, Lilly Research Laboratories,
`Michael J. Pikal
`Eli Lilly and Company, Indianapolis, Indiana
`
`Abu T. M. Serajuddin Section Head and Senior Laboratory Supervisor,
`Department of Pharmaceutical Research and Development, E. R. Squibb &
`Sons, New Brunswick, New Jersey
`
`Ralph F. Shangraw Professor and Chairman, Department of Pharmaceutics,
`The University of Maryland School of Pharmacy, Baltimore, Maryland
`
`Deodatt A. Wadke Director, Product Development, Department of
`Pharmaceutical Research and Development, E. R. Squibb & Sons, New
`Brunswick, New Jersey
`
`*Current affiliation: Pharmacist, Treworgy Pharmacy, Calais, Maine
`
`

`

`Contents of Pharmaceutical Dosage
`Forms: Tablets, Second Edition, Revised
`and Expanded, Volumes 2 and 3
`
`edited by Herbert A. Lieberman, Leon Lachman, and Joseph B. Schwartz
`
`VOLUME 2
`
`Mixing, RusselZ J. Lantz, Jr. and Joseph B. Schwartz
`
`Drying, Kurt G. Van Scoik, Michael A. Zoglio, and Jens T. Carstensen
`
`3. Size Reduction, Russell J. Lantz, Jr.
`
`4. Compression, Eugene L. Parrott
`
`5.
`
`6.
`
`Granulation and Tablet Characteristics, Roger E. Gordon, Dale E.
`Fonner, Neil R. Anderson, and Gilbert S. Banker
`
`Bioavailability in Tablet Technology, Salomon A. Stavchanskv,
`James W. McGinity, and Alfred Martin
`
`7. Pharmaceutical Tablet Compression Tooling, Glen Ebey and George F.
`Loeffler
`
`VOLUME 3
`
`1. Principles of Improved Tablet Production System Design, Garnet E.
`Peck, Neil R. Anderson, and Gilbert S. Banker
`
`2. Pan Coating of Tablets and Granules, Stuart C. Porter
`
`3. Particle-Coating Methods, Dale E. Wurster
`
`xiii
`
`

`

`xiv
`
`Contents of Other Volumes
`
`Sustained Drug' Release from Tablets and Particles through Coating,
`Ronff-Kun Chang and Joseph R. Robinson
`
`5. Pharmaceutical Pilot Plant, Charles I. Jarowski
`
`6.
`
`Tablet Production, Robert Connelly, Frank Berstler, and David
`Coffin-Beach
`
`7. Stability/Kinetics, Samir A. Hanna
`
`8. Quality Assurance, Samir A. Hanna
`
`

`

`Contents of Pharmaceutical Dosage
`Forms: Parenteral Medications,
`Volumes 1 and 2
`
`edited by Kenneth E. Avis, Leon Lachman,
`and Herbert A. Lieberman
`
`VOLUME 1
`
`1.
`
`2 ,
`
`The Dosage Form and Its Historical Development, Kenneth E. Avis
`and Beth G. Morris
`
`Routes, Precautions, Problems,
`Parenteral Drug Administration:
`and Complications, Richard J. Duma and Michael J. Akers
`
`3. Biopharmaceutics of Injectable Medication, Sol Mo tola
`
`Preformulation of Parenteral Medications, Sol Motola and
`Shreeram Agharkar
`
`5.
`
`6.
`
`Formulation of Small Volume Parenterals, Patrick P. DeLuca and
`James C. Boylan
`
`The Processing of Small Volume Parenterals and Related Sterile
`Products, Joel Benton Portnoff, Richard J. Harwood, and Edward
`William Sunbery
`
`7. Manufacturing of Large Volume Parenterals, Nicholas J. Kartinos and
`Michale J. Groves
`
`Records and Reports, David C. Fry
`
`Environmental Factors in the Design of a Parenteral Production
`Facility, A. Michael Keller
`
`10.
`
`Personnel :
`
`The Key Factor in Clean Room Operations, Cecelia J. Luna
`
`xv
`
`

