Editor: Donna Balado
`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 LippincottW1lliams & Wflkins
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of this book may be re-
`produced in any form or by any means, including photocopying, or utilized by any infor-
`mation 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 publication contains in-
`formation relating to general principles of medical care which should not be construed as
`specific instructions for individual patients. Manufacturers’product information and pack-
`age inserts should be reviewed for current information, including contraindications,
`dosages, and precautions.
`
`Printed in the United States ofAmerica
`
`Library of Congress Cataloging-in-Publication Data
`
`Ansel, Howard C., 1933-
`Pharmaceutical dosage forms and drug delievery systems / Howard C.
`Ansel, LoydV. Allen, ]r., Nicholas G. Popovich. —— 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0—683—30572—7
`2. Drug delivery systems.
`1. Drugs—-Dosage forms.
`Il. Popovich, Nicholas G.
`Ill Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A618i 1999]
`RS200.A57
`1999
`615’.1—dc21
`DNLM/DLC
`for Library of Congress
`
`1. Allen, LoydV.
`
`99-17498
`CIP
`The publishers have made every efiort to trace the copyright holders for borrowed material. Ifthey
`have inadvertently overlooked any, they will be pleased to make the necessary arrangements at
`the first opportunity.
`
`The use of portions of the text of USP23/NF18, copyright 1994, is by permission of the USP
`Convention, Inc.The Convention is not responsible for any inaccuracy of quotation or for
`any false or misleading implication that may arise from separation of excerpm from the
`original context or by obsolescence resulting from publication of a supplement.
`
`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.
`
`99 00 01 O2
`1 2 3 4 5 6 7 8 9 10
`
`Astrazeneca Ex. 2095 p. 2
`
`

`
`
`
`Contents
`
`Preface
`
`Acknowledgments
`
`Section I. PRINCIPLES OF DOSAGE FORM DESIGN AND DEVELOPMENT
`
`I
`
`2
`
`3
`
`4
`
`5
`
`Introduction to Drugs and Pharmacy
`
`New Drug Development and Approval Process
`
`Dosage Form Design: Pharmaceutic and
`Formulation Considerations
`
`Dosage Form Design: Biopharrnaceutic and
`Pharmacokinetic Considerations
`
`Current Good Manufacturing Practices and Good
`Compounding Practices
`
`Section II. SOLID DOSAGE FORMS AND MODIFIED-RELEASE DRUG DELIVERY SYSTEMS
`
`6
`
`7
`
`8
`
`Powders and Granules
`
`Capsules and Tablets
`
`Modified~Release Dosage Forms and Drug Delivery Systems
`
`Section III. SEMI-SOLID AND TRANSDERMAL SYSTEMS
`
`_
`
`9
`
`TO
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`‘244
`
`263
`
`ix
`
`Astrazeneca Ex. 2095 p. 3
`
`

`
`X
`
`Contents
`
`Section IV. PHARMACEUTICAL INSERTS
`
`II
`
`Suppositories and Inserts
`
`Section V.
`
`LIOUID DOSAGE FORMS
`
`I 2
`
`I3
`
`Solutions
`
`Disperse Systems
`
`Section VI. STERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`T4
`
`T5
`
`T6
`
`Parenterals
`
`Biologicals
`
`Ophthalmic Solutions and Suspensions
`
`Section VII. NOVEL AND ADVANCED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVICES
`
`Radiopharmaceuticals
`
`Products of Biotechnology
`
`Novel Dosage Forms and Drug Delivery Technologies
`
`Systems and Techniques of Pharmaceutical Measurement
`
`T7
`
`T8
`
`T9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
`
`Astrazeneca Ex. 2095 p. 4
`
`

`
`
`
`CAPSULES AND TABLETS
`
`
`
` Chapter of cl Glance
`
`Capsules
`Hard Gelatin Capsules
`The Manufactllre ofHard Gelatin Capsule
`shens
`cap..,1,;5;,-.35
`Preparation 0! Filled Hard Gelatin Capsules
`Developing the Formulation ans SEIECELDII of
`Capsule Size
`Filling Hard Capsule Shells
`Capsule Seating
`and Polishing Capsules
`Scfi Gelatin Capsules
`Preparation of Soft Gelatin
`Utilization of Soft Gelatin Capsules
`Campendial Requirnnmtsjbr Capsules
`Addedfiubstanoes
`
`Containers for Dispensing Capsules
`Disintegration Test for Capsules
`Dissolution Test for Capsules
`Weight Variation
`Content Unifonnity
`Content Labeling Requirement
`Stability Testing
`Moisture Permeation Test
`
`Oflicial and Commercially Available Capsules
`Inspecting, Counting, Packaging, and Star-
`ing Capsules
`Tablets
`
`Types ofTablets
`Compressed Tablets (C51'.)
