SEVENTH EDETION
`
`AND DRUG
`
`DELIVERY SYSTEMS
`
`PHARMACEUTICAL
`DOSAGE FORMS
`
`
`
`Howard C. Ansel
`
`Loyd V. Allen, Jr.
`
`Nicholas G. Popovich
`
`AstraZeneca Exhibit 2095 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`

`

`Editor: Donna Balado
`Managing Editor: jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 Lippincott Williams & Wilkins
`
`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, Lode. Allen, Ir., 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.
`11. 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, Lode.
`
`99—17498
`CIP
`
`The publishers have made every effort 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 excerpts 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 02
`1 2 3 4 5 6 7 8 9 10
`
`AstraZeneca Exhibit 2095 p. 2
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`

`

`
`
`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
`
`_
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`'244
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`263
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`ix'
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`AstraZeneca Exhibit 2095 p. 3
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`

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`x
`
`Contents
`
`Section IV. PHARMAEEUTICAL INSERTS
`
`IT
`
`Suppositories and Inserts
`
`Section V. LIQUID DOSAGE FORMS
`
`I 2
`
`T3
`
`S olutions
`
`Disperse Systems
`
`Section VI. STERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`T 4
`
`I 5
`
`lb
`
`Parenterals
`
`Biologicals
`
`Ophthalmic Solutions and Suspensions
`
`Section VII. NOVEL AND ADVAN(ED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVIEES
`
`Radiopharmaceuticals
`
`Products of Biotechnology
`
`Novel Dosage Forms and Drug Delivery Technologies
`
`Systems and Techniques of Pharmaceutical Measurement
`
`T 7
`
`18
`
`T9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
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`AstraZeneca Exhibit 2095 p. 4
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`

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`
`
`
`
`
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`
`
`CAPSULES AND TABLETS
`
`
`
`
`Chapter at a Glance
`
`
`Capsules
`Hard Gslsfifl Capsules
`The Manufacture 8f Hard Gelatin Caysuls
`Shells
`
`Capsule Sizes
`Preparafisn a? Fiflsd Hard Gsiatin Capsules
`Devslsping the Farmtds dam ans; Sslectiun 0f
`Capsule Size,
`Filling Hard Caysuls Sheila
`CapSUIe Sealing
`Cleamng and Psiishmg Capsules
`szi‘ Gslaiifi Capsules
`Preparatimx of Saft Gelatin Capsules
`Utflirsatiau of SCI-ft Gelatin Capsuiies
`Csmpms‘z‘sl Requirsrrzemsfss Cspssiss
`édcied Substamss
`
`Cantamers far flispsnsing Capsuies
`Disintegrafian ”Task fur Caysules
`Bissaiutiun Test f0: Capsules
`Weight Variaticm
`Cfintent Unifmmity
`Cmtent Labeling quuimmcm
`Stability Testing
`Maismre Parmestian Test
`
`Qjfi‘sisfi and Csmmerciaily Amflskxis Capsmss
`Inspectmg, Counting], Packaging; and Sims
`mg Capsules
`Tablets
`
`Types of'l‘sblsfs
`Campressed Tabists {CIR}
`Multiple Campresssd Tablets {M.C.T.)
`Sugarélaated Tamara {EAST}
`Film {Seated stiets {F.CI.)
`Gelstimffuated Tahlsts
`
`Effervescsm Tamers
`
`Msldeai Tablas {MT .)
`Tablet Trimates {TIL}
`
`Hypcéermic Tabiets {H.323
`fiisyensing ’I‘sblsts {H.T.)
`inunscliate Release Tablets {11%.}
`
`Instant Qismtagmtingf Dissaiving Tabists
`Extended Release ”fablets {23.1%.}
`
`Vaginal Tablets
`Csmpre‘ssssf Tablets
`Quafity Standards and Campendisl Require-
`meats
`
`Cnmpmssed Tablet Manufacture
`We? Granuiafim
`Alivinflflna Gssnuiatitm Methads
`
`Dry Gramdafimn
`Tablsting sf Gramflaiian
`Direct Camprsssian Tableting
`Tabb»: Dedusting
`Chewsfie Tablets
`Msféed Tablets
`
`Talkies Casting
`Smgarmating Iahlets
`Fi1m~mating Tamers
`Enteric Casting
`Fluid~Bad 0r Air Suspensicm Costing
`Cmmpxessim {ligating
`Impact sstmgfscfm‘ng Chmges cm Salas
`[1333ng Famis
`Dfim‘si and. Csmmsssislly Azrsiisbls
`Tablets
`
`Packaging and Sfm‘ing Twists
`Om! Adminisfmiisn sf 8022]?! {image Fern-Is
`Gthsr 5332335? Esssge Farms fsr
`Om! Admirsistmfim-x
`
`Enisricvthated Tablets (EC?)
`Lmzsngss
`anneal at Suhlingual Tahists
`Pills
`Qhewable Tablets
`
`
`179
`
`Astraleneca Exhibit 2095 13* 5
`
`