`

`xvi
`
`VOLUME 2
`
`Contents of Other Volumes
`
`1. Industrial Sterilization: A Review of Current Principles and
`Practices, Frank J. Marino and Floyd Benjamin
`
`2. Formulation for Large Volume Parenterals, Levit J. Demo rest
`
`3. Glass Containers for Parenterals, Frank R. Bacon
`
`Plastic Containers for Parenterals, Donald D. Solomon, Raymond
`W. Jurgens, Jr., and K. Lim Wong
`
`5 •
`
`Elastomeric Closures for Parenterals, Edward J. Smith and Robert J.
`Nash
`
`Particulate Matter, Patrick P. DeLuca and Julius Z. Knapp
`
`7, Environmental Control in Parenteral Drug Manufacturing, Franco
`DeVecchi
`
`8. Quality Assurance, Samir A. Hanna
`
`0
`
`Federal Regulation of Parenterals, Jonas L. Bassen and Bernard
`T. Loftus
`
`10. Medical Devices: Design, Manufacture, and Quality Control,
`David H. Wayt
`
`11. Quality Assurance for Parenteral Devices, Carl W. Bruch
`
`12. Regulatory and GMP Considerations for Medical Devices,
`Larry R. Pilot
`
`13. Parenteral Products in Hospital Practice, John W. Levchuk
`
`

`

`Contents of Pharmaceutical Dosage Forms:
`Disperse Systems, Volumes 1 and 2
`
`edited by Herbert A. Lieberman, Martin M. Rieger, and Gilbert S. Banker
`
`VOLUME 1
`
`Introduction, Norman Weiner
`
`2. Theory of Suspensions, Michael J. Falkowicz
`
`3. Theory of Emulsions, Stig E. Friberg, Lisa B. Goldsmith, and
`Martha L. Hilton
`
`4. Theory of Colloids, John Vanderhoff and Mohamed S. EhAasser
`
`5* Pharmaceutical Suspensions, Robert A. Nash
`
`Pharmaceutical Emulsions, Bernard Idson
`
`7. Specislized Pharmaceutical Emulsions, Morton Rosoff
`
`9.
`
`10.
`
`Surfactants, Martin M. Rieger
`
`Rheology of Dispersed Systems, Donald E. Deem
`
`Experimental Design, Modeling, and Optimization Strategies for Product
`and Process Development, Robert M. Franz, Jeffrey E. Browne, and
`Allen R. Lewis
`
`xv it
`
`

`

`xviii
`
`VOLUME 2
`
`Contents of Other Volumes
`
`1. A Practical Guide to Equipment Selection and Operating Techniques,
`Roy Scott
`
`2. Preservation of Dispersed Systems, Harun Takruri and Claude B.
`Anger
`
`3. Bioavailability of Disperse Dosage Forms, R. D. Schoenwald and
`Douglas R. Flanagan
`
`4. Viscosity-Imparting Agents in Disperse Systems, Joel Zatz, Joseph J.
`Berry, and Daniel A. Alderman
`
`5. Antacids and Clay Products, Richard Norwood, Joseph R. Luber, and
`Edward W. Sunbery
`
`6 .
`
`Oral Aqueous Suspensions, Clyde M. Ofner III, Rogrer L. Schnaare,
`and Joseph B. Schwartz
`
`7. Topical Suspensions, Hridaya N. Bhargava and Daniel W. Nicolai
`
`8.
`
`Reconstitutable Suspensions, Clyde M. Ofner III, Rogrer L. Schnaare,
`and Joseph B. Schwartz
`
`Emulsions and Microemulsions, Lawrence H. Block
`
`Injectable Emulsions and Suspensions, Joe Bruce Boyett and
`Craig W. Davis
`
`Aerosol suspensions and Emulsions, John J. Sciarra and Anthony J.
`Cutie
`
`Ophthalmic Ointment Suspensions, Krishna M. Bapatla and Gerald
`Hecht
`
`10.
`
`11.
`
`12.
`
`13.
`
`Gels, Joel L. Zatz and Gregory P. Kushla
`
`14.
`
`Toothpastes, David Garlen
`
`15.
`
`16.
`
`17.
`
`Suppositories, Marion F. Gold
`
`Liposomes, Mohammad Riaz, Norman Weiner, and Frank Martin
`
`Regulatory Affairs, John P. Tomaszewski
`
`18.
`
`Quality Assurance, Samir A. Hanna
`
`

