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`MYLAN - EXHIBIT 1050
`
`

`

`£
`
`2 1 S T E D I T I O N
`
`Remington
`
`The Science and Practice
`of Pharmacy
`
`LIPPINCOTT WILLIAMS 6 WILKINS
`A Wolters Kluwer Company
`Philadelphia • Baltimore • New York • London
`Buenos Aires • Hong Kong • Sydney • Tokyo
`
`

`

`Editor: David B. Troy
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Marisa A. O'Brien
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`Baltimore, Maryland 21201-2436 USA
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`including photocopying, or utilized by any information storage and retrieval system without written permission from the copy­
`right 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 publication contains information relating to general principles of medical care which should not
`be construed as specific instructions for individual patients. Manufacturer's 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 to Act of Congress, 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 Philadelphia College of Pharmacy and Science
`
`Copyright 2000, 2006, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-7817-4673-6
`
`Remington: The Science and Practice of Pharmacy . . . A treatise on the theory
`and practice 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 work for pharmacists, physicians, and other practitioners of
`the pharmaceutical and medical sciences.
`
`EDITORIAL BOARD
`
`Paul Beringer
`
`Pardeep K. Gupta
`
`Ara DerMarderosian
`
`John E. Hoover
`
`Linda Felton
`
`Steven Gelone
`
`Nicholas G. Popovich
`
`William J. Reilly, Jr
`
`Alfonso R. Gennaro
`
`Randy Hendrickson, Chair
`
`AUTHORS
`
`The 133 chapters of this edition of Remington were written by
`
`the editors, by members of the Editorial Board, and by the au­
`
`thors listed on pages xi to xv.
`
`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 first opportunity.
`
`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 responsible for any inaccuracy contained herein.
`
`Notice—This text is not intended to represent, nor shall it be interpreted to be, the equivalent of or a substitute for the official
`United States Pharmacopeia (USP) and! or the National Formulary (NF). In the event of any difference or discrepancy between the
`current official USP or NF standards of strength, quality, purity, packaging and labeling for drugs and representations of them
`herein, the context 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 (301)
`824-7390. International customers should call (301) 714-2324.
`
`2 3 4 5 6 7 8 9 1 0
`
`Director
`
`Philip P Gerbino 1995-2005
`
`Twenty-first Edition—2005
`
`Published in the 185th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`

`

`Contents
`
`5
`6
`
`8
`
`20
`30
`35
`40
`51
`
`,64
`74
`.87
`
`.495
`553
`565
`599
`,633
`,672
`
`part 1 Orientation
`Scope of Pharmacy
`1
`Evolution of Pharmacy
`2
`Ethics and Professionalism
`The Practice of Community Pharmacy ....
`Pharmacists in Industry
`Pharmacists in Government
`Pharmacists and Public Health
`Information Resources in Pharmacy and the
`Pharmaceutical Sciences
`Clinical Drug Literature
`9
`Research
`10
`Part 2 Pharmaceutics
`,99
`Metrology and Pharmaceutical Calculations
`1 1
`127
`Statistics
`1 2
`Molecular Structure, Properties, and States of Matter . . .162
`13
`186
`Complex Formation
`14
`.201
`Thermodynamics
`15
`, 2 1 1
`Solutions and Phase Equilibria
`16
`,231
`Ionic Solutions and Electrolytic Equilibria
`17
`,250
`Tonicity, Osmoticity, Osmolality, and Osmolarity
`18
`266
`Chemical Kinetics
`19
`,280
`Interfacial Phenomena
`20
`,293
`Colloidal Dispersions
`2 1
`,319
`Coarse Dispersions
`22
`,338
`Rheology
`23
`Part 3 Pharmaceutical Chemistry
`Inorganic Pharmaceutical Chemistry
`24
`Organic Pharmaceutical Chemistry
`25
`Natural Products
`26
`Drug Nomenclature—United States Adopted Names .
