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`

`
`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 Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright © 1956, 1960, 1965, .1970, 1975, 1980, 1985, 1990, by The Philadelphia College of
`Pharmacy and Science
`'
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`ISBN 0-912734-O4-3
`
`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
`Formaiary (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 cornpendia shall
`prevail.
`
`Printed in the United States of America by the Mach Printing Company, Easton, Pennsylvania
`
`Astrazeneca Ex. 2093 p. 2
`
`

`
`Table of Contents
`
`Part 1
`
`Orientation
`
`.
`.
`.
`.
`. . . . . . .
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`. . . . . .
`.
`. . . .
`. . . . .
`.
`.
`Scope .
`1
`.
`.
`.
`.
`. . . . . . . .
`.
`.
`.
`2 Evolution of Pharmacy .
`. . . . . .
`. . .
`.
`. . . . . . . .
`.
`.
`.
`3 Ethics
`.
`.
`.
`. . . . .
`. . . .
`.
`. . . . . . . .
`4 The Practice of Community Pharmacy . . . . . . . .
`. .
`5 Opportunities for Pharmacists in the Pharmaceuti-
`cal industry . . . . . . . .
`.
`. . . . . . .
`. . .
`.
`. . . . . . .
`. .
`. .
`6 Pharmacists in Government
`. . . .
`.
`. . . . . . . . . .
`.
`. .
`7 Druginformation...........................
`8 Research . . .
`. . . . .
`
`Part 2
`
`Pharmaceutics
`
`.
`. . .
`. . . . . . .
`.
`.
`.
`.
`9 Metrology and Calculation . . . .
`.
`.
`.
`.
`. . . . . .
`. .
`.
`.
`10 Statistics . . . . . . . . . .
`. . . . . . . . . .
`.
`.
`.
`.
`. . . . . . . .
`.
`.
`11 Computer Science . .
`.
`. . . . . . . . .
`. . .
`. . . . . . . . . ..
`12 Calculus . .
`. . . . . . .
`13 Molecular Structure. Properties and States of
`. .
`.
`.
`Matter
`. .
`. . . . . . . . . .
`.
`. . . . . . .
`. .
`.
`.
`. . . . . . .
`. ..
`.
`14 Complex Formation .
`. .
`. . . . .
`.
`.
`. . .
`.
`15 Thermodynamics...........................
`16 Solutions and Phase Equilibria .
`.
`. .
`.
`. . . . . . . . .
`. .
`17
`Ionic Solutions and Electrolytic Equilibria . . . . . .
`. .
`13 Reaction Kinetics .
`.
`.
`.
`. . . . . . . .
`.
`.
`.
`. . . . . . . . . .
`. .
`19 Dlsperse Systems . . .
`. . . .
`. . . . . . .
`.
`. . . . . . . . .
`.
`. .
`20 Rheology . . . . . .
`. . . .
`. .
`. . . . . .
`.
`.
`. . .
`. . . . . .
`.
`.
`. .
`
`Part 3
`
`Pharmaceutical Chemistry
`
`. . . . .
`inorganic Pharmaceutical Chemistry . . .
`21
`. . . . .
`22 Organic Pharmaceutical Chemistry . . . .
`23 Natural Products
`. . .
`.
`. . . .
`. . . . . . .
`.
`. . . . . . . .
`24 Drug Nomenc|ature—United States Adopted
`Names . .
`. . . . . . . . . .
`.
`.
`. . . . . . . . . .
`. . . . . . . . . . .
`25 Structure-Activity Relationship and Drug
`Design . .
`. . .
`. . . . . . .
`.
`. . . . . . . . . .
`.
`. . . . . . . .
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`
`. .
`
`Part 4
`
`Testing“ and Analysis
`
`.
`. .
`
`.
`.
`
`26 Analysis of Medicinais
`27 Biological Testing . . .
`23 Ci|nicaiAnalysis
`.
`29 Chromatography . . .
`.
`30 instrumental Methods of Analysis
`31 Dissolution . . . .
`. . . .
`.
`. . . . . . . .
`. . .
`
`. . . . . . .
`. . .
`.
`.
`
`. . . .
`. . .
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`. .
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`.
`.
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`. . . . . . . .
`. . . . . . . .
`
`.
`.
`
`. .
`.
`.