`Multiple Compressed Tablets {M.CT.)
`Sugar-Coated Tablets (S.C.T.)
`Film Coated Tablets [l-'.C.'1‘.}
`GelaLin—Coated Tablets
`
`Effervescent Tablets
`Molded Tablets (M-T-J
`Tab1etTriturates CI-T-J
`Hypodm-mic Tablets {I-LT.)
`Dispensixug Tablets (om)
`Immediate Release Tablets [I.R.)
`Instant Disinhegmfing/Dissolving Tablets
`Extended Release Tablets (E.R.]
`Vaginal Tablets
`Compressed Tablets
`Quality Standards and Compendial R.8q'I.1‘l.‘:'e-
`moms
`
`Compressed Tablet Manufacture
`Wet Granulation
`All-in—0ne Granulation Methods
`Dry Granulation
`Tableting of Granulation
`Direct Compression Tablet-ing
`Tabletfledusfing
`Chewable Tablets
`Molded Tablets
`
`Tablet Coating
`Sugarcoating Tablets
`Film-coating Tablets
`Enteric Coating
`Fluid-Bed or Air Suspension Coating
`Compression Coating
`Impact ofManufactiaing Changes on Solid
`Dosage Forms
`Ofiiciaf and Commercially Available
`Tablets
`Pa
`‘:13 and Storing Tablets
`Oral dministration o_fSob'd Dosage Forms
`Other Solid Dosage Formsfilr
`Oral Administration
`
`Enteric-Coated Tablets (E.C.T.}
`T-muses
`Buocal or Sublingual Tablets
`Pills
`Chewable Tablets
`
`
`179
`
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`
`

`
`ran
`
`Capsralzsarrdlltblcts
`
`WHEN MEDICNHDNS are to be administered orally
`to adults, capsules and tablets usually are preferred
`because they are conveniently carried, readily iden-
`tified, and easily taken...
`Consider the convenience of a patient carrying a
`day's, weelc’s, or month's -supply of capsules or
`tablets compared with equivalent doses of a liquid
`rnedication. With capsules and tablets as dosing
`units, there isno need for spoons or other mea-
`suring devices, which -sometimes may be inconve-
`nient and may result in less than accurate dosing.
`Also, most capsules and tablets are tasteless when
`swallowed, which is not the case with oral liquid
`medication.
`
`The characteristic shapes and colors of capsules
`and tablets and the manufacturer’: name and prod-
`uctcodenurnber commonly entbossedmirnprinted
`on theirsurfaoe make themreadilyidenttfled.'I'his
`communications between the patient and
`health care providers, assists patient compliance,
`and fosterssafe-and effective medication use.
`
`Capsules and tablets are available for1.na.nymed-
`ications in a variety of dosage strengths thereby
`
`prUv1£lmg''
`prescribing flexibility to the prescciber
`and accurate individualized dosagefor the patient.
`Some tablets are scored, -or grooved, which allows
`them tube easilybroltmi intotwo ormoreparts.
`This enables the patient to swallow smaller por-
`tions as may be desired, or-when prescribed, it al-
`lows the tablet to be taken in reduced or divided
`
`dosage. Tablets. that are not scored are not ‘Intended
`to be broken or cut by the patient since they may
`have special coatings filtdior drug-release features
`that would be
`by altering the tablets
`physical integdty.
`From a pharrnaceutic standpoint, solid dosage
`forms are etticiently and productively manufac-
`tured; they are packaged and shipped bymanu-
`facturers-at-lower cost andwithless breakage than
`comparable liquid forms; and are more -stable and
`have a longer shelf-life than their liquid counter-
`parts.
`As discussed later in this chapter, empty hard
`gelatin capsules are often used by the pharmacist in
`the exbemporaneous compounding ofpreserlptions.
`On occasion, a pharmacist may use commercially
`available capsules and tablets as the source of a
`medicinal agent when it is not otherwise available.
