`
`"Apotexv.Cellgene- IPR2023-00512.
`
`Petitioner Apotex Exhibit 1030-0001
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0001
`
`

`

`Remington: The
`Science and Practice
`of Pharmacy
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0002
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0002
`
`

`

`collated on thebilliard table.
`
`Dr. Remington (seated right) reading galley proof. Galley proofs of USP Monogracns =
`
`WEPas.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0003
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0003
`
`

`

`2 0 TH EDITION
`
`
`DC Library
`
`JUN 03 2022
`
`Steptoe & Johnson LLP
`
`ALFONSO R GENNARO
`rial Board
`Chairman of the Edito
`and Editor
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0004
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0004
`
`

`

`.,.« Daniel Limmer
`Welptore
`4asith Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`Lippincott Williams & Wilkins
`a51 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`227 East Washington Square
`Philadelphia, PA 19106
`All rights reserved. This bookis protected by copyright. No part ofthis book may
`pe reproduced in any form orby any means, including photocopying, oF utilized
`y any information storage and retrieval system without written permission
`from the copyright owner.
`‘The publisher is not responsible (as a matter of product liability, negligence or
`otherwise) for any injury resulting from any material contained herein. This
`ublication contains information relating to general principles of medical care
`which should not be construed as specific instructions for individual patients.
`Manufacturers’ product information and package inserts should be reviewed for
`current information, including contraindications, dosages and precautions.
`printed in the United States of America
`Entered according +9 Act BY Congres, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`Copyright 1926, 1936, by the Joseph P Remington Estate
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila-
`delphia College of Pharmacy and Science
`Copyright 2000, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-683-306472
`
`The publishers have made every effort to trace the copyright holders for borrowed
`material. If they have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the firstspportunity.
`The use of structural formulas from USAN and the USP Dictionary of Drug
`Names is by permission of The USP Convention. The Convention is not respon
`gible for any inaccuracy contained herein.
`Notice—Tliis text ts not intended to represent, norshall it be interpretedto be, the
`equivalent ofoF & substitute for the official United States Pharmacopeia (USP)
`andlor the National Formulary (NF), In the event of any difference or discrep-
`anney between the current official USP or NF standards of strength, quality,
`nurity, packaging and labeling: for drugs and representations ofthemherein, the
`wontext and. effect of the official compendia shall prevail,
`To purchase additional copies of this book call our customer service department
`at (800) 638-3030 or fax orders to (801) 824-7390. International customers
`ghould call (801) 714-2324,
`;
`00 01 02.03 04
`12245678910
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0005
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0005
`
`

`

`Remington: The Science and Practice of Pharmacy .. . A treatise on the theory
`andpractice of the pharmaceutical sciences, with essential
`information about pharmaceutical and medicinal agents; also, a
`guide to the professional responsibilities of the pharmacist as the
`drug information specialist of the health team... A textbook and
`reference worl for pharmacists, physicians, and other practitioners of
`the pharmaceutical and medical sciences.
`
`EDITORS
`
`Alfonso R Gennaro, Chair
`
`Nicholas G Popovich
`
`Ara H Der Marderosian
`
`Glen R Hanson
`
`Thomas Medwick
`
`Roger L Schnaare
`
`Joseph B Schwartz
`
`H Steve White
`
`AUTHORS
`
`The 119 chapters of this edition of Remington were written by the
`
`editors, by members of the Editorial Board, and by the authors
`
`listed on pagesviii to x.
`
`Managing Editor
`
`John E Hoever, BSc (Pharm)
`
`Editorial Assistant
`
`Bonnie Grigharn Packer, RNC, BA
`
`Director
`
`Philip P Gerbina VR 5-200
`‘es
`
`Twentieth Edition—2000
`
`Published in the 180th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0006
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0006
`
`