`27
`Structure-Activity Relationship and Drug Design
`28
`Fundamentals of Medical Radionuclides
`29
`Part 4 Pharmaceutical Testing, Analysis, and Control
`Analysis of Medicinals
`30
`Biological Testing
`31
`Clinical Analysis
`32
`Chromatography
`33
`Instrumental Methods of Analysis
`34
`Dissolution
`35
`Part 5 Pharmaceutical Manufacturing
`,691
`Separation
`36
`702
`Powders
`37
`,720
`Property-Based Drug Design and Preformulation
`38
`,745
`Solutions, Emulsions, Suspensions, and Extracts
`39
`,776
`Sterilization
`40
`,802
`Parenteral Preparations
`41
`,837
`Intravenous Admixtures
`42
`,850
`Ophthalmic Preparations
`43
`,871
`Medicated Topicals
`44
`,889
`Oral Solid Dosage Forms
`45
`,929
`Coating of Pharmaceutical Dosage Forms
`46
`Extended-Release and Targeted Drug Delivery Systems . .939
`47
`The New Drug Approval Process and
`48
`.965
`Clinical Trial Design
`
`,361
`,386
`.410
`. . .443
`.468
`.479
`
`94
`95
`96
`97
`98
`99
`
`Biotechnology and Drugs
`49
`Aerosols
`50
`Quality Assurance and Control
`51
`. . .
`Stability of Pharmaceutical Products
`52
`Bioavailability and Bioequivalency Testing
`53
`Plastic Packaging Materials
`54
`Pharmaceutical Necessities
`55
`Part 6 Pharmacokinetics and Pharmacodynamics
`. . .
`Diseases: Manifestations and Pathophysiology
`56
`Drug Absorption, Action, and Disposition
`57
`. .
`Basic Pharmacokinetics and Pharmacodynamics
`58
`Clinical Pharmacokinetics and Pharmacodynamics .
`59
`Priniciples of Immunology
`60
`Adverse Drug Reactions and Clinical Toxicology
`61
`Pharmacogenomics
`62
`Pharmacokinetics/Pharmacodynamics in
`63
`Drug Development
`Part 7 Pharmaceutical and Medicinal Agents
`1 2 6 1
`Diagnostic Drugs and Reagents
`64
`1277
`Topical Drugs
`65
`1294
`Gastrointestinal and Liver Drugs
`66
`Blood, Fluids, Electrolytes, and Hematological Drugs . . .1318
`67
`1350
`Cardiovascular Drugs
`68
`1371
`Respiratory Drugs
`69
`1379
`Sympathomimetic Drugs
`70
`1389
`Cholinomimetic Drugs
`71
`Adrenergic Antagonists and Adrenergic
`72
`1399
`Neuron Blocking Drugs
`1405
`Antimuscarinic and Antispasmodic Drugs
`73
`1411
`Skeletal Muscle Relaxants
`74
`1422
`Diuretic Drugs
`75
`1432
`Uterine and Antimigraine Drugs
`76
`1437
`Hormones and Hormone Antagonists , .
`77
`1474
`General Anesthetics
`78
`1479
`Local Anesthetics
`79
`1486
`Antianxiety Agents and Hypnotic Drugs
`80
`1501
`Antlepileptic Drugs
`81
`1509
`Psychopharmacologic Agents
`82
`Analgesic, Antipyretic, and Anti-Inflammatory Drugs . . .1524
`83
`1543
`Histamine and Antihistaminic Drugs
`84
`1551
`Central Nervous System Stimulants
`85
`1556
`Antineoplastic Drugs
`86
`1588
`Immunoactive Drugs
`87
`1595
`Parasiticides
`88
`1600
`Immunizing Agents and Allergenic Extracts
`89
`1626
`Anti-lnfectives
`90
`1685
`Enzymes
`91
`1688
`Nutrients and Associated Substances
`92
`1719
`Pesticides
`93
`Part 8 Pharmacy Practice
`A Fundamentals of Pharmacy Practice
`Application of Ethical Principles to Practice Dilemmas . . 1745
`1753
`Technology and Automation
`1762
`The Patient: Behavioral Determinants
`1770
`Patient Communication
`1782
`Patient Compliance . . .
`1796
`Drug Education
`
`,976
`1000
`1018
`1025
`1037
`1047
`1058
`
`1095
`1142
`1171
`1191
`1206
`1 2 2 1
`1230
`
`1249
`
`. .
