Exhibit 1008
`
`Bandelin , F., Compressed Tablets by Wet
`Granulation, Pharmaceutical Dosage Forms:
`Tablets, Vol. 1, 2nd Ed., Herbert Lieberman, et
`al. eds., Marcel Dekker, Inc., New York (1989)
`(“Bandelin”)
`
`

`
`

`
`PHARMACEUTICAL
`
`DOSAGE FORMS
`
`Tablets
`
`SECOND EDITION, REVISED AND EXPANDED
`
`In Three Volumes
`
`VOLU1\/IE 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
`
`MARCEL DEKKER, INC.
`
`New York and Basel
`
`

`
`Library of Congress Cataloging—in—Pub|ication 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)
`I. Lieberman,
`1. Tablets (Medicine)
`2. Drugs——Dosage forms.
`Herbert A.
`II. Lachman, Leon.
`III. Schwartz, Joseph B.
`[DNLM:
`1. Dosage Forms.
`2. Drugs--administration & dosage. QV
`785 P535]
`RS201.T2P46
`615'.191——dc19
`DNLM/DLC
`for Library of Congress
`
`89-1629
`CIP
`
`1989
`
`Copyright © 1989 by MARCEL DEKKER, INC. All 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
`5
`4
`3
`2
`1
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`

`
`Contents I
`
`Preface
`Contributors
`
`Contents of Pharmaceutical Dosage Forms: Tablets, Second Edition
`Volumes 2 and 3
`
`Contents of Pharmaceutical Dosage Forms: Par'enter'alMedications,
`Volumes 1 and 2
`
`Contents of Pharmaceutical Dosage Forms: Disperse Systems,
`Volumes 1 and 2
`
`Chapter 1.
`
`Preformulation Testing
`
`Deodatt A. Wadke, Abu T. M. Serajuddin, and
`Harold Jacobson
`
`Introduction
`I .
`II. Organoleptic Properties
`III. Purity
`IV. Particle Size, Shape, and Surface Area
`V
`Solubility
`Dissolution
`Parameters Affecting Absorption
`Crystal Properties and Polymorphism
`Stability
`IX.
`X. Miscellaneous Properties
`XI. Examples of Preformulation Studies
`References
`
`VII.
`
`Chapter 2.
`
`Tablet Formulation and Design
`
`Garnet E. Peck, George J. Baley, Vincent E. McCur'dy,
`and Gilbert S. Banker
`
`I .
`II.
`
`Introduction
`Preformulation Studies
`
`III. A Systematic and Modern Approach to
`Tablet Product Design
`)
`J
`IV. Tablet Components and Additives
`V. Regulatory Requirements for Excipients ‘in
`the United States
`‘
`References
`
`

`
`viii
`
`Chapter 3.
`
`Compressed Tablets by Wet Granulation
`Fred J. Bandelin
`
`I.
`II.
`III.
`IV.
`V.
`VI.
`VII.
`VIII.
`
`Properties of Tablets
`Formulation of Tablets
`Tablet Manufacture
`Granulation
`
`Excipients -and Formulation
`Multilayer Tablets
`Prolonged Release Tablets
`Manufacturing Problems
`References
`
`Chapter 4.
`
`Compressed Tablets by Direct Compression
`
`Ralph F. Shangraw
`I.
`II.
`
`III.
`IV .
`V .
`VI.
`VII.
`VIII.
`
`IX.
`X.
`
`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
`
`Chapter 5 .
`
`Compression—Coated and Layer Tablets
`William C. Gunsel and Robert G. Dusel
`
`I.
`II.
`III.
`IV.
`V.
`
`Compression Coating
`Formulations (Compression Coating)
`Inlay Tablets
`Layer Tablets
`Formulations (Layer)
`References
`
`Chapter 6.
`
`Effervescent Tablets
`
`Raymond Mohrle
`I.
`Introduction
`II.
`Raw Materials
`III.
`.IV.
`V.
`
`Processing
`Manufacturing Operations
`Tablet Evaluation
`
`

`
`nd Banker
`
`1
`
`1973).
`
`"Fences,
`
`36).
`65: 1155
`
`T1).
`(1977) .
`D. C.
`(1979).
`982).
`
`-0 (1970).
`
`418 (1966).
`
`e:.ists of
`
`‘. Academic
`
`).
`
`1- pre-
`a sym-
`ularkets,"
`. Orlando,
`
`Compressed Tablets by Wet Granulation
`
`Fred J . Banolelin
`
`Schering—PZough 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
`
`