`
`3
`8
`20
`28
`
`33
`38
`49
`60
`
`69
`104
`138
`145
`
`153
`162
`197
`207
`226
`247
`257
`310
`
`329
`356
`380
`
`412
`
`422
`
`435
`434
`495
`529
`555'
`589
`
`Part 5
`
`Iladioisotopes in Pharmacy and Medicine
`
`.
`32 Fundamentals of Raciioisotopes . . . . . . . . . . . .
`33 Medical Applications of Radiolsoiopes
`. . . . . . .
`
`. .
`. .
`
`605
`624
`
`Pharmaceutical and Medicinal Agents
`Part 6
`34 Diseases: Manifestations and Patho-
`physiology 655
`35 Drug Absorption. Action and Disposition . . . .
`.
`.
`.
`.
`697
`36 Basic Pharmacokinetics . . . . .
`. .
`.
`. . . . . . . . . .
`. . .
`.
`725
`37 Clinical Pharmacol-rlnetics . . . . .
`.
`. . .
`. . . . .
`. . . .
`.
`.
`746
`36 Topical Drugs . . . . .
`. .
`. .
`. . . . . .
`.
`. . .
`. . . . .
`. . . . . .
`757
`:39 Gastrointestinal Drugs . . . . . . . . .
`.
`.
`. . . . . . . . . . .
`.
`774
`40 Blood, Fluids. Electrolytes and Hematologic
`.
`.
`Drugs
`. . .
`. . . . . . . . . .
`.
`.
`. . . . . . . . .
`.
`. . . . . . . . .
`‘41
`Cardiovascular Drugs
`. .
`. .. . . . .
`.
`.
`.
`.
`. . . . .
`. . . . . .
`42 RespiratoryDrugs
`.
`. . . . ..
`43 Sympathomimetic Drugs . . . . . .
`. . . . .
`. . . .
`.
`.
`
`.
`
`. . .
`
`800
`631
`860
`870
`
`44
`45
`
`46
`47
`45
`49
`50
`51
`52
`53
`54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`
`71
`72
`
`73
`74
`
`75
`76
`77
`73
`79
`B0
`31
`82
`33
`
`64
`35
`36
`87
`86
`89
`90
`9 1
`92
`
`93
`94
`95
`96
`
`xv
`
`. . . .
`
`339
`. . . . . .
`. . . . . .
`. . .
`Chollnomimetic Drugs . . . .
`‘
`Adrenergic and Adrenergic Neuron Blocking
`Drugs 898
`Antlmuscarinic and Antisposmodic Drugs
`. . . . . . .
`907
`1 Skeletal Muscle Relaxants . . .
`. . . . .
`. - -
`- '-
`-
`-
`- - - -
`916
`DlureticDrUgs
`. . . .
`929
`. . . . . . . . . . . . . .
`Uterine and Antimigralne Drugs
`943
`Hormones . . . .
`. .
`. . . .
`. . . .
`. .-.
`. . . . . . . . . . . .
`. . . .
`943
`Vitamins and Other Nutrients .
`. . .
`. . . . . . . . . . . . .
`1002
`Enzymes
`. . . . .
`.
`. . . . .
`. . . .
`.
`.
`. . .
`. . . . . . . . . . . . .
`1035
`General Anesthetics . .
`. . . . . .
`. . .
`. . . . . .
`.
`.
`. . . . .
`1039
`Local Anesthetics . . . . . . . . . . .
`. . .
`. . . . . .
`. . . . . . .
`1043
`Sedatlves and Hypnatics . .
`. . .
`. .
`. . .
`. . . .
`.
`.
`. . . . .
`1057
`Antlepileptlcs
`. . . . . . . . . ..
`1072
`. . .
`Psychopharmacologic Agents
`. . . . . .
`.
`. . . . . .
`1052
`Analgesics and Antlpyreiics .. . . .
`. . .
`. . .
`.
`. .
`. . . .
`1097
`Histamine and Antihistamines . . .
`. . .
`. . .
`.
`. . . . ..
`1123
`Central Nervous System Stimulants . . . . . .
`.
`. . . . .
`1132
`Antineoplastlc and immunosuppressive Drugs . . .
`1133
`Antimicrobial Drugs . . . . . . .
`.
`.
`. . . . . . . . .
`.
`.
`. . . . .
`1163
`Parasiticides . .
`.
`. .
`. . . . . . .
`. . .
`. . . . . . . . .
`.
`. . . . . .
`1242
`Pesticides . . .