`
`. . . .
`
`xxi
`
`

`

`CONTENTS
`
`xxii
`
`100
`1 0 1
`1 0 2
`
`103
`104
`105
`106
`107
`108
`109
`1 1 0
`
`1 1 1
`1 1 2
`113
`114
`115
`1 1 6
`
`- -.
`
`. ...
`
`.1808
`1823
`
`1840
`1881
`1889
`1903
`1913
`1925
`.1958
`1968
`. .1979
`
`.
`
`Professional Communications
`The Prescription
`Providing a Framework for Ensuring
`Medication Use Safety
`Poison Control
`Drug Interactions
`Extemporaneous Prescription Compounding
`Nuclear Pharmacy Practice
`Nutrition in Pharmacy Practice
`Pharmacoepidemiology
`Surgical Supplies
`. -
`Health Accessories
`B Social, Behavioral, Economic, and
`Administrative Sciences
`.2015
`Laws Governing Pharmacy
`.2055
`Re-engineering Pharmacy Practice
`,2070
`Pharmacoeconomics
`Community Pharmacy Economics and Management . .2082
`2098
`Product Recalls and Withdrawals
`2107
`Marketing Pharmaceutical Care Services
`
`117
`
`1 1 8
`119
`
`120
`1 2 1
`1 2 2
`
`123
`124
`125
`1 2 6
`127
`128
`129
`130
`131
`132
`133
`
`,2155
`,2163
`
`2114
`,2124
`,2130
`
`Documenting, Billing, and Reimbursement for
`Pharmaceutical Care Services
`Pharmaceutical Risk Management
`Integrated Health Care Delivery Systems ....
`C Patient Care
`Specialization in Pharmacy Practice
`Pharmacists and Disease State Management
`Development of a Pharmacy Care Plan and
`2170
`Patient Problem-Solving
`,2179
`Ambulatory Patient Care
`.2197
`Self-Care
`.2206
`Diagnostic Self-Care
`.2223
`Preventive Care
`.2247
`Hospital Pharmacy Practice
`.2255
`Emergency Medicine Pharmacy Practice
`.2272
`Long-Term Care
`Aseptic Processing for Home Infusion Pharmaceuticals .2290
`2303
`The Pharmacist's Role in Substance Use Disorders
`Complementary and Alternative Medical Health Care . .2318
`2342
`Chronic Wound Care
`
`P A R T 1
`
`Orientation
`
`Ara DerMarderosian, PhD
`Professor of Pharmacognosy
`Research Professor of Medicinal Chemistry
`University of the Sciences in Philadelphia
`Philadelphia, PA
`
`

`

`888
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`note that with few exceptions, most of these compounds—in
`contrast to the parabens—do not have a half-century history
`of use nor have had extensive patch-testing experiments car­
`ried out.
`Following selection of preservative candidates and prepara­
`tion of product prototypes, the efficacy of the preservative sys­
`tem must be evaluat ed. A variety of methods to accomplish this
`have been proposed. The organism challenge procedure is cur­
`rently the most acceptable. In this procedure, the test-product
`formulation is inoculated with specific levels and types of mi­
`croorganisms, Preservative efficacy is evaluated on the basis of
`the number of organisms killed or whose growth is inhibited as
`determined during a specific sampling schedule. Critical to the
`organism challenge procedure are the selection of challenge mi­
`croorganisms, the level of organisms in the inoculum, the sam­
`pling schedule, and data interpretation.
`In addition to efficacy in terms of antimicrobial effects, the
`preservative system must be assessed in terms of chemical
`and physical stability as a function of time. This often is done
`using antimicrobial measurements in addition to chemical
`analysis.
`
`REFERENCES
`1. Bodde HE, van den Brink I, Koerten HK, et al. J Control Rel 1991;
`15:227.
`2. Rougier A, Lotte C. In Shah VP, Maibach HI, eds. Topical Drug
`Bioavailability, Bioequivalence, and Penetration. New York: Plenum
`Press, 1993, p 163.
`3. Franz TJ. J Invest Dermatol 1975; 64:191.
`4. Scheuplein RJ, Ross LW. J Invest Dermatol 1974; 63:353.