`In these instances, the pham1a|:ist.musttake into
`account any excipients that are present in the com-
`mercial ‘product to ensure‘ compatibility with the
`other ingredients in the compounded prescription.
`Capsules and tablets designed to provide modified
`drug release are dismissed in Chapter 8.
`
`Capsules-
`
`Capsules are solid dosage forms in which medic-
`inal agents andlor inert substances are enclosed
`within asmall shell ofgelaiin. Gelatin Capsule ‘shells
`maybe hard orsofi
`on their composition.
`Tbevastmajoaityoffilledcapsules areintendedto
`be swallowed whole by the patient tor the benefit of
`the medication contained therein. However, it is not
`unusual practice in hospitals and extended care fa-
`cilifiesforacaregivertoopencapsulesoroush
`tablets to mlxwith foodordrlnk, especial1yforchil-
`dren or other patients unable to swallow solid
`dosage forms.Thisshould be done onlywith the
`concurrence ofthe-pharrnacistsinoa the drugrclease
`characterisfiosofcertaindosageform5cmddbeal-
`cared and adversely affect the patients welfare.
`Dosage forms that must beleft irrtactirtclude-. en-
`terlc coated tablets, designed to pass through the
`stzornech fiat drug release and absorption in the in-
`teslirte; extended-release dosage forms, designedto
`provide prolonged release of the
`and
`sublingual or buocal tablets, formulated to dissolve
`underthetongue orintheoralcavity(1).Inln-
`stances in which a‘ patient is unable to swallow an
`intact solid dosagefonn, an alternative producbsuch
`as a chewable tablet, instant dissolving tablet, oral
`liquid, suppository or injection may be employed-
`
`Hard Gelatin Capsules
`
`Hardgelatin capsuleshellsareused to manufac-
`ture most of the commercially available medicated
`capsules..'1'hey are also oorrunonly employed in clin-
`ica1drugl:rial5,tocomparetheeffiectsofan
`irrvestigational drug to another drug product or
`p1aoebo.Hardgelatincapsu1esalsoareusedbyt11e
`comirturlity phannacistin the extemporaneous com-
`pounding of prescriptions. The em_pt_v,r capsule shells
`are-madeiromamixtm-e ofgeletin, sugarandwaoer
`As such. they are clean colorless, and essentially
`tasteless. They may be colored with various FD&C
`andD&C_ dyes andrnaybe made opaquebyadding.
`agents such as titanium dioxide. Most commercially
`available medicated capsules conlain combinations
`ofcolorantsandopaquantstomakethemdistinctlve.
`tnanywithcapsandbodies ofdiffetent colors.
`Gelatinls obtainedbythe partial hydrolysis of
`collagen obtained from the skin, white connective
`tissue,andbonesofanimals.Incornmeroe,itis
`availableirtthetomrofafirrepowdenacoarse
`powder, shreds, flakes, or sheets (Fig. 7.1).
`Gelatin is stable in airwhen dry but is subject to
`microbial decomposition when it becomes moist.
`
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`

`
`Capsules and Tablets
`
`181
`
`times its weight of water. Some patients prefer to
`swallow a capsule wetted with water or saliva be-
`cause a wetted capsule slides down the throat more
`readily than a dry capsule. Gelatin is soluble in hot
`water and in warm gastric fluid a gelatin capsule
`rapidly dissolves and exposes its contents. Gelatin,
`being a protein, is digested by proteolytic enzymes
`and absorbed.
`
`A number of methods have been developed to
`track the passage of capsules and tablets through
`the gastrointestinal tract to map their transit time
`and drug-release patterns. Among these is gamma
`scintigruphy, a noninvasive procedure which in-
`volves use of a gamma ray-emitting radiotracer in-
`corporated into the formulation with a gamma
`camera coupled to a data recording system (4-5).
`The quantity of material added to allow gamma
`scintigraphy is small and does not compromise the
`usual in vivo characteristics of the dosage form
`being studied. When scintigraphy is combined
`with pharmacokinetic studies, the resultant pharma-
`cosciatogmphic evaluation provides information of
`the transit and drug release patterns of the dosage
`form as well as the rate of drug absorption from the
`various regions of the gastrointestinal tract (4) .This
`method is particularly useful
`in:
`(a)
`identifying
`whethera correlation exists between invitro and in
`
`vivo bioavailability for immediate-release products;
`(b) assessing the integrity and transit time of en-
`teric coated tablets through the stomach enroute to
`the intestines; and (c) drug.-‘dosage form evaluation
`in new product development
`(4-5). A separate
`technique, using a pl-I—sensitive, nondigestible, ra-
`diotelemetric device termed the Heidelberg cap-
`sule, the approximate size of a No. 0 gelatin cap-
`sule, has been used as a nonradioactive means to
`measure gastric pH, gastric residence time, and
`gastric emptying time of solid dosage forms in test-
`ing and nonfasting human subjects (6).