`.
`. . . .
`. . . .
`. .
`.
`.
`.
`. . . . . . . . . . . . . . . .
`1249
`Diagnostic Drugs
`. .
`. . . . . . . . . . . . .
`. . . . .
`.
`.
`. . . . .
`1272
`Pharmaceutical Necessities
`. . . . . .
`. . . . .
`.
`.
`. . . . .
`1266
`Adverse Drug Reactions .
`. . . . . . . . . . . . .
`.
`.
`. . . . .
`1330
`_Pharmacogenetics
`1344
`. . . . . . .
`Pharmacological Aspects of Drug Abuse .
`1349
`introduction of New Drugs
`.
`.
`. .
`. . . . . . . . . . . . . . .
`1365
`
`Port 1
`
`Ilioiogical Products
`
`. . .
`. . .
`. .
`. .
`Principles oi Immunology . . .
`immunizing Agents and Diagnostic Skin
`Antigens
`A|iergenicEr-(tracts
`Biotechnology and Drugs . .
`
`.
`
`.
`
`. . .
`
`. . . .
`
`. .
`
`.
`
`.
`
`. . . . .
`
`1379
`
`1369
`1405
`1416
`
`.
`
`.
`
`. . . . .
`
`Part 8
`
`Pharmaceutical Preparations and Their
`Manufacture
`
`. . . . . . . . . . ..
`Preformulation
`Bioavailobility and Bioequivalency Testing . . . . .
`Separation . . .
`. .
`. . . .
`. . . .
`. .
`.
`. . . . .
`. . . . . .
`. . . . .
`Sterilization . . . .
`. . . . . . . . .
`.
`. . .
`. . . . .
`. . . . . . . . .
`Tonlclty, Osmoticity, Osmoiaiity and Osmolarity .
`Plastic Packaging Materials
`.
`.
`. .
`. . . . . . .
`.
`.
`. . . . .
`Stability of Pharmaceutical Products
`. . . . . .
`. . . . .
`Quality Assurance and Control
`. . . . . . . .
`.
`. .
`. . . .
`Solutions, Emulsions, Suspensions and
`Extractives .
`. . . . .
`.
`.
`. . . .
`. . . . .
`.
`.
`. . . . . . .
`Parenteral Preparations . . . . . .
`.
`. .
`. . . . . .
`intravenous Admixtures . . . . . .
`. . .
`. . . . . .
`Ophthalmic Preparations . . .
`.
`.
`. . .
`. . . . . .
`Medicated Applications .
`. .
`. . .
`.
`. .
`. . . . . .
`Powders . . . . . .
`.
`. . .
`. . . . . . .
`.
`.
`.
`. . . . . . . .
`Oral Solid Dosage Forms .
`. . . . .
`.
`. . . . . . . .
`Coating of Pharmaceutical Dosage Forms .
`Sustained-Release Drug Delivery Systems
`Aerosols
`
`. . .
`.
`. .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`. . . . . .
`. . . . . .
`
`1435
`1451
`1459
`1470
`1431
`1499
`1504
`1513
`
`1519
`1545
`1570
`1561
`1596
`1615
`1633
`1666
`1676
`1694
`
`Part 9
`
`Pharmaceutical Practice
`
`. . .
`. .
`Ambulatory Patient Care . . . .
`. . .
`institutional Patient Care .
`.
`.
`. . .
`Long-Term Care Facilities . . . .
`. . . . .
`The Pharmacist and Public Health . .
`
`. . . .
`. . . .
`. . . .
`. .
`. .
`
`.
`.
`.
`.
`
`.
`.
`.
`.
`
`. . . . .
`. . . . .
`. . . . .
`. . . . .
`
`1715
`1737
`1758
`1173
`
`Astrazeneca Ex. 2093 p. 3
`
`

`
`97
`96
`99
`100
`101
`102
`103
`104
`105
`
`The Patient: Behavioral Determinants . .
`Patlentcommunlcotion
`DrugEducation
`. . . . . . .
`. .
`.
`.
`Patient Compliance
`. . . . . ._ . . . .
`.
`The Prescription . . . .
`.
`. . . . . . . . .
`.
`Drug Interactions . . .
`Clinical Drug Literature . .
`. . .
`. . . .
`Health Accessories
`.
`.
`. . . . . .
`. . . .
`
`.
`.
`.
`. . .
`. . .
`.
`.
`.
`.