`

`Table of Contents
`
`Part 1 Orientation
`
`oOnernRoOnea
`
`Scope of Pharmacy... 6.65.02. e reer
`Evolution of Pharmacy.......-.-+-228e8825 88
`Ethics and Professionalism. ....----- 2255574 sg
`The Practice of Community Pharmacy... . 6-6 6+
`Pharmacists in Industry... 6 ee es
`Pharmacists in Government ...- 00502 e ee eee
`Pharmacists and Public Health... ..---+25 25055
`Information Resources in Pharmacy and the
`Pharmaceutical Sciences... es
`Clinical Drug Literature... es
`Research... ee
`
`Part 2 Pharmaceutics
`
`Pharmaceutical Calculations... 6... eee ee eee
`Statistics... ee
`MolecularStructure, Properties, and States of Matter. .
`.
`Complex Formation. . 5... 05s s eter terete
`Thermodynamics... 62 es
`Solutions and Phase Equilibria... .. .
`lonic Solutions and Electrolytic Equilibria. .........
`Tonicity, Osmoticity, Osmolality, and Osmolarity....
`Chemical Kinetics 6.0 ee
`Interfacial Phenomena... 6.6 ee ee
`Colloidal Dispersions. 6... 6 es
`Coarse Dispersions... ee
`Rheology........---
`
`Part 3 Pharmaceutical Chemistry
`
`Inorganic Pharmaceutical Chemistry ...--.---- +>
`Organic Pharmaceutical Chemistry .. 2... +--+:
`Natural Products... 0. ee
`Drug Nomenclature—United States Adopted
`Names... 0. ee tee
`Structure-Activity Relationship and Drug Design... .
`.
`Fundamentals of Radionuclides .. 6... 50. eee
`
`Part 4 Pharmaceutical Testing, Analysis and Control
`
`Analysis of Medicinals. 0.0 ee
`Biological Testing ©... eet eee
`Clinical Analysis... ee
`Chromatography... ees
`Instrumental Methods of Analysis... 6... eee
`Dissolution... 0.2 ee
`
`Part 5 Pharmaceutical Manufacturing
`
`94
`124
`159
`183
`198
`208
`227
`246
`263
`275
`288
`316
`335
`
`359
`385
`409
`
`441
`458
`469
`
`485
`540
`552
`587
`614
`654
`
`AQ Biotechnology and Drugs... 6... eee eee
`50 Aerosols... ee
`54 Quality Assurance and Control... . 6 eee eee
`52 Stability of Pharmaceutical Products... ...-- +++
`53 Bioavailability and Bioequivalency Testing. ......-
`54 Plastic Packaging Materials... 5... eee eee ees
`55 Pharmaceutical Necessities... 2... ee eee ees
`
`Part 6 Pharmacodynamics
`
`56 Diseases: Manifestations and Pathophysiology ...- -
`57 Drug Absorption, Action, and Disposition .......--
`58 Basic Pharmacokinetics. 6... 666 eee
`59 Clinical Pharmacokinetics 2... es
`60 Principles of Immunology... 6. ese
`61 Adverse Drug Reactions... 6. eee ee
`62 Pharmacogenetics.6 es
`63 Pharmacological Aspects of Substance Aduse......
`
`Part 7 Pharmaceutical and Medicinal Agents
`
`64 Diagnostic Drugs and Reagents. ...-- 66+ ese eee