`As discussed in Chapter 4, drug absorption from
`the gastrointestinal tract depends on a number of
`factors, including the solubility characteristics of
`the drug substance, the type of product formulation
`(i.e., immediate-release, rnodified—releese, enteric
`coated), the gastrointestinal contents and intersub-
`ject differences in physiologic character and re-
`spouse.
`
`The Manufacture of Hard Gelatin
`
`Capsule Shells
`
`Hard gelatin capsule shells are manufactured in
`two sections, the capsule body and a shorter cap.
`The two parts overlap when joined, with the cap fit-
`ting snugly over the open end of the capsule body.
`
`Astrazeneca Ex. 2095 p. 7
`
`in the
`Fig. 7.‘! Pork skin gelatin used as raw material
`rriartufacture of gelatin capsules. (Courtesy of Smitzhitline
`Beechnm.)
`
`Normally, hard gelatin capsules contain between
`13 and 16% of moisture (2). However, if stored in
`an environment of high humidity, additional mois-
`ture is absorbed by the capsules, and they may
`become distorted and lose their rigid shape. In an
`environment of extreme dryness, some of the mois-
`ture normally present in the gelatin capsules is lost
`and the capsules may become brittle and crumble
`when handled.Therefore, it is desirable to maintain
`hard gelatin capsules in an environment free from
`excess humidity or dryness.
`Because moisture may be absorbed by gelatin
`capsules and affect hygroscopic agents contained
`within, many capsules are packaged along with a
`small packet of a desiccant material
`to protect
`against the absorption of atmospheric moisture.
`The desiccant materials most used are dried silica
`
`gel, clay, and activated carbon.
`Prolonged exposure to high humidity can affect in
`euro capsule dissolution. Such changes have been
`observed in capsules containing tetracycline, chlor-
`arnphenicol, and nitrofurantoin (3). Because such
`changes could forewarn of possible changes in
`bioavaiiability, capsules subjected to such stress con-
`ditions must be evaluated on a case by case basis (3).
`Although gelatin is insoluble in cold water,
`it
`does soften through the absorption of up to ten
`
`

`
`182
`
`Capsules and Tablets
`
`The shells are produced industrially by the me-
`chanical dipping of pins or pegs of the desired
`shape and diameter into a temperature—controlled
`reservoir of melted gelatin mixture (Figs. 7.2, 7.3).
`The pegs, made of manganese bronze, are affixed
`to plates, each capable of holding up to about 500
`pegs. Each plate is mechanically lowered to the
`gelatin bath, the pegs submerged to the desired
`depth and maintained for the desired period to
`achieve the proper length and tluckness of coating.
`Then the plate and the pegs are slowly lifted from
`the bath and the gelatin dried by a gentle flow of
`temperature- and humidity-controlled air. When
`dried, each capsule part is trimmed rnechanically to
`the proper length, removed from the pegs and the
`capsule bodies and caps are joined together. It is
`important that the thickness of the gelatin walls be
`strictly controlled so that the capsule’s body and
`cap fit snugly to prevent disengagernertt.The pegs
`on which the caps are formed are slightly larger in
`diameter than the pegs on which the bodies are
`formed, allowing the telescoping of the caps over
`the bodies. In capsule shell production, there is a
`continuous dipping, drying, removing and joining
`of capsules as the peg-containing plates are rotated
`in and out of the gelatin bath. As noted earlier, cap-
`sule shells may be made distinctive by adding col-
`orants andlor opaquants to the gelatin bath.