`.
`.
`
`. . .
`. . .
`. .
`.
`. . .
`. . .
`
`.
`
`. . . . .
`
`.
`
`.
`
`. . . . . . .
`. . . . .
`.
`.
`. . . . .
`.
`.
`. . . . .
`.
`.
`. . . . .
`.
`.-
`
`106
`107
`105
`
`109
`
`1788
`1796
`1803
`1813
`1628
`1642
`1859
`1664
`
`. . . . .
`. . .
`.
`.
`. . . .
`. . . . .
`.
`.
`.
`.
`.
`Poison Control
`. . . . . . . .
`.
`.
`Laws Governing Pharmacy . . .
`Community Pharmacy Economics and
`. . . . . .
`Management
`. .
`. .
`.
`.
`. . . . . . . .
`. .
`.
`. . .
`Dental Services .
`.
`.
`.
`-. . .’.
`. . . . . .
`._
`. . .
`. . . . .
`.
`.
`
`.
`.
`
`.
`.
`
`. . .
`. . .
`
`. . .
`. . .
`
`1905
`1914
`
`1940
`1957
`
`Index
`
`Surgical Supplies . . . . .
`
`. . . . . . . . .
`
`. . .
`
`. .
`
`. . . . . .
`
`. .
`
`1895'
`
`Alphabetic Index .
`
`. . . . . . . . . . .
`
`.
`
`.
`
`. . . .
`
`. . . . .
`
`.
`
`. .
`
`1967
`
`xvi
`
`Astrazeneca Ex. 2093 p. 4
`
`

`
`CHAPTER 69
`
`Oral Solid Dosage Forms
`
`Edward Rudnlc, PhD
`Director. Formulation Development
`Sche-ring.Plough Research
`Miami. Fl. OM69
`
`Joseph ll Schwartz, PhD
`Tlce Professor of Pharmaceutics
`Phlloclelphln College of Pharmacy and Science
`Phlladelphln. PA 19104
`
`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. Addi-
`tives also may be included in the formulations to enhance
`the physical appearance, improve stability and aid in disin-
`tegration after administration. These supposedly inert in-
`gredients, as well as the production methods employed, have
`been shown in some cases to influence the release of the drug
`substances} Therefore care must be taken in the selection
`and evaluation of additives and preparation methods to en-
`sure that the physiological availability and therapeutic effi-
`cacy of the active ingredient will not be diminished.
`In a limited number of cases it has been shown that the
`drug substance’s solubility and other physical characteris-
`tics 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 polymorphic form. After clinically
`effective formulations are obtained, variations among dos-
`age units of a given batch, as well as batch-to-batch differ-
`ences, are reduced to a minimum through proper in-process
`controls and good manufacturing practices. The recogni-
`tion of the importance of validation both for equipment and
`processes has greatly enhanced assurance in the reproduc-
`ibility of formulations.
`It is in these areas that significant
`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
`
`
`
`Fig 89-1.
`Tablet press operators checking batch record in confor-
`mance with Current Good Manufacturing Practices (courtesy. Lilly).
`
`but also on the raw materials, facilities, personnel, validated
`processes and equipment, packaging and the controls used
`during and after preparation (Fig 89-1).
`
`Tablets
`
`Tablets may be defined as solid pharmaceutical dosage
`forms containing drug substances with or without suitable
`diluents and prepared either by 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 Vliyeth and Brother of Philadelphia. During
`this same period, molded tablets were introduced to be used
`as “hypode1-mic" tablets for the extemporaneous prepara-
`tion of solutions for injection. Tablets remain popular as a
`dosage form because of the advantages afforded both to the
`manufacturer (eg, simplicity and economy of preparation,
`stability and convenience in packaging, shipping and dis-
`pensing) and the patient (eg, accuracy of dosage, compact-
`ness, portability, blandness of taste and ease of administra-
`tion).
`Although the basic mechanical approach for their manu-
`facture has remained the same, tablet technology has under-
`gone great improvement. Efforts are being made continual-
`ly to understand more clearly the physical characteristics of
`tablet compression and the factors affecting the availability
`
`of the drug substance from the dosage form after oral admin-
`istration. Compression equipment continues to improve
`both as to production speed and the uniformity of tablets
`compressed. Recent advances in tablet technology have
`been reviewed.3"13
`Although tablets frequently are more discoid in shape,
`they also may be round, oval, oblong, cylindrical or triangu-
`lar. They may differ greatly in size and weight depending
`on the amount of drug substance present and the intended
`method of administration. They are divided into two gener-
`al classes, whether they are made by compression or mold-
`ing. Compressed tablets usually are prepared by large-scale
`production methods while molded tablets generally involve
`small-scale operations. The various tablet types and abbre-
`viations used in referring to them are listed below.