`

`188
`
`Capsules {and Tablets
`
`WHEN mmcmms am ta be administered orally;
`in .wziutltsg capsules and tablets usually are prefexrad
`because they are canveniently carried; zeaciily 1162611w
`fified, and 951531}? taken
`Ctmsider the canvenienca 9f 3 patient canyiflg a
`day’s, week I at munth‘s supply Qf tagsulea 331’
`tablets camPared with equivalent dusss sf a liquid
`mdicatizm. With capaukas and tabiets as dusing
`units-g them is m mad fat apwns v31" (Lather megaw
`Suiting devices, which sometimes may be intuitive»
`went and may result in less than accurata dasmg
`A150, most capsules and tablets are tasteless when
`swaflamdg which is net the case with caral Equid
`medicatiarz.
`
`The characteristic shapes and calms 0? capsules
`and tabieta and the manufacturer’s 11351143 and pmciw
`that code number mmwly ambusseci m unprimed
`an thew surface make them reaciily ifienfifiedé This
`enhancea commumcatiuns batsmen the: patient: and
`health cam prwiders‘, assists patient campfianceli
`and fasten safe and effective medicafiun use»
`
`Capsules-s and tablets are available E05: many med~
`icatiwns in a variety af (image: strengths thareby
`pruwiding praycdbing flexibility m thE presmiber
`and accurate individualizéd damage far ma patient.
`Some tabiets are scored! at gmuva¢ which allsws
`then”: re be easily braken inta We :21: mars part3
`Ms mables the patient 15:: fiwafluw amaliar pmw
`rims as may be defied! :31: Wham pmscribsd, it: ai-
`mws the tablet ta be taken in reducaci or dividad
`
`dusagefahlets that are not scar-mi are that intem‘ied
`tr: be braken a: cut by the patient sincse they may
`have apeaiai matings andfar dmgmralease features
`that wauid baa campmnfiséxfi by altmng the tabigt‘s
`physiual integrity.
`Earn a pharmaceuiic stanépnimf 501k}; dusage
`fiurms are Efficiently and pwduetiveiy manufac»
`tum-ti; they are packaged ané shipped by manu—
`factu mm at lawer cagt and wiih 1:235 breakage than
`comparable liquid forms; and are mere stable and
`have a inngar shalfwlifa than thair liquid com-map
`parts.
`As discusseé later in this chapter, empty hard
`geiafin Capsules: are mften 1155261 by the pharmacigt in
`the extemporaneous campaunding GE prescriptiam,
`Cm accasian, a pharmacist may use mmmercialiy
`available capsules and tablets; as; the saurce mi a
`medicinal again? when it 33 mt: athenfise availabie.
`In these instances, the pharmacist must: take mm
`account any exflipiemg {hat 3:2 pres-sent in the cum-
`merciai product ta ensure campatibifity with the
`other ingredients in the cempoundad prescriptiem
`Capsmfles and tablets designed {an prmicie modifiad
`drug releaae are distugsed ifl Chapter 8.
`
`Capsules
`
`Capsules. are saiicl claaaga films in which medic»
`inal agents afldfar inert substances are: amassed
`within a small small {if gelatin. Gelatin cagsuie sheils
`may be had a: 56;? dapending an that campaaitim.
`Tm vast majority cf filled capsules axe intended m
`be swafiuwed whale by the Fatiertt fat the benefit {3f
`the medizafian cantained therem Heweva; it is not
`
`unusual practice in hasPitaJs and mended cam fa—
`cilities f0: a caregiver ta {men capaulea a: crush
`tableta t6: mix mth fwd m citink; especially far chill»
`dren DI? ather patients Whig to mafiaw 593d
`dasage firms! This shatfld be time wily with the
`comments: uf th a pharmacist aince the fimg {alga-133
`charactarisfics cf cartain dusaga faring; maid {3% 31*
`taxed and adversely affect the. patient? waifare.
`Baggage Evans that mum he: left him: ifidude: an!
`taxis: coated tabla; dasigneci ti: pass through the
`stomach f0}: drug release and ahsmptim in the inw
`tastine; manéeciqeiease dwsage Emma, designed tr.)
`prwifie pmiengaé release 0f the madicatim; ami
`subling‘ual 0r buccal whims, fammated ta dissalve
`under the {0:1ng at in the arid cam}? {13, In in»
`Stan-tea in which. a patient is mabie ta swajluw an
`intact 50km {image farm; an akamafive madman such
`as. a chewable tablet; inatant disscxlfing tame; {Bra}
`liquifl, suppasitmy €111?“ injecticm may be empmyad
`
`Hemi Galafin (Tamales
`
`Rani galaifirt capstfie shells are used 5:: mamfav
`m mast {11? the tammsmiafly avaflabk mefiicated
`capsflesfi’hey axe also cammaniy empiayed in slim
`icai
`fimg triadsg t0 campsite:
`the effects af art
`investigatinnal dmg ts: anather drug prminct my:
`placabe. Hard gelatin capsules 3.13:; as used by the
`mmmmflyphamacist in the extempuraneaus com-
`psmding cf preacriptiansffhe empty cagsuie 52113313
`are madfi fiam a mixture 0f geiatifi, sugar and water.
`as such. they are alga}; mbrless; and essentially
`tasteless. They may be calmeé with varima FD<E£C
`and [315:6 dyes ané may be made opaque by addmg
`agents such as fitarflum Liimdde. Must: commercially
`available medicated capsndefi comm mmbinatmm
`nfmlmrm and upaquantfi 13:: make them cfisfimfim
`many with caps: am? bmdies of éififerent mien.
`Gelatin i3 mbtained by the partial hydmiysig {3f
`callagen sbtained fmm the 5km, white connective
`tissue, emd hams {3f animals. In cammaxca it: is
`available in the form 0f 3 fine puwdea; a coarse
`pewciam weds, flakes, or aheeta (Fig. 3H).
`Gelatin is stahia in air when dry but is subject m
`mirmbial éecamycaifion when it hemmes maist.
`
`Astraleneca Exhibit 2095 13* 6
`
`