`5. Bartek MJ, La Bodde JA, Maibach HI. J Invest Dermatol 1972;
`58:114.
`6. Maibach HI, ed. Animal Models in Dermatology. Edinburgh:
`Churchill Livingstone, 1975, p 110.
`7. Wester RC, Maibach HI. J Invest Dermatol 1976; 67:518.
`8. Bronaugh RL. In Kemppainen BW, Reifenrath WG, eds. Methods for
`Skin Absorption. Boca Raton, FL: CRC Press, 1990, p 61,
`9. Mershon MM, Callahan JF. In Maibach HI, ed. Animal Models in
`Dermatology. Edinburgh: Churchill Livingstone, 1975, p 36.
`10. Lorenzetti OJ. In Maibach HI, ed. Animal Models in Dermatology.
`Edinburgh: Churchill Livingstone, 1975, p 212.
`11. Maibach HI. In Maibach HI, ed. Animal Models in Dermatology. Ed­
`inburgh: Churchill Livingstone, 1975, p 221.
`12. Niemiec SM, et al. Drug Delivery 1997; 4:33.
`13. Flynn GL. In Shah VP, Maibach HI, eds. Topical Drug Bioavailabil-
`ity, Bioequivalence, and Penetration. New York: Plenum Press, 1993,
`p 369.
`14. Walters KA. In Hadgraft J, Guy RH, eds. Transdermal Drug Deliv­
`ery. New York: Dekker, 1989, p 197.
`15. Ghosh TK, Banga AK. Pharm Technol 1993; 17(4);62; 1993; 17(5):68.
`16. Scheuplein RJ, Ross LW. J Soc Cosmet Chem 1970; 21:853.
`17. Christophers E, Kligman AM. In Montagna W, ed. Advances in the
`Biology of Skin, vol 6. Oxford: Pergamon, 1965, p 163.
`18. Benowitz NL, et al. Clin Pharmacol Ther 1992; 52:223.
`19. Roskos KV, Maibach HI, Guy RH. J Pharmacokin Biopharm 1989;
`17:617,
`20. Sloan KB, Bodor N. Int J Pharm 1982; 12:299.
`21. Wood E, Wilson CG, Hardy JG. Int J Pharm 1985; 25:191.
`22. Bottger WM, et al. J Pharmacokinet Biopharm 1990; 18:1.
`
`23. Abd-El-Maeboud KH, et al. Lancet 1991; 338:798.
`24. Tukker JJ, de Blaey C.I, Charbon GA. Pharm Res 1984 1
`25. Parrott EL. Pharm Res 1971; 60:867.
`26. Benziger DP, Edelson J. J. Drug Metab Rev 1983: 14:137
`27. Patel LG, Warrington SJ, Pearson RM. Br Med J 1983- 2&
`28. Roffe BD, Zimmer RA, Derewicz HJ. AJHP 1977; 34-13,<• '
`29. Allen LV, Stiles ML. US Pharm 1988; 13(1):16.
`30. Ostrenga J, Steinmetz C, Poulsen B. J Pharm Sci 197i
`31. Flynn GL, Weiner ND, et al. Int J Pharm 1989; 55:229
`32. Banga AK, Chien YW. J Control Rel 1988; 7:1.
`33. Bumette RR. In Hadgraft J, Guy RH, eds. Transdermal br
`ery. New York: Dekker, 1989, p 247.
`34. Hsu C-S, Block LH. Pharm Res 1996; 13:1865.
`35. Ramanathan S, Block LH. -7 Contr Rel 2001; 70:109.
`36. Ghosh TK, Banga AK. Pharm Technol 1993; 17(3):2.
`37. Balsam MS, Sagarin E, eds. Cosmetics Science and Teehnl
`ed, vol. 1. New York: Wiley-Interscience, 1972, p 205.
`38. Merino G. Kalia YN, Guy RH. J Pharm Sci 2003; 92-11 •
`39. Henry S, et al. J Pharm Sci 1998; 87:922.