`
`Compressed Tablets (CT)
`These tablets are formed by compression and contain no special coat-
`ing. They are made from powdered. crystalline or granular materials,
`alone or in combination with binders, disintegrants, lubricants, diluent-.5
`and in many cases, colorants.
`
`1633
`
`Astrazeneca Ex. 2093 p. 5
`
`

`
`1534
`
`CHAPTER 89
`
`Sugar-Coated Tablets (SCT)—These are compressed tablets con-
`taining a sugar coating. Such coatings may be colored and are beneficial
`in covering up drug substances possessing objectionable tastes or odors,
`and in protecting materials sensitive to oxidation.
`Film-Coated Tablets (FCT)—These are compressed tablets which
`are covered with a thin layer or film of a water-soluble material. A
`number of polymeric substances with film-forming properties may be
`used. Film coating imparts the same general characteristics as sugar
`coating with the added 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 disinte-
`grate in the intestine. Enteric coatings can be used for tablets contain-
`ing drug substances which are inactivated or destroyed in the stomach,
`for those which irritate the mucosa oras a means of delayed release of the
`medication.
`Multiple Compressed Tablets (MCT)—These are compressed tab-
`lets made by more than one compression cycle.
`-
`Layered Toblets—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 layers. Special tabletpresses are required to make layered tablets
`such as the Versa press (.S'tokes/Permwalt).
`‘
`Pres.r—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, etc, while
`retaining 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 Dress is the Manesty Drycota. Press-coated tablets also can be
`used to separate incompatible drug substances; in addition, they can
`provide a means to give an enteric coating to the core tablets. Both
`types of multiple-compressed tablets have been used widely in the de-
`sign of prolonged-action dosage forms.
`Controlled-Release Table1;s—Compressed tablets can be formulat-
`ed 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 which
`respond to some physiological condition to release the drug, such as
`enteric coatings; (2) those that release the drug in a relatively steady,
`controlled manner and (3) those that combine combinations of mecha-
`nisms to release “pulses" of drug, such as repeat-action tablets. The
`performance of these systems are described in more detail in Chapter 91.
`Tablets for Solution—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 Permanganate 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 dioxide
`which acts as a clistintegrator and produces effervescence. Except for
`small quantities of lubricants present, effervescent tablets are soluble.
`Compressed Suppositories or Inserts——0ccasionally, vaginal sup-
`positories. such as Metronidazole Tablets, are prepared by compression.
`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 manner in which it is to be used.
`Buccal and Sublingual Tablets—These are small, flat, oval tablets.
`Tablets intended for buccal administration by inserting into the buccal
`pouch may dissolve or erode slowly; therefore, they are formulated and
`compressed with sufficient pressure to give a hard tablet. Progesterone
`Tablets may be administered in this way.
`Some newer approaches use tablets that melt at body temperatures.
`The matrix of the tablet is solidified while the drug is in solution. After
`melting, the drug is automatically in solution and available for absorp-
`tion, thus eliminating dissolution as a rate-limiting step in the absorp-
`tion of poorly soluble compounds. Sublingual tablets, such as those
`containing nitroglycerin, isoproterenol hydrochloride or erythrityl te-
`tranitrate, 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 Tritur.-ates (TT)
`Tablet triturates usually are made from moist material using a trit-
`urate mold which gives them the 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 to weigh small quantities.
`These tablets are supplied primarily as a convenience for extemporane-
`ous compounding and should never be dispensed as-a dosage form.
`‘Hypodermic Tablets (I-IT)—I-Iypodermic tablets are soft, readily
`soluble tablets and originally were used for 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 he made but for oral administration. No hypodermic
`tablets have ever been recognized by the official compendia.