`

`
`
`4...‘.r
`
`in the
`Fig. 7.1 Park skin gelatin used as raw material
`manufacture of gelatin capsules. (Courtesy of Smiihkline
`Beet-limit.)
`
`Normally, hard gelatin capsules contain between
`13 and 16% of moisture (2). However, if stored in
`an environ ment 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 handledTherefore, it is desirable to maintain
`
`hard gelatin capsules in an enuronment 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
`vitro capsule dissolution. Such changes have been
`observed in capsules containing tetracycline, chlor-
`arnphetu'col, and nitrofurantoin (3]. Because such
`changes could forewam 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
`
`Capsules and Thblets
`
`181
`
`times its weight of water. Sorne patients prefer to
`swallow a capsule wetted with water or saliva be-
`cause awetted 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
`scintigraphy a noninvasive procedure which in-
`volves use of a gamma ray—emitting radiotIacer 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 die
`usual in vivo characteristics of the dosage form
`being studied. When scintigraphy is combined
`with pharmacokinetic studies, the resultant pharma-
`cuscintographic 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
`whether a correlation exists between in vitro 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) drugldosage form evaluation
`in new product deve10pment
`(4—5). A separate
`technique, using a pH-sensitive, nondigestible, ra—
`diotelemetric device termed the Heidelberg cap-
`sule, the approximate size of a No. D 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 fast-
`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 ofproduct formulation
`(i.e., immediate-release, modified-release, enteric
`coated), the gastrointestinal contents and inteISub -
`iect 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.
`
`AstraZeneoa Exhibit 2095 p. 7
`
`