`
`Bandelin
`
`Compressed Tablets by Wet Granulation
`
`179
`
`in diameter depending on the size of the granules, and ob-
`3/8 to 1 in.
`serving the efflux time. The glidant efficiency factor may then be deter-
`mined as follows:
`
`f:
`
`rate of flow in presence of glidant
`rate of flow in absence of glidant
`
`Since many materials used as glidants are also efficient lubricants, a
`reduction in interparticulate friction may also be encountered. This re-
`duction can occur in two ways:
`(a) The fine material may adhere to the
`surface rugosity, minimizing the mechanical interlocking of the particles.
`(Rugosity refers to surface roughness or deviation of shape from spherical.
`The coefficient of rugosity is defined as the ratio of actual surface area,
`as determined by a suitable method,
`to the geometric surface area found
`by microscopy.) (b) Certain glidants, such as talc and silica aerogels, roll
`under shear stresses to produce a "ball bearing" effect or type of action,
`causing the granules to roll over one another.
`in mixing, or
`Many powders acquire a static charge during handling,
`in an induced die feed. The addition of 1% or more of magnesium stearate
`or polyethylene glycol 4000 or 2% or more of talc effectively lowers the ac-
`cumulated charge.
`Magnesium oxide should be considered an auxiliary glidant to be used
`in combination with silica-type glidants, especially for granulations that
`tend to be hygroscopic or somewhat high in moisture content. Magnesium
`oxide binds water and keeps the granulation dry and free flowing.
`That anomalies exist in the action of glidants has been pointed out
`[86] in some cases of the physical and mechanical properties of mixtures of
`lactose, paracetamol, and oxytetracycline when small amounts of silica
`glidants are added to them. Owing to the differing propensities to coat
`the particles of the host powders,
`the silica aerogels act as a glidant for
`lactose and paracetamol but as an antiglidant for oxytetracycline.
`Selection of glidants must be determined by the formulator by trial and
`error since there is no way of predicting which will be effective in a spe-
`cific granulation.
`
`properties ,
`t varies
`
`VI . MULTILAYER TABLETS
`
`Multilayer tablets are tablets made by compressing several different granu-
`lations fed into a die in succession, one on top of another,
`in layers. Each
`layer comes from a separate feed frame with individual weight control. Ro-
`tary tablet presses can be set up for two or three layers. More are pos-
`sible but the design becomes very special.
`Ideally, a slight compression
`of each layer and individual layer ejection permits weight checking for
`control purposes.
`
`A. Advantages of Multilayer Tablets
`
`1.
`
`Incompatible substances can be separated by formulating them in
`separate layers as a two-layer tablet or separating the two layers
`by a third layer of an inert substance as a barrier between the
`two.
`
`BY
`'1gle of a
`Talc added
`
`size from
`
`