`

`PHARMACEUTICAL
`
`PHARMACEUTICAL
`DOSAGE FORMS
`
`DOSAGE FORMS
`
`

`

`3
`Compressed Tablets by Wet Granulation
`
`Fred J. Bandelin
`Schering-Plough Corporation and University of Tennessee, Memphis,
`Tennessee
`
`Compressed tablets are the most widely used of all pharmaceutical dosage
`forms for a number of reasons. They are convenient, easy to use, portable,
`and less expensive than other oral dosage forms. They deliver a precise
`dose with a high degree of accuracy. Tablets can be made in a variety of
`shapes and sizes limited only by the ingenuity of the tool and die maker
`(i.e. round, oval, capsule-shaped, square, triangular, etc.).
`Compressed tablets are defined as solid-unit dosage forms made by com­
`paction of a formulation containing the drug and certain fillers or excipients
`selected to aid in the processing and properties of the drug product.
`There are various types of tablets designed for specific uses or func­
`tions. These include tablets to be swallowed per se; chewable tablets form­
`ulated to be chewed rather than swallowed, such as some antacid and vita­
`min tablets; buccal tablets designed to dissolve slowly in the buccal pouch;
`and sublingual tablets for rapid dissolution under the tongue. Effervescent
`tablets are formulated to dissolve in water with effervescence caused by the
`reaction of citric acid with sodium bicarbonate or some other effervescent
`combination that produces effervescence in water. Suppositories can be
`made by compression of formulations using a specially designed die to pro­
`duce the proper shape.
`The function of tablets is determined by their design. Multilayer tab­
`lets are made by multiple compression. These are called layer tablets and
`usually consist of two and sometimes three layers. They serve several
`purposes:
`to separate incompatible ingredients by formulating them in
`separate layers, to make sustained or dual-release products, or merely for
`appearance where the layers are colored differently. Compression-coated
`tablets are made by compressing a tablet within a tablet so that the outer
`coat becomes the coating. As many as two coats can be compressed around
`a core tablet. As with layer tablets, this technique can also be used to
`separate incompatible ingredients and to make sustained or prolonged
`
`131
`
`

`

`132
`
`Bandelin
`
`release tablets. Sugar-coated tablets are compressed tablets with a sugar
`coating. The coating pay vary in thickness and color by the addition of
`dyes to the sugar coating. Film-coated tablets are compressed tablets with
`a thin film of an inert polymer applied in a suitable solvent and dried.
`Film coating is today the preferred method of making coated tablets. It is
`the most economical and involves minimum time, labor, expense, and expo­
`sure of the tablet to heat and solvent. Enteric-coated tablets are compressed
`tablets coated with an inert substance which resists solution in gastric fluid,
`but disintegrates and releases the medication in the intestines. Sustained
`or prolonged release tablets are compressed tablets especially designed to
`release the drug over a period of time.
`Most drugs cannot be compressed directly into tablets because they
`lack the bonding properties necessary to form a tablet. The powdered
`drugs, therefore, require additives and treatment to confer bonding and
`free-flowing properties on them to facilitate compression by a tablet press.
`This chapter describes and illustrates how this is accomplished by the
`versatile wet granulation method.
`
`I. PROPERTIES OF TABLETS
`
`Whatever method of manufacture is used, the resulting tablets must meet a
`number of physical and biological standards. The attributes of an accept­
`able tablet are as follows:
`
`1. The tablet must be sufficiently strong and resistant to shock and
`abrasion to withstand handling during manufacture, packaging,
`shipping, and use. This property is measured by two tests, the
`hardness and friability tests.
`2. Tablets must be uniform in weight and in drug content of the in­
`dividual tablet. This is measured by the weight variation test and
`the content uniformity test.
`3. The drug content of the tablet must be bioavailable. This property
`is also measured by two tests, the disintegration test and the dis­
`solution test. However, bioavailability of a drug from a tablet, or
`other dosage form, is a very complex problem and the results of
`these two tests do not of themselves provide an index of bioavail­
`ability. This must be done by blood levels of the drug.
`4. Tablets must be elegant in appearance and must have the charac­
`teristic shape, color, and other markings necessary to identify the
`product. Markings are usually the monogram or logo of the manu­
`facturer. Tablets often have the National Drug Code number print­
`ed or embossed on the face of the tablet corresponding to the official
`listing of the product in the National Drug Code Compendium of the
`Food and Drug Administration. Another marking that may appear
`on the tablet is a score or crease across the face, which is intended
`to permit breaking the tablet into equal parts for the administration
`of half a tablet. However, it has been shown that substantial vari­
`ation in drug dose can occur in the manually broken tablets.
`5. Tablets must retain all of their functional attributes, which include
`drug stability and efficacy.
`
`