`

`182
`
`Capsules end Tablete
`
`The shells are predeced industrially by the me-
`elrienicel clipping {3f pine e: pegs Elf the deeitetl
`shape arid diameter irate a temperemteweentrellecl
`reeeweir ef melted gelatin mixture (Figs. 1&2, “3.3).
`The page; made ef meeganeee breeze: ere affixed
`te tiliseteeg each capable 0f fielding up lit) abeut 50E}
`eege. Each plate is mecheeicaél}! leweteti tea the
`gelatin teeth, the pegs submetgeel ts: the desired
`depth and maintained fer the desired period to
`achieve the preper length and thieltness at" meeting.
`Then the plate anti the pegs are slewly liftecl frem
`the bath anti the gelatin clzieel by a gentle flew Elf
`temeetetete- and humidiW»eenttelled alt. When
`tirierl, each cape-tile part is trimmed meehenieelly tea
`the prayer length ren'teeecl fmm the pegs and the
`ceeeule bediee and cape are jeittecl together. It is
`impertent that the thickness at the gelatin wells be
`strictly centrelleel 50 that the capsules bed}? and
`rep fit snugly te erevent disengagement. The pegs
`en which the caps: are termed Sift? slightly larger in
`dime-tea: than the pegs cm which the bediee are
`fumed, allewing the teleeceping ef the cape over
`the beeiiee. in capsule shell preduetien, there is a
`centimteue clipping; drying, remeving and jeitting
`{if capsulee es the pegwetiteiningplatee are related
`in anti Get ef the gelatin bath, As netetl earlier, we
`eule sheila may be made ciietinetiee try adding eel—k
`rat-ante atelier epaeeeete to the gelatin beetle
`A manufacturer else may etepere distinctive»
`
`leaking capsules by altering the usual teentletl
`ehepe ei the eepeulevmaking page. ii}! teeetieg the
`end ef the bedyereducing eeg while leaving the
`ceewmalting peg mumieci, eee meeufecturer peew
`pares capsules tliffetetitietetl item these ef other
`manufacturers (FULVULES, Eli Lillyleeethet man»
`efaetuxet utilizes eepeelee with the eetle ef bath the
`beetles and eeee highly tattered {SPANSULE Cate
`eeleel Smithlfiline fieechem).‘t‘et anether innate»
`tier: it“: eagezfie shell design is the SNerFl’l} CON}
`Swell anti COM-SNAP EWRO heed gelatin
`capsules depicted in Figures 33.4 and Eilhe aegi-
`nel SNARETI‘ eeeetructien enables the twe halves
`
`ef the capsule eheile te lee eeeitively §eitied thzettgh
`leekieg gmevee in the shell wells. The We greeeee
`fit lute each ether and time ensute reliable cleeing
`ef the filled capsule; lilutiag the closing preceee, the
`capsule hotly is inserted late the cap. With the
`ltiglt»tepeei:y filling tetee {if the meciem capsule
`filling mechieee (ever ISQUQG capsules pet betel
`eepetfie egalitting {"teleeceping") anemic denting ef
`the eepeule shell meets with the slightest eenteet
`between the We capsule—part time when they are
`leinecl. This ptablem, wl’tieh exists primatily with
`etrelght~welled capeule shells, led te the eleveiee»
`meet et the SON—Elle? capsule; in which the rite
`ef the capsule heel}; is not eteaight. but tapered
`slightly (Pig. 3’53). This reduces the tielt ei the
`capsule~tim§ teecliing en jeining and essentially
`
`
`
`Eig‘ 5&2 8:11:33; ef capsules end their sees are Slim?! :25 they meet: tizrmgh esteemed eeeeeievmetmg machine, Each magmas is
`cepeéie mfpredeaieg 3mm eepsuies earliest}: It takes :1 Ala—mime: cycle it: ermine e camels. {Ceertesy emez‘tiiKline Bee—item}
`
`
`AstraZeneca Exhibit 2095 p 8
`
`