`A manufacturer also may prepare distinctive-
`
`looking capsules by altering the usual rounded
`shape of the capsule—mal<ing pegs. By tapering the
`end of the body—producing peg while leaving the
`cap-making peg rounded. one manufacntrer pre-
`pares capsules differentiated from those of other
`manufacturers (PULVULES, Eli Lilly). Another man-
`ufacturer utilizes capsules with the ends of both the
`bodies and caps highly tapered (SPANSULE Cap-
`sules, SrnithK.line ‘Beecharn).Yet another innova-
`tion in capsule shell design is the SNAP-FIT, CONT-
`SNAP, and CONT—SNAP SUPRO hard gelatin
`capsules depicted in Figures 7.4 and 7.5. The origi-
`nal SNAP-FIT construction enables the two halves
`
`of the capsule shells to be positively joined through
`locking grooves in the shell walls. The two grooves
`fit into each other and thus ensure reliable closing
`of the filled capsule. During the closing process, the
`capsule body is inserted into the cap. With the
`high-capacity filling rates of the modern capsule
`filling machines (over 180,000 capsules per hour),
`capsule splitting (“telescoping”) ancllor denting of
`the capsule shell occurs with the slightest contact
`between the two capsule-part rlrns when they are
`joined. This problem, which exists primarily with
`straight-walled capsule shells, led to the develop-
`ment of the CONl—SNAP capsule, in which the rim
`of the capsule body is not straight, but tapered
`slightly (Fig. 7.5). This reduces the risk of the
`capsule-rirns touching on joining. and essentially
`
`Fig. 7.2 Body ofccpsttles and their caps are shown as they move through automated capsule-melting machine. Each machine is
`capable ofpmducing 30,000 capsules per item‘. It takes Gt 40-minute cycle to produce rt capsule. (Courtesy ofsmitltiiline BeerJ1am.l
`
`Astrazeneca Ex. 2095 p. 8
`
`

`
`Consoles and Tablets
`
`183
`
`amount of fill material to be encapsulated. The den-
`sity and compressibility of the till will largely deter-
`mine to what extent it may be packed into a capsule
`shell (7). For estimation, a comparison may be made
`with powders of well—known features (Table 7.1)
`and an initial judgment made as to the approxirnate
`capsule size needed to hold a specific amount of ma ~
`terial. However, the final determination largely may
`be the result of trial. For human use, empty capsules
`ranging in size from 000 {the largest) to 5 (the small-
`est) are commercially available (Fig. 7. 7). Larger cap-
`sules are available for veterinary use.
`For prescriptions requiring exrernporaneous corn-
`pounding, hard gelatin capsules permit a wide pre-
`scribing latitucle by the physician. The pharmacist
`may compound capsules of a single medicinal agent
`or combination of agents at the precise dosage pre-
`scribed for the individual patient.
`
`Preparation of Filled Hard Gelatin Capsules
`
`The large-scale or 5ma.ll—scale preparation of
`filled hard gelatin capsules is divided into the fol-
`lowing general steps.
`
`CONI-SNAP?”
`
`I3F
`
`5
`
`3
`
`r -»o.~:.«.-u
`
`o us closer!
`
`0.05-'1
`
`Fig. 7.4 Line drawings of the CDNI-SNAP capsule in
`open, pre-closed, and closed positions. The tapered rims I}
`ovoid lelescopi:1g; the indentations 2.3 prevent premature open-
`ing, and the grooves 3) lock the two capsule parts together of-
`rer the capsule has been filled. {Courtesy ofCopsugel Division,
`Women Lambs)? Co.)
`
`AstraZeneca Ex. 2095 p. 9
`
`Fig. 7.3 Capsules beingdippedforwlorfng on automated cap-
`sule-mokirrg equipment. (Courtesy o}‘Smi:hl(lr'r:e Beeclmm.)
`
`eliminates the problem of splitting during large-
`scale filling operations. In the CONLSNAP SUPRO
`capsules, the upper capsule part extends so far over
`the lower part that only the rounded edge of the
`latter is visible (Fig. 7.5). Opening of such a filled
`capsule is difficult because the lower surface offers
`less gripping surface to pull the two halves apart.
`This increases the security of the contents and the
`integrity of the capsule.
`After filling, some manufacturers render their
`capsules tamper-evident through various capsule
`sealing techniques. These methods are discussed
`later in this section. Capsules and tablets also may
`be imprinted with the names or monograms of
`the manufacturer, the assigned national drug code
`(NDC) number and other markings making the
`product identifiable and distinguishable from other
`products (Fig. 7.6).