`

`Compressed Tablets by Wet Granulation
`
`133
`
`I I . F O R M U L A T I O N O F T A B L E T S
`
`The size and, to some extent, the shape of the tablet are determined by
`the active ingredient(s). Drugs having very small doses in the microgram
`range (e.g., folic acid, digitoxin, reserpine, dexamethasone, etc.) require
`the addition of fillers also called excipients to be added to produce a mass or
`or volume of material that can be made into tablets of a size that is con­
`venient for patients, A common and convenient size for such low-dosage
`drugs is a 1/4-in. round tablet or equivalent in some other shape. It is
`difficult for some patients to count and handle tablets smaller than this.
`Tablets of this size ordinarily weigh 150 mg or more depending on the den­
`sity of the excipients used to make up the tablet mass.
`As the dose increases, so does the size of the tablet. Drugs with a
`dose of 100 to 200 mg may require tablet weights of 150 to 300 mg and
`round die diameters of 1/4 to 7/16 in. in diameter depending on the density
`and compressibility of the powders used. As the dose of the active ingredi­
`ent (s) increases, the amount of the excipients and the size of the tablet
`may vary considerably depending on requirements of each to produce an
`acceptable tablet. While the diameter of the tablet may in some cases be
`fixed, the thickness is variable thus allowing the formulator considerable
`latitude and flexibility in adjusting formulations.
`As the dose, and therefore the size, of the tablet increases, the formu­
`lator uses his expertise and knowledge of excipients to keep the size of the
`tablet as small as possible without sacrificing its necessary attributes. Form­
`ulation of a tablet, then, requires the following considerations:
`
`1. Size of dose or quantity of active ingredients
`2. Stability of active ingredient(s)
`3. Solubility of active ingredient(s)
`4. Density of active ingredient(s)
`5. Compressibility of active ingredient(s)
`6. Selection of excipients
`7. Method of granulation (preparation for compression)
`8. Character of granulation
`9. Tablet press, type, size, capacity
`10. Environmental conditions (ambient or humidity control)
`11. Stability of the final product
`12. Bioavailability of the active drug content of the tablet
`
`The selection of excipients is critical in the formulation of tablets. Once
`the formulator has become familiar with the physical and chemical properties
`of the drug, the process of selecting excipients is begun. The stability of
`the drug should be determined with each proposed excipient. This can be
`accomplished as follows:
`In the laboratory, prepare an intimate mixture of
`the drug with an excess of each individual excipient and hold at 60oC for
`72 hr in a glass container. At the end of this period, analyze for the
`drug using a stability-indicating assay. The methods of accelerated testing
`of pharmaceutical products have been extensively reviewed by Lachman et
`al in The Theory and Practice of Industrial Pharmacy, 3rd Ed., Lea and
`Febiger (1986).
`
`