`
`Compressed Tablets (CT)
`
`In order for medicinal substances, with_or without dilu-
`ents, to be made into solid dosage forms with pressure, using
`available equipment, it is necessary that the material, either
`in crystalline or powdered form, possess a number of physi-
`cal characteristics. These characteristics include the ability
`to flow freely, cohesiveness and lubrication. Other ingredi-
`ents such as disintegrants designed to break the tablet up in
`gastrointestinal fluids, and controlled-release polymers de-
`signed to slow down drug release, ideally should possess
`these characteristics, or not interfere with the desirable per-
`formance traits of the other excipients. Since most materi-
`als have none or only some of these properties, methods of
`~ tablet formulation and preparation have been developed to
`impart these desirable characteristics to the material which
`is to be compressed into tablets.
`tablet-compression
`in all
`The basic mechanical unit
`equipment includes a lower punch which fits into a die from
`the'bottom and an upper punch, having 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
`89-2. 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 which fills the die cavity. Therefore, the ability of
`the granulation to flow freely into the die is important in
`insuring a uniform fill, as well as the continuous movement
`of the granulation from the source of supply or feed hopper.
`
`If the tablet granulation does not possess cohesive proper-
`ties, the tablet after compression will crumble and fall apart
`on handling. As the punches must move freely within the
`die and the tablet must be ejected readily from the punch
`faces, the material must have a degree of lubrication to
`minimize friction and allow for the removal of the com-
`pressed tablets.
`There are three general methods of tablet preparation:
`the wet-granulation method, the dry—granulation method
`and direct compression. The method of preparation and
`
`
`
`Fig 89-2. Basic mechanical unit for tablet compression:
`punch. die and upper punch'(courtesy, Vectorlcolton).
`
`lower
`
`Astrazeneca Ex. 2093 p. 6
`
`

`
`the added ingredients are selected in order to give the tablet
`formulation the desirable physical characteristics allowing
`the rapid compression of tablets. After compression the
`tablets must have a number of additional attributes such as
`appearance, hardness, disintegration ability, appropriate
`dissolution characteristics and uniformity which also are
`influenced both by the method of preparation and by the
`added materials present in the formulation.
`In the prepara-
`tion of compressed tablets the formulator also must be cog-
`nizant of the effect which the ingredients and methods of
`preparation may have on the availability of the active ingre-
`dients and hence the therapeutic efficacy of the dosage form.
`In response to a request by physicians to change a dicumarol
`tablet in order that it might be broken more easily, a Canadi-
`an company reformulated to make a large tablet with a score.
`Subsequent use of the tablet containing the same amount of
`drug substance as the previous tablet, resulted in complaints
`that larger-than—usual doses were needed to produce the
`same therapeutic response. On the other hand, literature
`reports indicate that the reformulation of a commercial di-
`goxin tablet resulted in a tablet, although containing the
`same quantity of drug substance, that gave the desired clini-
`cal response at half its original dose. Methods and princi-
`ples that can be used to assess the effects of excipients and
`additives on drug absorption have been reviewed.”-1‘-15 See
`Chapters 36, 75 and 76.
`
`Tablet Ingredients
`
`In addition to the active or therapeutic ingredient, tablets
`contain a number of 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 which help to impart satisfactory processing
`and compression characteristics to the formulation. These
`include diluents, binders and glidants and lubricants. The
`second group of added substances helps to give additional
`desirable physical characteristics to the finished tablet.
`In-
`cluded in this group are disintegi-ants, 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. Prefor-
`mulation 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 Academy of Pharmaceutical Sciences and the
`Council of the Pharmaceutical Society of Great Britain.
`The result is called the Handbook of Pharmaceutical Excip-
`ients. This reference is now distributed Widely throughout
`the world.”
`
`Diluents
`
`Frequently the single dose of the active ingredientis small
`and an inert substance is added to increase the bulk in order
`to make the tablet a practical size for compression. Com-
`pressed tablets of dexamethasone contain 0.75 mg steroid
`per tablet; hence, it is obvious that another material must be
`added to make tableting possible. Diluents used for this
`purpose include dicalciurn phosphate, calcium sulfate, lac-
`tose, oellulose, kaolin, mannitol, sodium chloride, dry starch
`and powdered sugar. Certain diluents, such as mannitol,
`lactose, sorbitol, sucrose and inositol, when present in suffi-
`cient quantity, can impart properties to some compressed
`tablets that permit disintegration in the mouth by chewing.
`
`ORAL SOLID DOSAGE FORMS
`
`1535
`
`Such tablets commonly are called chewable tablets. Upon
`chewing, properly prepared tablets will disintegrate smooth-
`ly 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
`compressibility. These are discussed under Direct Com-
`pression, page 1645.