`
`Capsule Sizes
`
`Empty gelatin capsules are manufactured in var-
`ious sizes, varying in length, in diameter, and capac-
`ity. The size selected for use is determined by the
`
`

`
`are performed to determine if all of the formulations
`bulk powders may be effectively blended together as
`such or if they require reduction of particle size or
`other processing to achieve homogeneity.
`A diluent or filler may be added to the formula-
`tion to produce the proper capsule fill volume. Lac-
`tose, microcrystalline cellulose and starch are
`commonly used for this purpose. In addition to pro-
`viding bulk, these materials often provide cohesion
`to the powders, which is beneficial in the transfer
`of the powder blend into capsule shells (2). Disin-
`tegrants are frequently included in a capsule for-
`mulation to assist the breal<~up and distribution
`of the capsule contents in the stomach. Among
`the disintegrants used are pregelatinized starch,
`croscarmellose, and sodium starch glycolate.
`To achieve uniform drug distribution, it is advan~
`tageous if the density and particle size of the drug
`and nondrug components are similar. This is par—
`
`
`
`
`
`is I
`
`'-
`
`{fit
`
`Fig. 7.6 Examples of tablets and capsules marked witli tr
`letter-number code to facilitate identification, (Courtesy of Eli
`Lilly and Company.)
`
`184
`
`Capsules and Tablets
`
`BONI-SNAP ‘*9
`
`com-soar suPno”5'
`
`ll Tapeien nu-n_Io emu Iaieitvong
`tllonu-Sn.-4p"5'l
`1] Games which Inn the Me halves
`Ingmar once the llniull has bun
`hllrtl Isrup-in "'3 ulna;-gnu
`31 Inantaluuns ta am-an: prmaturt
`unlmllil
`
`Fig. 7.5 Line drawings of the CONI-SNAP and COM-
`SNAP SUPRO {on right) cepsules.Ti:e latter is designed to be
`smaller and to have the lowerporiion afrhe capsule shell cou~
`ceoled exoepifor the rounded emi.Tl1is makes separation ofthe
`two parts more digital: and contributes to capsule integrity.
`(Courtesy of Capsugel Division, Warner-Lambert Co.)
`
`1. Developing and preparing the formulation and
`selecting the size capsule.
`2. Filling the capsule shells.
`3. Capsule sealing (optional).
`4. Cleaning and polishing the filled capsules.
`
`Developing the Formulation and Selection of
`Capsule Size
`
`In developing a capsule formulation, the goal is
`to prepare a capsule with accurate dosage, good
`bioavailability, ease of filling and production. sta-
`bility, and elegance.
`In dry formulations, the active and inactive com—
`ponents must be blended thoroughly to ensure a
`uniform powder mix for the capsule fill. Care in
`blending is especially critical for low-dose drugs
`since lack of homogeneity could result in significant
`therapeutic consequences. Preformulatlon studies
`
`AstraZer1eca Ex. 2095 p. 10
`
`

`
`Capsules and Tablets
`
`I85
`
`Table 7.1. Approximate Capacity of Empty Gelatin Capsules
`
`Capsule Size
`Volume (mm
`1.40
`0.95
`0.53
`0.50
`0.37
`0.30
`0.21
`0.13
`
`
`Drug Substance (mg)*
`Qujnine Sulfate
`sodium Bicarbonate
`Aspfijn
`
`650
`1430
`1040
`
`390
`975
`650
`
`325
`715
`520
`
`227
`510
`325
`
`195
`390
`260
`
`130
`325
`195
`
`97
`260
`162
`
`65
`130
`97
`
`‘Amount may vary according to the degree of pressure used in filling the capsules.
`
`ticularly important when a drug of low dosage is
`blended with other drugs or nondrug fill (8). When
`necessary, particle size may be reduced by milling to
`produce particles ranging from about 50 to 1000
`microns. Milled powders may be blended effec-
`tively for uniform distribution throughout a pow-
`der mix when the drug's dosage is 10 mg or greater
`(8). For drugs of lower dose or when smaller parti-
`cles are required, rrricronizafion is employed. De-
`pending on the materials and equipment used, mi-
`cronization produces particles ranging from about
`1 to 20 microns in size.
`
`In preparing capsules on an industrial scale using
`high-speed automated equipment, the powder mix
`or granules must be free-flowing to allow steady
`passage of the capsule fill from the hopper through
`the encapsulating equipment and into the capsule
`shells. The addition of a lubricant or giidrmt such as
`fumed silicon dioxide, magnesium stearate, calcium
`stearate, stearic acid, or talc (about 0.254%) to the
`powder mix enhances flow properties (2).