`65 Topical Drugs... 6.6... eee eee trees
`66 Gastrointestinal and Liver Drugs... .. 2... 05 5-++-
`67 Blood, Fluids, Electrolytes, and Hematological Drugs.
`.
`.
`.
`68 Cardiovascular Drugs... -ee
`69 Respirarory Drugs... . 6-2 ees
`70 Sympathomimetic Drugs 6.66... es
`741 Cholinomimetic Drugs 1...
`72 Adrenergic and Adrenergic Neuron Blocking Drugs. .
`73. Antimuscarinic and Antispasmodic Drugs ....-. +.
`74 Skeletal Muscle Relaxants... 6... eee ees
`75 Diuretic Drugs... es
`76 Uterine and Antimigraine Drugs .... 6.6... eres
`77 Hormones and Hormone Antagonists ........++-
`78 General Anesthetics... 0 eee
`79 Local Anesthetics... 06. ee
`80 Sedative and Hypnotic Drugs... 6... eee eee
`81 Antiepileptic Drugs... 6... es
`82 Psychopharmacolagic Agents... .. +. ere e es
`83 Analgesic, Antipyretic, and Anti-Inflarnmatory
`DIUGS2. es
`B84 Histamine and Antihistaminic Drugs... 2.2... .. 6
`85 Central Nervous System Stimulants... 2... 6 ee
`86 Antineoplastic and Immunoactive Drugs ...... +.
`87 Anti-lnfectives . 6... es
`BB Parasiticides... 0. eee
`89 Immunizing Agents and Allergenic Extracts ......
`Part 8 Pharmacy Practice
`
`944
`963
`980
`986
`995
`1005
`41015
`
`1053
`4098
`1427
`1145
`1156
`4165
`1169
`44175
`
`1185
`4200
`1219
`1243
`1274
`1297
`1305
`1314
`1322
`1328
`1333
`1344
`1354
`1358
`1395
`1400
`1407
`1421
`1429
`
`1444
`1464
`1471
`1477
`1507
`1562
`1567
`
`Part 8A Pharmacy Administration
`
`1640
`
`1650
`1666
`
`669
`Separation 2...ee ees
`681
`Powders... 2.0 es
`1595
`90 Laws Governing Pharmacy «6... 6. eee ens
`700
`1625
`Preformulation. 2.0.0... ee ee
`94 Pharmacoeconomics ... 05-6 ee ees
`721
`1634
`Solutions, Emulsions, Suspensions, and Extracts..
`92 Marketing Pharmaceutical Care Services . 6... . 21:
`7153
`Sterilization... es =
`93 Documenting and Billing for Pharmaceutical Care
`780
`Parenteral Preparations... 6. ee
`SEVICES2 es
`807
`Intravenous Admixtures 6... 5.02. ee eee
`94 Community Pharmacy Economics and
`824
`Ophthalmic Preparations ...........-5-- xis
`Management...00.
`836
`Medicated Topicals 60... 2. eee
`95 Product Recalls and Withdrawals ...--.--.. 5565
`858
`Oral Solid Dosage Forms»... 0.0.00. ees
`acs
`894
`Coating of Pharmaceutical Dosage Forms ..... -
`903
`Controlled-Release Drug-Delivery Systems... ---.
`930
`The Introduction of New Drugs ..... 6.0.6 bee
`
`Part 8D Fundamentals of Pharmacy Practice
`
`96 Drug Education... 2.2... et ees
`
`1677
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0007
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0007
`
`