`40. Lowenthal W, Borzelleca JF. J Pharm Sci 1965; 54:1790,
`41. Collins AP, Hohmann JR, Zopf LC. Am Prof Pharm 1 tK" j
`42. Snipes WC. US Pat 5,004,601, Apr 2, 1991.
`43. Davis H. Bentley's Text-Book of Pharmaceutics, 7th ed, L01
`Here, Tindall & Cox, 1961, p 569.
`44. Buchi J. Pharm Acta Helv 1940; 20:403.
`45. Lorenzetti OJ, Wernet TC. Dermatologica 1977; 154:244.
`
`BIBLIOGRAPHY
`Chien YW, ed. Transdermal Controlled Systemic Medicaa
`York: Dekker, 1987.
`Chien YW. Novel Drug Delivery Systems, 2nd ed. New
`1992.
`Flynn GL. In Shah VP, Maibach HI, eds. Topical Drug Bim
`Bioequivalence, and Penetration. New York: Plenum fJr.;
`369.
`Frost P, Gomez EC, Zaias N. Recent Advances in
`ogy. New York: Spectrum Publ, 1978.
`Glas B, deBlaey CJ, eds. Rectal Therapy. Barcelona: .IR I'mut, uH
`Guy RH, Hadgraft J. In Maibach H, Lowe R, eds. Models in /Jt-rJ
`ogy, vol 2, 5. Basel: Karger, 1985, p 170.
`Higuchi T. J Soc Cosmet Chem 1960; 11:85.
`Hoover JE, ed. Dispensing of Medication, 8th ed. Easton, PA: M.-.ckW
`Co, 1976.
`Illel B. Crit Rev Ther Drug Carrier Systems 1997; 14:207,
`Wenninger JA, ed. International Cosmetic Ingredient DictM
`Handbook. Baltimore: The Cosmetic, Toiletry and Fragrffl*
`1998.
`Kemppanien BW, Reifenrath WG, eds. Methods for Skin AS
`Boca Raton, FL: CRC Press, 1990.
`Maibach HI. Animal Models in Dermatology. Edinburgh; Chut
`ingstone, 1975.
`Mier PD, Cotton DWK. The Molecular Biology of Skin. OxlnrirH
`well, 1976.
`Montagna W, Parrakkal PF. The Structure and Function of^H
`3rd ed. New York: Academic Press, 1974.
`Marples MJ. The Ecology of the Human Skin. Springfield It: Hi
`1965.
`Scranton AB, Peppas NA. Adv Drug Del Rev 1993; 11:1-
`Walters KA. In Hadgraft J, Guy RH, eds. Transdermal l>rJS
`New York: Dekker, 1989, p i97.
`Wester RC, Maibach HI. Clin Pharmakinet 1992; 23:253.
`
`Oral Solid Dosage Forms
`Edward M Rudnic, PhD
`Joseph B Schwartz, PhD
`
`C H A P T E R 45
`
`£
`
`, J substances most frequently are administered orally by
`nr.in- of solid dosage forms such as tablets and capsules.
`production methods used for their preparation, as
`yv nl. <f later in the chapter, require the presence of other ma-
`i addition to the active ingredients. Additives also may
`I n:iU i
`jj|included in the formulations to facilitate handling, enhance
`he physical appearance, improve stability, and aid in the de-
`nn of the drug to the bloodstream after administration.
`\ supposedly inert ingredients, as well as the production
`urtii".!- employed, have been shown in many cases to influence
`II nbsi rption or bioavailability of the drug substances.1 There-
`•JV cire must be taken in the selection and evaluation of ad-
`litivi s aid preparation methods to ensure that the drug-deliv-
`TV goals and therapeutic efficacy of the active ingredient(s)
`riD jim be diminished.