`When magnesium stearate is used as the lubri-
`cant,
`the water-proofing characteristics of this
`water-insoluble material can retard penetration by
`the gastrointestinal fluids and delay drug dissolu-
`tion and absorption. The addition of surface active
`agents, as sodium lauryl sulfate, to capsule and
`
`tablet formulations is used to facilitate wetting by
`the gastrointestinal fluids to overcome the problem
`(9). Even in instances in which a water-insoluble
`lubricant is not used, after the gelatin capsule shell
`dissolves, gastrointestinal fluids must displace the
`air that surrounds the dry powder and penetrate
`the drug before it can be dispersed and dissolved.
`Powders of poorly soluble drugs have a tendency to
`resist such penetration. Disiritegratlon agents in-
`cluded in a capsule formulation facilitate the break
`up and distribution of the capsule’s contents.
`Whether it be the presence of a lubricant, sur-
`factant, disintegrating agent, or some other phar-
`maceutic excipient, formulation can influence the
`bioavailability of a drug substance and can account
`for differences in drug effects, which may be en-
`countered between two capsule products of the
`same medicinal substance. Pharmacists must be
`
`aware of this possibility when product-interchange
`is considered.
`
`Inserting tablets or small capsules within cap-
`sules is sometimes a useful technique in the com-
`mercial production of capsules and in a pharma-
`cist’s extemporaneous preparation of capsules
`(Fig. '7.8).'l'his may be done to separate chemically
`incompatible agents or to add prerneasured (as
`tablets) amounts of potent drug substances. Rather
`
`
`
`Fig. 7.7 Actual sizes ofhrmi gelatin capsules. From lcfi to right, sizes 000, 00, 0, 1, 2. 3, 4, and 5.
`
`Astrazcnoca Ex. 2095 p.
`
`1 l
`
`

`
`
`
`Capsules and Tablets
`
`186
`
`Fig. 7.8 Examples cffill in hard gelatin capsules. 1, powder or gramtlate; 2, pellet mixture; 3, paste; 4, capsule; and 5, tablet.
`(Courtesy ofCaps:tg1:l, Division ofwameclambertl
`
`than weighing a potent drug, a pharmacist may
`choose to insert an available prefabricated tablet of
`the desired strength in each capsule. Other less po-
`tent agents and diluents may then we weighed and
`added. On an industrial scale, coated pellets de-
`signed for modified-release drug delivery are also
`commonly placed in capsule shells.
`Gelatin capsules are unsuitable for the encapsu-
`lation of aqueous liquids because water softens
`gelatin and distorts the capsules. resulting in leak-
`age of the contents. However, some liquids such as
`fixed or volatile oils that do not interfere with the
`
`stability of the gelatin shells may be placed in lock-
`ing gelatin capsules [or the capsules may be sealed
`with a solution of gelatin thinly coating the inter-
`face of the cap and body] to ensure the retention of
`the liquid. Rather than placing a liquid in a capsule
`as such, the liquid maybe rnixecl with aninert pow-
`der to make a wetted mass or paste. which may
`then be placed in capsules in the usual manner
`(Fig. 7.8]. Eutectic mixtures of drugs, or mixtures of
`agents that have a propensity to liquefy when ad-
`mixed, may be mixed with a diluent or absorbent
`such as magnesium carbonate, l<a.oll11. or light mag-
`nesium oicide to separate the interacting agents and
`to absorb any liquefied material WlIlC.l'l may form.
`In large-scale capsule production, liquids are
`placed in soft gelatin capsules that are sealed during
`the filling and manufacturing process. Soft cap-
`sules are discussed later in this chapter.
`In most instances the amount of drug placed in
`a capsule represents a single dose of the medica-
`tion. In some instances, when the usual dose of the
`drug is too large to place in a single capsule, two or
`more capsules may be required to provicle the de-
`sired dose. The total amount of formula prepared is
`that amount necessary to fill the desired number of
`capsules. On an industrial scale this means hun-
`
`dreds of thousands of capsules. In community prac-
`tice, an individual prescription may call for the
`preparation of only six or a dozen capsules. Any
`slight loss in Eill-material during the preparation
`and capsule-filling process will not tna terially affect
`an industrial size batch. but in the community
`pharmacy, a slight loss of powder would result in an
`inadequate quantity to fill the last capsule. To en-
`sure enough fill in the compounding of srnall num-
`bers of capsules, the community pharmacist may
`calculate for the preparation of one or two more
`capsules than is required to fill the prescription.