`

`97
`98
`99
`400
`401
`402
`403
`
`104
`405
`406
`107
`108
`109
`
`Part 8C Patient Care
`110
`441
`112
`
`Ambulatory Patient Care... .
`Institutional Patient Care,
`Long-Term Care Facilities ,
`
`.
`
`The Prescription ©... ees
`Extemporaneous Prescription Compounding .. .
`Poison Control
`........00-. 000.
`Nutrition in Pharmacy Practice
`Self-Care/Diagnostic Products... ........0...02.
`Drug Interactions.
`.
`Complementary and Alternative Medical Health
`Care.
`Nuclear Pharmacy Practice
`Enzymes
`Vitamins and Orher Nutrients .
`Pesticides .,....
`Surgical Supplies .
`Health Accessories
`
`.
`
`.
`
`.
`
`1687
`1706
`1716
`1725
`1738
`1746
`
`1762
`1784
`1792
`1796
`1825
`1846
`1857
`
`1893
`1941
`4932
`
`.
`143 The Patient: Behavioral Determinants ,
`114 Patient Communication. ............
`115 Patient Compliance
`Ly
`116 Pharmacoepidemioclogy
`117 Integrated Health-Care Delivery Systems
`118 Home Health Patient Care
`119 Aseptic Technology for Home-Care
`Pharmaceuticals 6.6... eee
`
`Appendixes
`
`Dose Equivalents
`Periodic Chart. .....
`Logarithms ....
`
`Glossary .
`Index. .
`
`1948
`1957
`1966
`1980
`1990
`2012
`
`2020
`
`2033
`2034
`2036
`
`2037
`2039
`
`xv
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0008
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0008
`
`