`

`
`
`Fig. 7.3 Capsules being dippedfor coloring on automated cap-
`sule-making equipment. {Courtesy of SmitliKli rte Beediam.)
`
`eliminates the problem of splitting during large—
`scale filling operations. In the COM-SNAP 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
`
`Capsules and Tablets
`
`183
`
`arnOunt or' fill material to be encapsulated'lhe den
`sity and compressibility of the fill 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—know features (Table 7.1)
`and an initial judgment made as to the approximate
`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 extemporaneous com-
`pounding, hard gelatin capsules permit a wide pres
`scribing latitude 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 small—scale preparation of
`filled hard gelatin capsules is divided into the fol-
`lowing general steps.
`
`CONLSNAPE
`
`-
`_
`
`3‘ -
`
`-?
`
`I
`
`' _
`3 _
`
`l'I’ONI‘JtJ
`
`5‘9 L'lOSEU
`
`0.09"
`
`Fig. 7.4 Lure drawings of the COM-SNAP capsule in
`open, pat-closed, and closed positions. The tapered rims I)
`avoid telescoping; the indentations 2) prevent premature open—
`ing, and the grooves 3) lack the two capsule pairs together af-
`ter the capsule has beeafilled. (Courtesy of Capsagel Division,
`Warmer-Lambert Co;l
`
`AstraZeneca Exhibit 2095 p. 9
`
`

`

`are performed to determine if all of the formulation’s
`bull: 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 preper 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 break-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-
`
` Q
`
`~ ‘
`
`4*.
`
`9’?
`
`Fig. 7.6 Examples of tablets and capsules marked with a
`letter-number code tofocililrrte identification. {Courtesy of Eli
`Lilly and Company.)
`
`184
`
`Capsules and Tablets
`
`comvsme ‘9
`
`com-snap suenofl‘
`
`|I
`
`tangled me to haul IeIescootng
`mom soap"?!
`2| Grants «ll-(II mt the In nature;
`lagging: one: the capsule has [mo
`mm [Shay-inn") uunmlu
`1| Indentation; lo mun-u premalur:
`open-n9
`
`Fig. 7.5 Line drawings of the COMSNAP and CON!—
`SNAP SLH’RO {on right) mpsules. The latter is designed to be
`smaller and to haoe the lower portion of the capsule shell con—
`cealed exoeptfir the rounded end. This makes separation oflhe
`two parts more drfi‘icult and contributes to capsule integrity.
`{Courtesy of Capsngel 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. Preformulation studies
`
`AstraZeneca Exhibit 2095 p. 10
`
`

`

`
`Table 7.1. Appmximate Capacity of Emgty Gelatin Capsules
`
`Capsules Md Tablefs
`
`135
`
`Capsm‘e Size:
`6.50 £3.13 £13? £3.30 5121
`
`ME (1951%sz {mu £3.58W
`
`
`
`
`
`
`
`
`
`
`
`
`
`3mg 3355:3336 (mg?
`55
`£537
`136]
`195
`22’?
`325
`3%
`6553
`Quinine Suifara
`130
`2550
`325
`390
`513
`3’15
`9’25
`1430
`Sodium Bicarbauare
`97
`162
`195
`260
`325
`
`maria
`1940
`6561
`520
`
`*Ammmt may vary awarding to the degree (if pressure used in {fling the? capsules;
`
`ticulariy impartant when a thug sf law ticsage is
`biendeci with Gthé‘f drugs at nandmg fill {8). WE“
`necessary; particle size may be :eéucaci by miZEERg ti;
`pruduce particles ranging 5mm abuut 53 is; 1mm
`microns‘ mfled pawdam may be bienzied BEES“
`rively far unifarm ciistxihutim thmughmfi a paw»
`:33: mix when the fimg’s dosage is ‘10 mg a: grater
`(a)? Fat drugs of lawer chase a: when smafier part?
`2135 are require& mismrzfmn’ars is empiayad. 133——
`pemfing an the materials and equipment usedik mi»
`cmnizafiim praduces particlsza ranging fmm 313mm
`1:0 538 micmns in size.
`
`In prepan‘ng capsules. an an indzzstrial Scaie usimg
`highvsipeed aummated equipmem, the pmwcier mix
`:3: granules must be fiee—Hwfing f0 ailflw steady
`gassage 0f tha capsule fill item the: kappa: thmugh
`the encapfiulating aquiyment anci mm the capsuie
`she-11$ The addifim {3:33 a quJrfcgnt 3r gés‘dgm sxmh as
`fumed silican {fiarxidag magnesium stearater calcium
`stearafre, stearic acid, 0: {aka {abwutfl.25~1%) m the
`pawder mix enhances flaw pmpemes {2}.
`Men magnagium stearate i3 uaacf as {he Iubri»
`taut;
`the waterprwfing characteristics of this
`water—insuiuble materiaI flan retmd penetraflm h}:
`the gastraint‘estinal fluids and flaky drug disgalw—
`than and absorpfimn. The aficfitiar: 13f surfam NEW:
`agents: as sodium lauryl gulfateg m capsule and
`
`iahlet fazmulatians is useé m €a€ti¥itate wetting by
`thfi gasiminzestinal fluids ti: avercwme the pmblem
`{‘3}, Even in matancea in which a watsefiinsalubie
`inbrican: is 110:: used, after the gelarén capsule Sim-":21
`disswhresg gasfi’aintestmai fluids must dispiace the
`air that sumunds the fir); pawcier ami panama
`the :1in baffle if can be dispersed and diasalvec}.
`Pawders 13f pmfiy saiuble dmgfi have a tendenqi *3}
`team gush gsenetratian‘ Bisintegrafian agents in»
`ciucied in a capsule fumulatian facilitate the break
`up and distributiafl 3f the caysule’s anthems.
`Wheihar it be the? pregame 0f 3 iubricam, surw
`fastz-mtf disintagzafing agent, Gr same ether phat»
`maceufic excipiem; famwafiun can iafiuence- thfa
`triaavaflabiliiy Of a drug; substance and can accaunt
`5C}! differmces in drug effects! which may be en»
`cwunterezfi between Mt} caysuie praciucis @f the
`same medisinal substance‘ Pharmacista must be
`
`aware czf this passibility when prsduct»interchanga
`is cansifieredf
`
`{marking habitats m amali capsulafi withia capw
`suites is samei'imes a useful technique in the cam-
`merciai pruductian a? capsuies anti in a pharma»
`{:isf‘s Exmmgcyransaua pregaratioa 0f capfiules
`{Fig ”5.8).This may be dame in separate Chewficafiy
`Encampatiblfi agents a: m add Premeasmed (as;
`iablets} ammms of patent {hug aubfirances. Rather
`
`fining! sizes ofhfird gelatin tapsufes. Pram lefl m right. sizes 890,. (‘30: CL 1, 2.» 3i 4; and 54
`
`Fig“ 7*?
`
`AstraZeneca Exhibit 2095 13* 1 l
`
`