`
`Two layer tablets may be designed for sustained release—one
`layer for immediate release of the drug and the second layer for
`extended release, thus maintaining a prolonged blood level.
`Layers may be colored differently to identify the product.
`
`Ban delin
`
`B. Layer Thickness
`
`Layer thickness can be varied within reasonable proportions within the
`limitations of the tablet press. Thinness is dependent on the fineness of
`the granulation.
`
`C. Sizes and Shapes
`
`Size is limited by the capacity of the machine with the total thickness
`being the same as for a single-layer tablet. Many shapes other than
`round are possible and are limited only by the ingenuity of the die maker.
`However, deep concavities can cause distorition of the layers. Therefore,
`standard concave and flat—face beveled edge tooling make for the best ap-
`pearance, especially when layers are of different colors.
`
`D . Granulations
`
`For good-quality tablets with sharp definition between the layers, special
`care must be taken as follows:
`
`1. Dusty fines must be limited. Fines smaller than 100 mesh should
`be kept at a minimum.
`Maximum granule size should be less than 16 mesh for a smooth,
`uniform scrape-off at the die.
`Materials that smear, chalk, or coat on the die table must be
`avoided to obtain clean scrape—off and uncontaminated layers.
`Low moisture is essential if incompatibles are used.
`Weak granules that break down easily must be avoided. Excessive
`amounts of lubrication, especially metallic stearates, should be
`avoided for better adhesion of the layers.
`Formulation of multilayer tablets is more demanding than that of single-
`layer tablets. For this reason, selection of additives is critical.
`
`E. Tablet Layer Press
`
`A tablet multilayer press is simply a tablet press that has been modified
`so that it has two die-filling and compression cycles for each revolution of
`the press.
`In short, each punch compresses twice, once for the first
`layer of a two—layer tablet and a second time for the second layer. Three-
`layer presses are equipped with three such compression cycles.
`There are two types of layer presses presently in use—one in which
`each layer can be ejected from the press separately for the purpose of
`weight checking, and the second in which the first layer is compressed so
`hard that the second layer will not bond to it, or will bond so poorly
`that upon ejection the layers are easily separated for weighing. Once the
`
`Compress
`
`p rope: w
`pressire
`layers .
`
`Continuou
`feed Era:
`that WOUL
`tablet her
`appearar.
`press wit’.
`Cert '
`
`compress:
`speed p-
`l
`ziaking 50
`
`VIII. PR
`
`Prolonged
`method 11-
`
`agents or
`corporate
`znatrices,
`metallic so
`late, coat.
`prolonged
`Freely
`drugs bec
`Idealig
`a blood Le
`
`every 4 ‘:1
`release th
`for 8 to 1’
`They are 4
`one dose
`Prolon
`testinal tr
`
`drug too
`whereas 0
`
`proper be
`people wh
`Also, whe
`after seve
`response.
`PI-olon
`
`

`
`Shangraw
`
`7).
`
`0 (1966).
`
`. 2091 (1986).
`
`(1983).
`377 (1977).
`
`Society of
`I ‘can Phar-
`
`Compression-Coated and Layer Tablets
`
`William C. Gunsel*
`
`Robert G. Dusel
`
`Ciba—Geigy Corporation
`Summit, New Jersey
`
`Lachman Consultant Services, Inc.
`Westbury, New York
`
`I. COMPRESSION COATING
`
`two major developments in tableting presses occurred.
`In the early 1950s,
`Machines for compressing a coating around a tablet core and machines for
`making layer tablets appeared on the market. They were accepted enthusi-
`atically through the 1960s, but the compression-coating technique is rarely
`employed today in the manufacture of new products because of the advent
`of film coating with its relative simplicity and its cost advantages.
`The chief advantage was the elimination of water or other solvent in
`the coating procedure. Thus there is no need for a barrier coating to pre-
`vent water from penetrating the cores—possib1y softening them or initiating
`an undesired reaction. Such barriers, if efficient, slow down disintegration
`and dissolution. The dry coating is applied in a single step (in contrast to
`the repeated applications of different syrups), reducing the time required
`to evaporate the water and eliminating the necessity of cleaning the coating
`pan each time it becomes heavily encrusted with dried syrup. With dry
`coating,
`incompatible substances can be separated by placing one of them
`in the core and the other in the coating. There may be some reactivity
`at the interface but this should be negligible in the dry state.
`In addition,
`if a drug tends to discolor readily or develop a mottled appearance because
`of oxidation or sunlight, these problems can be minimized by incorporating
`the drug in the core tablet.
`Compression—coated tablets function like sugar-coated or film-coated tab-
`lets in that the coating may cover a bitter substance, conceal an unpleasant
`or mottled appearance, or provide a barrier for a substance irritating to
`the stomach or one inactivated by gastric juice. The advent of film coating
`
`*Currently retired.
`
`