`

`
`
`
`
`
`CHAPTER 45
`
`Oral Solid Dosage Forms
`
`Edward M Rudnic, PhD
`Vice President, Pharmaceutical Research and
`Development
`Pharmavene, Inc
`Gaithersburg, MD 20878
`
`Joseph D Schwartz, PhD
`Burraughs-Wellcome Fund Professorof
`Pharmaceutics
`Director of Industrial Pharmacy Research
`Philadelphia College of Pharmacy
`University of the Sciences in Philadelphia
`Philadelphia, PA 19104
`
`sevnpnkaSEASn
`
`
`
`Drug substances most frequently are administered orally by
`means of solid dosage forms such as tablets and capsules.
`Large-scale production methods used for their preparation, as
`described later in the chapter, require the presence of other
`materials in addition to the active ingredients. Additives also
`may be included in the formulations to facilitate handling,
`enhancethe physical appearance, improve stability, and aid in
`the delivery of the drug to the bloodstream after administra-
`tion. These supposedly inert ingredients, as well as the produc-
`tion methods employed, have been shown in some cases to
`influence the absorption or bioavailability of the drug substan-
`ces.! Therefore, care must be taken in the selection and eval-
`uation of additives and preparation methodsto ensure that the
`drug-delivery goals and therapeutic efficacy of the active ingre-
`dient will not be diminished.
`In a limited numberof cases it has been shown that the drug
`substance’s solubility and other physicochemical characteris-
`
`tics have influenced its physiological availability from a solid
`dosage form. These characteristics include its particle size,
`whetherit is amorphousor crystalline, whetherit is solvated or
`nonsolvated, and its polymorphic form.Afterclinically effective
`formulations are obtained, such variations among dosage units
`of a given batch, as well as batch-to-batchdifferences, should
`be reduced to a minimum through proper in-process controls
`and good manufacturing practices. The recognition of the im-
`portance of validation for both equipment and processes has
`enhanced assurance in the reproducibility of formulations
`greatly. It is in these areas that significant progress has been
`made with the realization that large-scale productionof a sat-
`isfactory tablet. or capsule depends not only on the availability
`of a clinically effective formulation but also on the raw mate-
`rials, facilities, personnel, documentation, validated processes
`and equipment, packaging, and the controls used during and
`after preparation (Fig 45-1).
`
`
`
`Tablets may be defined as solid pharmaceutical dosage forms
`containing drug substances with or without suitable diluents and
`prepared by either compression or molding methods. They have
`been in widespread use since the latter part of the 19th century,
`and their popularity continues. The term compressed tablet. is
`believed to have been used first by John Wyeth and Brother of
`Philadelphia. During this same period, molded tablets were in-
`troduced to be used as hypodermic tablets for the extemmporancous
`preparationof solutionsfor injection. Tablets remain popular as a
`dosage form because of the advantages afforded both to the man-
`ufacturer (eg, simplicity and economy of preparation, stability,
`and convenience in packaging, shipping, and dispensing) and the
`patient (eg, accuracy of dosage, compactness, portability, bland-
`ness of taste, and ease of administration).
`Although the basic mechanical approach for their manutfac-
`ture has remained the same, tablet technology has undergone
`great improvement. Efforts are being made continually to un-
`derstand more clearly the physical characteristics of powder
`compaction and the factors affecting the availability of the drug
`substance from the dosage form after oral administration.
`Tableting equipment continues to improve in both production
`speed and the uniformity of tablets compressed. Recent ad-
`vances in tablet technology have been reviewed.2-*
`Although tablets frequently are discoid in shape, they also
`may be round, oval, oblong, cylindrical, or triangular. They
`maydiffer greatly in size and weight depending on the amount
`of drug substance present and the intended method of admin-
`istration. They are divided into two general classes by whether
`
`8538
`
`they are made by compression or molding. Compressed tablets
`usually are prepared by large-scale production methods, while
`molded tablets. generally involve small-scale operations. The
`various tablet types and abbreviations used in referring to
`them arelisted below.
`:
`
`COMPRESSED TABLETS (CT)
`These tablets are formed by compression and contain no special coating.
`They are made from powdered,crystalline, or granular materials, alone
`or in combination with binders, disintegrants, controlled-release poly-
`mers, lubricants, diluents, and in many cases colorants.
`Sugar-Coated Tablets (SCT)---These are compressed tablets con-
`taining a sugarcoating. Such coatings may be colored and are beneficial
`in covering up drug substances possessing ohjectionable tastes or odors
`and in protecting materials sensitive to oxidation.
`Film-Coated Tablets (FCT)—These are compressed tablets that
`are covered with a thin layer or film of a watcr-soluble material. A
`number of polymeric substances with film-forming properties maybe
`used. Film coating imparts the same general characteristics as sugar
`coating, with the addcd advantage of a greatly reduced time period
`required for the coating operation.
`Enteric-Coated Tablets (ECT)--These are compressed tablets
`coated with substances that resist solution in gastric fluid but disintegrate
`in the intestine: Enteric coatings can be used for tablets containing drug
`substances that are inactivated or destroyed in the stomach,for those that
`irritate the mucosa, or as a meansof delayed release of the medication.
`Multiple Compressed Tablets (MCT)—These are compressed
`tablets made by more than one comipression cycle.
`Layered Tablets—Such tablets are prepared by compressing addi-
`tional tablet. granulation on a previously compressed granulation. The
`operation may be repeated to produce multilayered tablets of two or
`
`Apotex v. Cellgene - IPR2023-00512 ]
`Petitioner Apotex Exhibit 1030-0009
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0009
`
`