`11; a number of cases it has been shown that the drug sub-
`solubility and other physicochemical characteristics
`
`have influenced its physiological availability from a solid dosage
`form. These characteristics include its particle size, whether it is
`amorphous or crystalline, whether it is solvated or nonsolvated,
`and its crystalline, or polymorphic form. After clinically effective
`formulations are obtained, such variations among dosage units
`of a given batch, as well as batch-to-batch differences, should be
`reduced to a minimum through proper in-process controls and
`good manufacturing practices. The recognition of the importance
`of performance qualification, and validation for both equipment
`and processes has enhanced assurance in the reproducibility of
`solid dosage formulations greatly. It is in these areas that sig­
`nificant progress has been made with the realization that large-
`scale production of a satisfactory tablet or capsule depends not
`only on the availability of a clinically effective formulation but
`also on the raw materials, facilities, personnel, documentation,
`validated processes and equipment, packaging, and the controls
`used during and after preparation (Fig 45-1),
`
`ini 1- may be defined as solid pharmaceutical dosage forms
`iBUmmg drug substances with or without suitable diluents
`ii.i'.ebeen traditionally prepared by either compression, or
`pling methods. Recently, punching of laminated sheets, elec-
`w.h: leposition methods, and three-dimensional printing
`have been used to make tablets. Tablets have been in
`•espri-ad use since the latter part of the 19th century, and
`Hir popularity continues. The term compressed tablet is be­
`have been used first by John Wyeth and Brother of
`Boelphva. During this same period, molded tablets were in-
`BBed to be used as hypodermic tablets for the extemporane-
`Ptparation of solutions for injection. Tablets remain popu-
`U a dosage form because of the advantages afforded both to
`•Wtifacturer (eg, simplicity and economy of preparation,
`•lity, and convenience in packaging, shipping, and dispens-
`pd the patient (eg, accuracy of dosage, compactness,
`ility, blandness of taste, and ease of administration),
`tough the basic mechanical approach for most tablet
`Mture has remained the same, tablet technology has un-
`* great improvement and experimentation. Efforts are
`continually to understand more clearly the physi-
`iWcteristics of powder compaction and the factors affect-
`• availability of the drug substance from the dosage form
`[Wl administration. Tableting equipment continues to
`"l' 'ri hoth production speed and the uniformity of tablets
`Mted Recent advances in tablet technology have been
`
`Although tablets frequently are discoid in shape, they also
`may be round, oval, oblong, cylindrical, or triangular. Other geo­
`metric shapes, such as diamonds and pentagons, and hexagons
`have also been used. They may differ greatly in size and weight
`depending on the amount of drug substance present and the in­
`tended method of administration. Most commercial tablets can be
`divided into two general classes by whether they are made by
`compression or molding. Compressed tablets usually are pre­
`pared by large-scale production methods, while molded tablets
`generally involve small-scale operations. The various tablet types
`and abbreviations used in referring to them are listed below.
`COMPRESSED TABLETS (CT)—These tablets are formed by
`compression and in their simplest form, contain no special coating. They
`are made from powdered, crystalline, or granular materials, alone or in
`combination with binders, disintegrants, controlled-release polymers,
`lubricants, diluents, and in many cases colorants. The vast majority of
`tablets commercialized today are compressed tablets, either in an un-
`coated or coated state.
`Sugar-Coated Tablets (SCT)—These are compressed tablets sur­
`rounded by a sugar coating. Such coatings may be colored and are ben­
`eficial in covering up drug substances possessing objectionable tastes or
`odors and in protecting materials sensitive to oxidation. These coatings
`were once quite common, and generally lost commercial appeal due to
`the high cost of process validation. Recently, they have made a come­
`back due to patient popularity and technical advances.
`Film-Coated Tablets (FCT)—These are compressed tablets that
`are covered with a thin layer or film of a water-soluble material, A num­
`ber of polymeric substances with film-forming properties may be used.
`Film coating imparts the same general characteristics as sugar coating.
`
`889
`
`

`

`890
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`V
`
`A
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`i
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`Figure 45-1, Tablet press operators checking batch record in confor­
`mance with Current Good Manufacturing Practices (courtesy, Lilly).
`
`with the added advantage of a greatly reduced time period required for
`the coating operation. Advances in material science and polymer chem­
`istry has made these coatings the first-choice of formulators.
`Enteric-Coated Tablets (ECT)—These are compressed tablets
`coated with substances that resist solution in gastric fluid but disinte­
`grate in the intestine. Enteric coatings can be used for tablets contain­
`ing drug substances that are inactivated or destroyed in the stomach,
`for those that irritate the mucosa, or as a means of delayed release of the
`medication.