`However, this procedure may not be followed for
`capsules containing a controlled substance since
`the amount of drug used and that called for in the
`prescription must strictly coincide.
`The selection of the capsule size for a commer-
`cial product is done during the product develop-
`ment stage. The choice is deterrnined by require-
`ments ol the formulation, including the dose of the
`active ingredient, and the density and compaction
`characteristics of the drug and nondrug compo-
`nents. Ifthe dose of the drug is inadequate to fill the
`volume of the capsule body. a diluent is added. In-
`formation on the density and compaction charac-
`teristics of a capsules active and inactive compo-
`nents and comparison to other similar materials
`and prior experiences can serve as a guide in se-
`lecting capsule size (7).
`Hard gelatin capsules are used to encapsulate be-
`tween about 65 trig and ‘l g of powdered material.
`As shown inTable 7.1. the smallest capsule (No. 5),
`may be expected to hold 65 mg of powder or more,
`depending on the characteristics of the powder sub-
`stance. Ofteniirnes, in the externporaneous com-
`pounding of prescriptions, the best capsule size to
`use is determined by trial. Use of the smallest size
`capsule, properly filled, is preferred. A properly filled
`
`Astrazeneca Ex. 2095 p. 12
`
`

`
`capsule should have its body filled with the drug
`mixture, not the cap. The cap is intended to fit
`snugly over the body to retain the contents.
`The following examples demonstrate the drug
`and nondrug contents of a few commercially avail-
`able capsules.
`
`litracycline Capsules
`Active ingredient
`
`Filler:
`
`'Il=.-tracycline
`250 mg
`Lactose
`
`hydrochloride.
`
`Lubricantiglidantr Magnesium stearete
`Capsule colorants:
`FD&:C'Yellow No. 6, D&C
`Yellow No. 10. Dec Red
`No. '28, I~'D&C Blue No. 1
`Capsule -opaquant: Titanium dioxide
`
`Acetanrinophen with Codeine" Capsules
`Active ingredients: Acetaminophen, 325 mg
`Codeine phosphate, 30 mg
`Sodium starch glyoolate
`Disintegrant:
`Lubricantfglidants: Magnesium stearate, stearic
`acid
`
`Capsule colorants: D&C Yellow No. 10, Edible
`Ink. FD&:C Blue No.
`1
`(FD&:C Green No. 3 and
`FD5:C Red No. 40}
`
`Diphsnhydrmrdne Hydrochloride Capsules
`Active ingredient: Diphenhydramine HCl,
`50 mg
`Confectionefis sugar
`Filler:
`Lubricantsfglidants: Talc, colloidal silicon dioxide
`Wetting agent:
`Sodium lauryl sulfate
`Capsule colorants:
`1"-'D:§cC Blue No.1, FDdtC Red
`No.3
`
`Capsule opaquant: Titanium dioxide
`
`Filling Hard Capsule Shells
`
`When filling a small number of capsules in the
`pharmacy, the pharmacist uses the”punch"metho_d.
`In this method, the pharmacist takes the precise
`number of empty capsules to be filled from his
`stock container. By counting the capsules as I:he-ini-
`rial step rather than taking a capsule from stock as
`each one is filled, the pharmacist guards against
`an erroneous number of capsules and avoids
`contarninating the stock container with drug pow-
`der. The powder to be encapsulated is placed on a
`sheet of clean paper oronaglass or porcelain plate.
`Using the spatula, the powder mix is formed into a
`cake having a depth of approximately one-fourth
`to one-third the length of the capsule body,'Then
`an empty capsule body is held between the thumb
`
`Capsules cud Iizblets
`
`187
`
`and forefinger and “punched” vertically into the
`powder cake repeatedly until filled. Some pharma-
`cists wear surgical gloves or late): finger cots to
`avoid handling the capsules with bare fingers. Be-
`cause the amount of powder packed into a capsule
`depends upon the degzee of compression, the phar-
`macist should punch each capsule in the same
`manner and aftercapping weigh the p1-oduct.When
`nonpotent materials are placed in capsules, the first
`filled capsule should be weighed {us