`

`
`
`
`
`
`ORAL SOLID DOSAGE FORMS
`
`859
`
`tion of poorly soluble compounds. Sublingual tablets, such as those
`containing nitroglycerin,
`isoprotcrenol hydrochloride, or erythrityl
`tetranitrate, are placed under the tongue. Sublingual tablets dissolve
`rapidly, and the drug substances are absorbed readily by this form of
`administration.
`
`MOLDED TABLETS OR TABLET TRITURATES (TT)
`Tablet triturates usually are made from moist material, using a tritu-
`rate mold that gives themthe shape of cut sections of a cylinder. Such
`tablets must be completely and rapidly soluble. The problem arising
`from compression of these tablets is the failure to find a lubricant that
`is completely water-soluble.
`Dispensing Tablets (DT)—These tablets provide a convenient
`quantity of potent drug that can be incorporated readily into powders
`and liquids,-thus circumventing the necessity Lo weigh small quantities.
`These tablets are supplied primarily as a convenience for ‘extempora-
`neous compounding and should never be dispensed as a dosage form.
`Hypodermic Tablets (HT)—Hypodermic tablets are soft, readily
`soluble tablets and originally were usedfor the preparation of solutions
`to be injected., Since stable parenteral solutions are now available for
`most drug substances, there is no justification for the use of hypodermic
`tablets for injection. Their use in this manner should be discouraged,
`since the resulting solutions are not sterile. Large quantities of these
`tablets continue to be made, but for oral administration. No hypodermic
`tablets ever have been recognized by theofficial compendia.
`
`
`
`
`
`Figure 45-1. Tablet press operators checking batch record in conform-
`ance with Current Good Manufacturing Practices (courtesy,Lilly).
`
`three layers, Special tablet presses are required to make layered tablets
`such as the Versa press (Stokes/Pennwealt).
`Press-Coated Tablets—Suchtablets, also referred to as dry-coated,;
`are prepared by feeding previously compressed tablets into a special
`tableting machine and compressing another granulation layer around
`the preformed tablets. They have all the advantages of compressed
`tablets, ic, slotting, monogramming, speed of disintegration, ete, while
`retainingthe attributes of sugar-coated tablets in masking the taste of
`the drug substance in the core tablets. An example ofa press-coated
`tablet press is the Manesty Drycota. Press-coated tablets also can be
`used to separate incompatible drug substances; in addition, they can
`provide a meansof giving an enteric coating to the core tablets. Both:
`types of multiple-compressed tablets have been used widely in the
`design of prolonged-action dosage forms:
`Controlled-Release Tablets--Compressed tablets can be formu-
`lated to release the drug slowly over a prolonged period of time. Hence,
`these dosage forms have been referred to as prolonged-release or
`sustained-release dosage forms as well. Thesetablets (as well as capsule
`versions) can be categorized into three types: (1) those that respond to
`some physiological condition to release the drug, such as entoric coat-
`ings;'(2) those that release the drug in a relatively steady,. controlled
`manner; and (3) those that combine combinations of mechanisms to
`release pulses of drug, such as repeat-action tablets. The performance of
`these systems is described in more detail in Chapter 47,
`Tablets for Solution—-Compressed tablets to be used for prepar-
`ing solutions or imparting given characteristics to solutions must be
`labeled to indicate that they are not to be swallowed. Examplesof these
`tablets are Halazone Tablets for Solution and Potassium Permanganate
`Tablets for Solution.
`Effervescent Tablets—In addition to the drug substance, these
`contain sodium bicarbonate and an organic acid.such as tartaric or
`citric, In the presence of water, these additives react, liberating carbon
`dioxide that acts as a distintegrator.and produceseffervescence. Except
`for small quantities of lubricants present, effervescent tablets are
`soluble.
`Compressed Suppositories or Inserts—Occasionally, vaginal
`suppositorics, such as Metronidazole Tablets, are prepared by compres-
`sion. Tablets for this use usually contain lactose as the diluent: In this
`case, as well as for any tablet intended for administration other than by
`swallowing, the label must indicate the mannerin whichitis to be used.
`Buccal and Sublingual Tablets—These are small, flat, oval tab-
`lets. Tablets intended for buccal administration by inserting into the
`buccal pouch may dissolve or erode slowly; therefore, they are formu-
`lated and compressed with sufficient pressure to give a hard: tablet.
`Progesterone Tablets may be administered in this way.
`Some newerapproaches use tablets that melt at body tempcratures.
`The matrix ofthe tablet is solidified while the drug is in solution. After
`melting, the drug is automatically in solutionand available for absorp-
`tion, thus eliminating dissolution as a rate-limiting step in the absorp-
`
`For medicinal substances, with or without diluents, to be made into
`solid dosage forms with pressure, using available equipment, it is
`necessary that the material, cither in crystalline or powdered form,
`possess a numberof physical characteristics. These characteristics in-
`clude the ability to flow freely, cohesiveness, and lubrication. The in-
`gredients such as disintegrants designed to break the tablet up
`in gastrointestinal (GI) fluids and controlled-release polymers designed
`to slow drug release ideally should possess these characteristics or not
`interfere with the desirable performance traits of the other excipients,
`Since most materials have none or only some of these properties, meth-
`ods of tablet formulation and preparation have been developed to im-
`part these desirable characteristics to the material that is to be com-
`pressed into tablets.
`The basic mechanical unit in all tablet-compression equipmentin-
`cludes a lower punch that fits into a dic from the bottom and an upper
`punch, with a head of the same shape and dimensions, which enters the
`die cavity from the top after the tableting material fills the die cavity
`(see Fig 45-2), The tablet is formed by pressure applied on the punches
`and subsequently is ejected from the die. The weight of the tablet is
`determined by the volume of the material that fills the die cavity.
`Therefore, the ability of the granulation to flow freely into the die is
`important in ensuring a uniformfill, as well as the continuous move-
`ment of the granulation from the source of supply or feed hopper. Ifthe
`tablet granulation does not possess cohesive properties, the tablet after
`compression will crumble and fall apart on handling. As the punches
`must movefreely within the die and the tablet must be ejected readily
`from the punchfaces, the material must have a degree of lubrication to
`minimize friction and allow the removalof the compressed tablets.
`There are three general methods of tablet preparation: the wet-:
`granulation mcthod, the dry-granulation method, and direct. compres-
`sion.’ The methodofpreparation and the added ingredients are selected
`to give the tablet formulation the desirable physical characteristics
`allowingthe rapid compression of tablets. After compression, the tab-
`
`
`
`Figure 45-2. Basic mechanical unit for tablet compression: lower
`punch, die, and upper punch (courtesy, Vector/Colton).
`
`
`
`
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0010
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1030-0010
`
`