`

`134
`
`Bandelin
`
`Table 1
`
`Suggested Excipient/Drug Ratio in Compatibility Studies
`
`Excipient
`
`Alginic acid
`Avicel
`Cornstarch
`Dicalcium phosphate
`dihydrate
`Lactose
`Magnesium carbonate
`Magnesium stearate
`Mannitol
`Methocel
`PEG 4000
`PVP
`Sta-Rxa
`Stearic acid
`Talc
`
`1
`
`24
`24
`24
`34
`
`34
`24
`1
`24
`2
`9
`4
`1
`1
`1
`
`Weight excipient per unit weight drug
`(anticipated drug dose, mg)
`
`5-10
`
`25-50
`
`75-150
`
`150
`
`24
`9
`9
`34
`
`9
`24
`1
`9
`2
`9
`4
`1
`1
`1
`
`9
`9
`4
`9
`
`4
`9
`1
`4
`2
`4
`2
`1
`1
`1
`
`9
`9
`2
`9
`
`2
`9
`1
`2
`2
`4
`1
`1
`1
`1
`
`9
`4
`2
`9
`
`1
`4
`1
`1
`1
`2
`1
`1
`1
`1
`
`3. Now called starch 1500.
`Source: Modified from Akers, M. J., Can. J. Pharm. Sci., 11:1 (1976).
`Reproduced with permission of the Canadian Pharmaceutical Association.
`
`The suggested ratio of excipient to drug is given in Table 1.
`are specified according to the function they perform in the tablet,
`are classified as follows:
`
`Excipients
`They
`
`Fillers (diluents)
`Binders
`Disintegrants
`Lubricants
`Glidants
`Antiadherents
`
`These additives are discussed in detail later in this chapter.
`
`

`

`Compressed Tablets by Wet Granulation
`
`135
`
`I I I . T A B L E T M A N U F A C T U R E
`A. Tablet Presses
`
`The basic unit of any tablet press is a set of tooling consisting of two
`punches and a die (Fig. 1) which is called a station. The die determines
`the diameter or shape of the tablet; the punches, upper and lower, come
`together in the die that contains the tablet formulation to form a tablet.
`There are two types of presses: single-punch and rotary punch. The
`single-punch press has a single station of one die and two punches, and
`is capable of producing from 40 to 120 tablets per minute depending on
`the size of the tablet. It is largely used in the early stages of tablet form­
`ulation development. The rotary press has a multiplicity of stations arranged
`on a rotating table (Fig. 2) in which the dies are fed the formulation pro­
`ducing tablets at production rates of from a few to many thousands per
`minute. There are numerous models of presses, manufactured by a number
`of companies, ranging in size, speed, and capacity.
`
`(Courtesy of
`Two punches and die, comprises one station.
`Figure 1
`Pennsalt Chemical Corporation, Warminster, Pennsylvania.)
`
`

`

`136
`
`Tablet presses consist of:
`
`Bandelin
`
`1. Hoppers, usually one or two, for storing and feeding the formula­
`tion to be pressed
`2. Feed frame(s) for distributing the formulation to the dies
`3. Dies for controlling the size and shape of the tablet
`4. Punches for compacting the formulation into tablets
`5. Cams (on rotary presses) that act as tracks to guide the moving
`punches
`
`All other parts of the press are designed to control the operation of the
`above parts.
`
`B. Unit Operations
`
`There are three methods of preparing tablet granulations. These are (a)
`wet granulation, (b) dry granulation (also called "slugging"), and direct
`compression (Table 2). Each of these methods has its advantages and dis­
`advantages .
`The first two steps of milling and mixing of the ingredients of the form­
`ulation are identical, but thereafter the processes differ. Each individual
`operation of the process is known as a unit operation. The progress or
`flow of materials through the process is shown in the schematic drawing
`(Fig. 3).
`
`HOPPER
`ISHEI1II*
`MATERIAL
`V''-' '•
`-
`•
`• \ . •
`• ,
`• . v
`- V - ' - " ' - .
`' ' /
`V ' . . •
`/r
`
`. .
`
`.
`
`H KNOCK-OFF
`
`a
`HI
`
`-ir-L,,-: a I
`
`SCI •fil*
`
`II
`
`- U p FltD
`GATE FRAME -r
`
`'•'/
`: L
`
`SeK
`
`Figure