`.
`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. Howev-
`er, in the formulation of new therapeutic agents the-com-
`patibility of the diluent with the drug must be considered.
`For example, calcium salts used as diluents for the broad-
`spectrum antibiotic tetracycline have been shown to inter-
`fere with the drug’s absorption from the gastrointestinal
`tract. When drug substances have low water solubility, it is
`recommended that water—so1uble diluents be used to avoid
`possible bioavailability problems. Highly adsorbent sub-
`stances, eg, bentonite and kaolin, are to be avoided in mak-
`ing tablets of drugs used clinically in small dosage, such as
`the cardiac glycosides, alkaloids and the synthetic estrogens.
`These drug substances may be adsorbed to the point where
`they are not completely available after administration. The
`combination of amine bases with lactose, or amine salts with
`lactose in the presence of an alkaline lubricant, results in
`tablets which discolor on aging.
`Microcrystalline cellulose (Avicel) usually is used as an
`excipient 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 tablet mottling.
`Many ingredients are used for several different purposes,
`even within the same formulation. For example, 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 hydroxypropylmethylcellu-
`lose (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 formulating tablets and
`capsules have many uses, and a thorough understanding of
`their properties and limitations is necessary in order to use
`them rationally.
`*
`
`Binders
`
`Agents used to impart cohesive qualities to thepowdered
`material are referred to as binders or granulators. They
`impart a cohesiveness to the tablet formulation which in-
`sures the tablet remaining intact after compression, as well
`as improving the free-flowing qualities by the formulation of
`granules of desired hardness and size. Materials commonly
`used as binders include starch, gelatin and sugars as sucrose,
`glucose, dextrose, molasses and lactose. Natural and syn-
`thetic gums which have been used include acacia, sodium
`alginate, extract of Irish moss, panwar gum, ghatti gum,
`mucilage of isapol husks, carboxymethylcellulose, methyl-
`cellulose, polyvinylpyrrolidone, Veegum and larch araboga-
`lactan. Other agents which may be considered hinders un-
`.der certain circumstances are polyethylene glycol, ethylcel-
`lulose, waxes, water and alcohol.
`The quantity of binder used has considerable influence on
`the characteristics of the compressed tablets. The use of too
`much binder or too strong a binder will make a hard tablet
`which will not disintegrate easily and which will cause exces-
`sive wear of punches and dies. Differences in binders used
`
`Astrazeneca Ex. 2093 p. 7
`
`

`
`1536
`
`CHAPTER 89 ,
`
`for CT Tolbutamide resulted in differences in hypoglycemic
`effects observed clinically.‘ Materials which have no cohe-
`sive qualities of their own will require astronger binder than
`those with these qualities. Alcohol and water are not bind-
`ers in the true sense of the word, but because of their solvent
`action on some ingredients such as lactose, starch and cellu-
`loses, they change the powdered 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 “pregelatin-
`ized” starches available are intended to be added in the dry
`form so that water alone can be used as the granulating
`solution. The same amount of binder in solution will be
`more effective than if it were dispersed in a dry form and
`moistened with the solvent. By the latter procedure the"
`binding agent is not as effective in reaching and wetting each
`of the particles within the mass of powders. Each of the
`particles in a powder blend has a coating of adsorbed air on
`its surface, and it is this film which must be penetrated
`before the powders can be wetted by the binder solution.
`After wetting, a certain period of time is necessary to dis-
`solve the binder completely and make it completely avail-
`able for use. Since powders differ with respect to the ease
`with which they can be wetted, and their rate of solubiliza-
`tion, it is preferable to incorporate the binding agent in
`solution. By this technique it often is possible to gain effec-
`tive binding with a lower concentration of binder.
`The direct compression method for preparing tablets (see
`page 1645) requires a material that not only is free-flowing
`but also sufficiently cohesive to act as a binder. This use has
`been described for a number of materials including micro-
`crystalline cellulose, microcrystalline dextrose, amylose and
`polyvinylpyrrolidone.
`It has been postulated that micro-
`crystalline cellulose is a special form of cellulose fibril in
`which the individual crystallites are held together largely by
`hydrogen bonding. The disintegration of tablets containing
`the cellulose occurs by breaking the intercrystallite bonds by
`the disintegrating medium.
`Starch Paste—Corn starch is used widely as a binder.
`The concentration may vary from 10 to 20