`

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`CHAPTER 45
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`lets must have a numberofadditiona! attributes such as appearance,
`hardness, disintegration ability, appropriate dissolution characteris-
`tics, and uniformity, which also are influenced both by the method of
`preparation and by the added materials present in the formulation. In
`the preparation of compressed tablets, the formulator also must be
`cognizantof the effect that the ingredients and methodsof preparation
`may have on the availability of the aclive ingredients and, hence, the
`therapeutic efficacy of the dosage form. In response tu a request by
`physicians to change a dicumarol tablet so that it might be broken more
`easily, a Canadian company reformulated to make a large tablet with a
`score. Subsequent use of the tablet, containing the same amountof drug
`substance as the previous tablet, resulted in complaints that larger-
`than-usual doses were needed to produce the same therapeutic re-
`sponse. On the other hand, literature reports indicate that the refor-
`mulation of a commercial digoxin tablet resulted in a tablet that,
`although containing the same quantity of drug substance, gave the
`desired clinical response at halfits original dose. Methods and princi-
`ples that can be usedto assess the effects of excipients and additives on
`drug absorption have been reviewed.”* See Chapters 38, 53, and 58.
`
`
`
`TABLET INGREDIENTS
`
`In addition to the active or therapeutic ingredient, tablets
`contain a numberof inert materials. The latter are known as
`additives or excipients. They may be classified according to the
`part they play in the finished tablet. The first group contains
`those that help to impart satisfactory processing and compres-
`sion characteristics to the formulation. These include diluents,
`binders, glidants, and lubricants. The second group of added
`substances helps to give additional desirable physical charac-
`teristics to the finished tablet. Included in this group are dis-
`integrants, colors, and, in the case of chewable tablets, flavors
`and sweetening agents, and in the case of controlled-release
`tablets, polymers or waxes or other solubility-retarding
`materials.
`Although the term inert has been applied to these added
`materials, it is becoming increasingly apparent that there is an
`important relationship between the properties of the excipients
`and the dosage forms containing them. Preformulation studies
`demonstrate their influence on stability, bioavailability, and
`the processes by which the dosage forms are prepared. The
`need for acquiring more information and use standards for
`excipients has been recognized in a joint venture of the Acad-
`emy of Pharmaceutical Sciences and the Council of the Phar-
`maceutical Society of Great Britain. The result is called the
`Handbook ofPharmaceutical Excipients. This reference now is
`distributed widely throughout the world.1¢
`
`‘Diluents
`
`Frequently, the single dose of the active ingredient is small,
`and an inert substance is added to increase the bulk to make
`the tablet a practical size for compression. Compressed tablets
`of dexamethasone contain 0.75 mg steroid per tablet; hence, it
`is obvious that another material must be added to maketablet-
`ing possible. Diluents used for this purpose include dicalcium
`phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol,
`sodium chloride, dry starch, and powdered sugar. Certain di-
`luents, such as mannitol, lactose, sorbitol, sucrose, andinositol;
`when present in sufficient quantity, can impart properties to
`some compressed tablets that permit disintegration in the
`mouth by chewing. Such tablets commonly are called chewable
`tablets. Upon chewing, properly prepared tablets will disinte-
`grate smoothly at a satisfactory rate, have a pleasant taste and
`feel, and leave no unpleasant aftertaste in the mouth. Diluents
`used as excipients for direct compression formulas have been
`subjected to prior processing to give them flowability and com-
`pressibility. These are discussed under Direct Compression,
`page 869.