`
`I and Dusel
`
`llection
`on,
`they
`struck by
`dies to
`
`ed with
`eeders into
`d frame
`I bin.
`ulation
`
`though the
`ot drop as
`1*‘ material
`
`econd layer
`ably need
`
`bove, except
`a cam
`
`yer is in-
`not bond to
`ffect is
`
`er tamping
`pression
`1 ey between
`equired to
`for several
`
`lets should
`' e fines
`pe—off at
`ion of a
`not dis-
`however,
`of fineness.
`cl should be
`
`ty in that
`the hydro-
`rtheless,
`rs; other-
`
`thickness
`~ formula-.
`' ed for
`the same
`es with
`
`Compression—Coated and Layer Tablets
`
`g\\\\\\\\\\\\\
`
`3
`
`Figure 12
`
`Cross sections of layer tablets.
`
`beveled edges or concave faces will make the top and bottom layers of a
`three—layer tablet appear thinner than the middle one. Flat-faced tooling
`will produce equal thickness of the layers, but unfortunately the edges of
`the tablets will tend to chip readily. Figure 12 shows cross sections of
`layer tablets and illustrates how the shape of the upper punch determines
`the shape of the layers.
`If the upper punch faces have monograms or
`other markings,
`the bonding between layers will be strengthened because
`the devices will act as keys between the layers. Additionally, precompres—
`sion lengthens dwell time and aids in bonding. The formulas previously
`given for compression-coated tablets will serve as a guide for the develop-
`ment of formulations for layer tablets, with the exception of two of those
`for direct compression (Examples 1 and 2), which are composed entirely of
`fine substances.
`
`An illustrative formula is one for an analgesic-antipyretic decongestant
`containing aspirin and phenylpropanolamine. A thin layer of placebo is
`placed between them to negate the chemical incompatibility of the active
`ingredients .
`
`Example 14: First Layer of
`Analgesic—Antipyretic Decongestant
`
`Ingredient
`
`Quantity per
`tablet
`
`Phenylpropanolamine HCI USP
`
`12.50 mg
`
`Lactose NF (spray—dried)
`
`55.00 mg
`
`Microcrystalline cellulose NF
`
`28.00 mg
`
`Colloidal silicon dioxide NF
`
`Stearic acid NF
`
`1.25 mg
`
`1.25 mg
`
`Screen where necessary to break down ag-
`glomerates or lumps (30 mesh screen is sat-
`isfactory) and blend the pheny|propanola—
`mine,
`lactose, colloidal silicon dioxide and
`stearic acid.
`
`

`
`Compress’
`
`Example 1
`Antacid T
`
`Sucrose N‘
`
`Saccharin
`
`Purified W
`
`Magnesium
`
`Peppermir:
`
`Blend the
`saccharin
`the sucro-
`
`and add i»
`tinue mixi
`is formed,
`
`if necessa
`'=.‘5 perfora
`ating at
`'
`Spread ‘tn
`:°;;:_'me:J:
`medium 5;:
`turn the -
`and add :2
`oil has
`.-
`
`280
`
`Gunsel and Dusel
`
`Example 15: Second Layer of
`Ana|gesic—Antipyretic Decongestant
`
`Ingredient
`
`Quantity per
`tablet
`
`Lactose NF (spray-dried)
`
`26.00 mg
`
`Microcrystalline Cellulose NF
`
`54.00 mg
`
`Colloidal silicon dioxide NF
`
`Stearlc acid NF
`
`1.00 mg
`
`1.00 mg
`
`Pass the lactose and microcrystalline cellulose
`through a 30 mesh screen and blend them in
`a suitable mixer. Add the stearic acid and
`colloidal silicon dioxide. Mix for 10 min.
`
`Example" 16: Third Layer of
`Analgesic-Antlpyretic Decongestant
`————————e:——j—————j
`
`Ingredient
`
`Aspirin 40 mesh crystals
`Starch 1500 NF
`Colloidal silicon dioxide NF
`
`Stearic acid NF
`
`Quantity per
`tablet
`
`81.0 mg’
`19.0 mg
`0.5 mg
`
`1.0 mg
`
`Blend in a suitable mixer until homogeneous
`(10 to 15 min). Compress the three layers
`together using 3/8-in. diameter,
`flat—faced,
`beve|ed—edge punches. The weight of each
`layer is:
`
`First layer, 98 mg
`Second layer, 82 mg
`Third layer, 101.5 mg
`
`layer to be pressed.
`The top layer is the last
`Since it
`is the aspirin portion,
`it will be most
`resistant to extrusion from the dies.
`
`Layer presses find employment in the manufacture of chewable antacid
`tablets. A possible formula for such a product follows. The mannitol pro-
`vides pleasant mouth—fee1 and sweetness, and the saccharin enhances the
`latter. Peppermint flavoring has a long and honorable association with ant-
`acid preparations. The sucrose acts as the binder, although, of course, it
`also contributes to the taste of the tablet.
`
`