`Multiple Compressed Tablets (MCT)—These are compressed
`tablets made by more than one compression cycle. This process is best
`used when separation of active ingredients is needed for stability pur­
`poses, or if the mixing process is inadequate to g uarantee uniform dis­
`tribution of two or more active ingredients.
`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
`three, or more layers. Special tablet presses are required to make lay­
`ered tablets such as the Versa press (Stokes/Pennwalt).
`Press-Coated Tablets—Such tablets, 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 (ie, slotting, monogramming, speed of disintegration) while re­
`taining the attributes of sugar-coated tablets in masking the taste of the
`drug substance in the core tablets. An example of a 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
`means of giving an enteric coating to the core tablets. Both types of mul­
`tiple-compressed tablets have been used widely in the design of pro­
`longed-action dosage forms.
`Controlled-Release Tablets (CRT)—Compressed tablets can be
`formulated 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. These tablets (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 enteric coat­
`ings; (2) those that release the drug in a relatively steady, controlled
`manner; and (3) those that combine combinations of mechanisms to re­
`lease pulses of drug, such as repeat-action tablets. The performance of
`these systems is described in more detail in Chapter 47. Other names
`for these types of tablets can be: Extended Release, Sustained Release,
`Prolonged Release, Delayed Release, and in the case of pulsatile tablets.
`Repeat Action, Pulsatile Release or Pulse Release.
`Tablets for Solution (CTS)—Compressed tablets to be used for
`preparing solutions or imparting given characteristics to solutions must
`be labeled to indicate that they are not to be swallowed. Examples of
`these tablets are Halazone Tablets for Solution and Potassium Per­
`manganate Tablets for Solution.
`Effervescent Tablets—In addition to the drug substance, these con­
`tain sodium bicarbonate and an organic acid such as tartaric or citric. In
`
`the presence of water, these additives react, liberating carbon dfaj
`that acts as a distintegrator and produces effervescence. Except for sm
`quantities of lubricants present, effervescent tablets are soluble.
`Compressed Suppositories or Inserts—Occasionally, vjwJ
`suppositories, such as Metronidazole tablets, are prepared by conja
`sion. Tablets for this use usually contain lactose as the diluent Infl
`case, as well as for any tablet intended for administration other thagf
`swallowing, the label must indicate the manner in which it is to be nj
`Buccal and Sublingual Tablets—These are small, flat,
`tablets. Tablets intended for buccal (the space between the lip ^3
`in the mouth) administration by inserting into the buccal pauaH
`dissolve or erode slowly; therefore, they are formulated and COITJ
`with sufficient pressure to give a hard tablet. Progesterone tabl
`1 •- QM
`be administered in this way. Some newer approaches have
`"inpUM
`materials that act as bioadhesives to increase absorption of the inai
`Some other approaches use tablets that melt at body tempem^H
`The matrix of the tablet is solidified while the drug is in solution.
`melting, the drug is automatically in solution and available tur abg^l
`tion, thus eliminating dissolution as a rate-limiting step in the aha^l
`tion of poorly soluble compounds. Sublingual tablets, such as ibotie^J
`taining nitroglycerin, isoproterenol hydrochloride, or erythriB
`tetranitrate, are placed under the tongue. Sublingual tablets t.hsstdfl
`rapidly, and the drug substances are absorbed readily by this nn aMB
`ministration.
`MOLDED TABLETS OR TABLET TRITURATES (TT»—TaUn
`triturates usually are made from moist material, using a tritui iiinm3
`that gives them the shape of cut sections of a cylinder. Such tabk-unqjl
`be completely and rapidly soluble. The problem arising from cani^S
`sion of these tablets is the failure to find a lubricant that is
`water-soluble.
`Dispensing Tablets (DT)—These tablets provide a convej
`quantity of potent drug that can be incorporated readily iiuq po*
`and liquids, thus circumventing the necessity to weigh small (joaifli
`These tablets are supplied primarily as a convenience for extennl
`ous compounding and should never be dispensed as a dosage form.