`
`Most formulators of immediate-release tablets tend to use
`consistently only one or two diluents selected from the above
`group in their tablet formulations. Usually, these have been
`selected on the basis of experience and cost factors. However, in
`the formulation of new therapeutic agents, the compatibility of
`the diluents with the drug must be considered;eg, calcium salts
`used as diluents for the broad-spectrum antibiotic tetracycline
`have been shown to interfere with the drug’s absorption from
`the GI tract. When drug substances have low water solubil-
`ity, it is recommended that water-soluble diluents be used to
`avoid possible bioavailability problems. Highly adsorbent sub-
`stances, eg, bentonite and kaolin, are to be avoided in making
`tablets of drugs used clinically in small dosage, such as the
`cardiac glycosides, alkaloids, and the synthetic estrogens.
`These drug substances may be adsorbed after administration.
`The combination of amine bases with lactose, or amine salts
`with lactose in the presence of an alkaline lubricant results in
`tablets that discolor on aging.
`Microcrystalline cellulose (Avicel) usually is used as an ex-
`cipient in direct-compression formulas. However, its presence
`in 5 to 15% concentrations in wet granulations has been shown
`to be beneficial in the granulation and drying processes in
`minimizing case-hardening of the tablets and in reducing tab-
`let. mottling.
`Many ingredients are used for several different purposes,
`even within the same formulation; eg, corn starch can be used
`in paste form as a binder: When added in drug or suspension
`form,it is a good disintegrant. Even though these two uses are
`to achieve opposite goals, some tablet formulas use corn starch
`in both ways. In some controlled-release formulas, the polymer
`hydroxypropylmethylcellulose (HPMC) is used both as an aid
`to prolong the release from the tablet as well as a film-former in
`the tablet coating. Therefore, most excipients used in formu-
`lating tablets and capsules have many uses, and a thorough
`understanding of their properties and limitations is necessary
`to use them rationally.
`
`Binders
`
`Agents used to impart cohesive qualities to the powdered ma-
`terial are referred to as binders or granulators. They impart a
`cohesiveness to the tablet formulation that ensures the tablet
`remaining intact after compression, as well as improving the
`free-flowing qualities by the formulation of granulesof desired
`hardness-and size. Materials commonly used as binders include
`starch, gelatin, and sugars such as sucrose, glucose, dextrose,
`molasses, and lactose. Natural and synthetic gums that have
`been used include acacia, sodium alginate, extract of Irish
`moss, panwar gum, ghatti gum, mucilage of isapol husks,
`carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
`Veegum, and larch arabogalactan. Other agents that may be
`considered binders under certain circumstances are polyethyl-
`eneglycol, ethylcellulose, waxes, water, and alcohol.
`The quantity of binder used has considerable influence on
`the characteristics of the compressed tablets. The use of too
`much binderor too strong a binder-will make a hard tablet:that
`will not disintegrate easily and will cause excessive wear of
`punches and dies. Differences in binders used for CT Tolbut-
`amide resulted in differences in hypoglycemic effects observed
`clinically. Materials that have no cohesive qualities of their
`own will require a stronger binder than those with these qual-
`ities. Alcohol and water:are not binders in thetrue senseof the
`word, but because of their solvent action on some ingredients
`such as lactose, starch, and celluloses, they change the pow-
`dered material to granules, and the residual moisture retained
`enables the materials to adhere together when compressed.
`Binders are used both as a solution and in a dry form,
`depending on the other ingredients in the formulation and the
`method of preparation. However,
`several pregelatinized
`starches’ available are intended to be added in the dry form so
`
`Apotex v. Cellgene - IPR2023-00512 ]
`Petitioner Apotex Exhib