`
`about the first edition .
`
`.
`
`.
`
`. represents the most comprehensive effort ever made in compiling technological, preformulation, and
`.
`“ .
`formulation concepts related to pharmaceutical tablets. .
`.
`. reviews the literature in a well-organized, highly
`cogent, and easily readable manner.”
`{
`—Pharmaceutical Technology
`
`. the editors have provided valuable information which is difficult to find elsewhere. Usually these unique
`.
`“ .
`tablet forms are treated very superficially or not at all in pharmaceutics textbooks.”
`—American Journal ofPharmaceutical Education
`
`about the second edition .
`
`.
`
`.
`
`Focusing on recent innovations in the field, the Second Edition continues to provide in-depth, authoritative
`information on the science and technology of tablet formulation, manufacture, and testing.
`
`Combining the work of 14 experts, Pharmaceutical Dosage Forms: Tablets, Second Edition
`contains new material on the formulation of sustained or prolonged release tablets by wet granulation, fluidized
`bed granulating, long-acting and controlled-release buccal tablets, vaginal and rectal tablets, and inclusion
`complexes and molecular complexes.
`
`Expanding its scope, the Second Edition also offers revised and updated coverage on such topics as drug
`substance purity, dissolution, partition coefficient, the permeability concept, miscellaneous pharmaceutical
`properties of solids, the development of prototype formulas, direct compression excipients, effervescent
`technology, stability testing and shelf-life, testing for airtightness of sealed packets, microencapsulation and
`spray coating, and more.
`
`about the editors .
`
`.
`
`.
`
`HERBERT A. LIEBERMAN is President of H. H. Lieberman Associates, Inc. in Livingston, New Jersey. He was for
`many years Vice-President of Proprietary Products Research and Director of Proprietary/Toiletry Product
`Development at Warner-Lambert Company, Inc. With Kenneth E. Avis and Leon Lachman he coedited the two-
`volume Pharmaceutical Dosage Farms: Parenteral Medications, and with Martin M. Rieger and Gilbert S.
`Banker he coedited the first volume of Pharmaceutical Dosage Forms: Disperse Systems (both titles, Marcel
`Dekker, Inc.). Dr. Lieberman received his undergraduate and graduate degrees in chemistry and pharmacy from
`Columbia University and the Ph.D. degree in pharmaceutical chemistry from Purdue University.
`
`LEON LACHMAN is President of Lachman,Consultant Services, Inc. in Westbury, New York. Dr. Lachman has
`over 30 years’ industrial experience in pharmaceutical science, including Director of Pharmacy Research and
`Development at CIBA Pharmaceutical Company and Vice President of Development and Control at DuPont
`Pharmaceuticals. Presently he is visiting professor at Rutgers University College of Pharmacy. Dr. Lachman
`has coedited, with Herbert A. Lieberman and Joseph L. Kanig, three editions of the textbook Theory and Practice
`of Industrial Pharmacy. He was honored with the Doctor of Science honoris causa (1976) from Columbia
`University and the Academy of Pharmaceutical Sciences Research Achievement Award (1979). Dr. Lachman
`received the B.Sc. degree in pharmacy and M.Sc. degree in industrial pharmacy from Columbia University, and
`Ph.D. degree in pharmaceutics from the University of Wisconsin.
`
`JOSEPH B. SCHWARTZ is the Linwood F. Tice Professor of Pharmaceutics and Director of Industrial Pharmacy
`Research at the Philadelphia College of Pharmacy and Science in Philadelphia, Pennsylvania. During 13 years at
`Merck Sharp & Dohme Research Laboratories, Dr. Schwartz was involved in the development of drug products,
`from the preliminary stages through scale-up and production. His research interests and publications have been
`in the areas of solid dosage form technology and processing, controlled release, and formulation and process
`optimization. The editor of the Journal ofParenteral Science and Technology, Dr. Schwartz is a Fellow of the
`Academy of Pharmaceutical Sciences and the American Association of Pharmaceutical Scientists. He received
`the B.S. degree from the Medical College of Virginia School of Pharmacy, and the M.S. and Ph.D. degrees from
`the University of Michigan.
`-
`is
`
`Printed in the United States ofAmerica
`
`ISBN: 0-8247-8044-2
`
`morcel dekker, inc./ new york - bosel