`Hypodermic Tablets (HT)—Hypodermic tablets are soft, id
`soluble tablets and originally were used for the preparation of MU|
`to be injected. Since stable parenteral solutions are now aviiilabi
`most drug substances, there is no justification for the use ofhynodi
`tablets for injection. Their use in this manner should be liismuq
`since the resulting solutions are not sterile. Large quanCiUoafjjl
`tablets continue to be made, but for oral administration. Ni i hypoda
`tablets ever have been recognized by the official compendia. J
`
`Compressed Tablets
`
`For medicinal substances, with or without diluents, to bon
`into solid dosage forms with pressure, using available
`ment, it is necessary that the material, either in crystamMj
`powdered form, possess a number of physical chararteriM
`These characteristics include the ability to flow freely,^
`siveness, and lubrication. The ingredients such as aiM
`grants designed to break the tablet up in gastrointestinal®
`fluids and controlled-release polymers designed to aow diVfl
`lease ideally should possess these characteristics oi not ag
`fere with the desirable performance traits of the o:.it>r fflBJj
`ents. Since most materials have none or only some «•
`properties, methods of tablet formulation and prepar UioMI
`been developed to impart these desirable characteri -tics tti
`material that is to be compressed into tablets.
`The basic mechanical unit in all tablet-compression
`ment includes a lower punch that fits into a die from the bflfl
`and an upper punch, with a head of the same shape
`mensions, which enters the die cavity from the top SM
`tableting material fills the die cavity (Fig 45-2). TMj^H
`formed by pressure applied on the punches and subK^ff^
`ejected from the die. The weight of the tablet is rtfctorOJB
`the volume of the material that fills the die cavity.
`the ability of the granulation to flow freely into the MS
`portant in ensuring a uniform fill, as well as the
`movement of the granulation from the source of suppw^H
`hopper. If the tablet granulation does not posse^^^B
`properties, the tablet after compression will cruniOB^M
`apart on handling. As the punches must move freely
`
`•
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`Si A
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`I
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`%
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`figure 45-2. Basic mechanical unit for tablet compression: lower punch,
`die, and upper punch (courtesy, Vector/Colton).
`
`Jjeand the tablet must be ejected readily from the punch faces,
`the material must have a degree of lubrication to minimize fric-
`tion and allow the removal of the compressed tablets.
`Tht re are three general methods typically used for commer-
`(tsl tablet preparation: the wet-granulation method, the dry-
`panulation method, and direct compression. The method of
`preparation and the added ingredients are selected to give the
`tablrt formulation the desirable physical characteristics allow­
`ing the rapid compression of tablets. After compression, the
`tableL nust have a number of additional attributes such as ap­
`pearance, hardness, disintegration ability, appropriate dissolu-
`Hp characteristics, and uniformity, which also are influenced
`by the method of preparation and by the added materials
`pi»t>nt in the formulation. In the preparation of compressed
`HifatSr the formulator also must be cognizant of the effect that
`tlw ingredients and methods of preparation may have on the
`«7ailaii ity of the active ingredients and, hence, the therapeutic
`tffican f the dosage form. In response to a request by physicians
`(sduin i a dicumarol tablet so that it might be broken more eas-
`fly, a C nadian company reformulated to make a large tablet
`Hjl 6 score. Subsequent use of the tablet, containing the same
`nnoui
`f drug substance as the previous tablet, resulted in com-
`HHfjithat larger-than-usual doses were needed to produce the
`therapeutic response. On the other hand, literature reports
`indirat hat the reformulation of a commercial digoxin tablet re-
`fulted n a tablet that, although containing the same quantity of
`^•lubstance, gave the desired clinical response at half its orig­
`inal do. Methods and principles that can be used to assess the
`^^Bg of excipients and additives on drug absorption have been
`^^HnNi.2'14'15
`
`ABI ET INGREDIENTS
`ddition to the active or therapeutic ingredient, tablets con-
`a r mber of inert materials. The latter are known as addi-
`••Wsor.' xipients. They may be classified according to the part
`1*? plav in the finished tablet. The first group contains those
`•>t help to impart satisfactory processing and compression
`^Hracte.istics to the formulation. These include diluents,
`ghdants, and lubricants. The second group of added
`•wrtanvos helps to give additional desirable physical charac-
`•WJCH tc the f