`

`186
`
`Capsules and Tablets
`
`
`
`Fig. 7.8 Examples offill in hard gelatin capsules. 1, powder or granulate- 2. pellet mixture; 3. paste; a, capsule; and 5. tablet
`(Courtesy ofCapsugel, Division of Warmer-Lambert)
`
`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, acme 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 may be mixed with an inert 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, kaolin, or light mag-
`nesium oxide to separate the interacting agents and
`to absorb any liquefied material which 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. Insome instances, when the usual close of the
`
`drug is too large to place in a single capsule, two or
`more capsules may be required to provide 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 fill~materia1 during the preparation
`and capsule-filling process will not materially 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 small num—
`bers of capsules, the conunumty 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 determined by require-
`ments of the tonnulation. including the dose of the
`active ingredient. and the density and compaction
`characteristics of the drug and nondrug compo-
`nents. If the 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 capsule's active and inactive compo~
`name 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 mg and 1 g of powdered material.
`As shown in Table 7.1, the smallest capsule (No. 5),
`may be expected to hold 65 mg of powder or more,
`depending on the characteristics of the powdersub»
`stance. Oftentimes, in the extemporaneous com~
`pounding of prescriptions, the. best capsule size to
`use is determined by trial. Use of the smallest size
`capsule, properly filled, isprefetred.Apr0perly filled
`
`AstraZencca Exhibit 2095 p. 12
`
`

`

`caps-Mina ghauhi have its had}; filled with the drug
`mixmm not
`the cap. The cap is: mtendeé to zit
`snugly we: the bad}? to retain the cmntenm.
`The 3:111:2an exampiea demmstrate the zimg
`and nundmg cements GE a few cummiérciafly avai1~
`able capsules.
`
`“fermayclifla Capsuies
`Active ingredient:
`
`Fifier:
`
`Tetracyciina
`230 mg
`Lactase
`
`hydrocthridQ
`
`Lubflcantigiidam: Magneaium stsaaram
`[Mac
`Capsula wimams:
`FDcixC Yellflw Na 6,
`Yeliaw N43.
`IQ, Raid? Rear}
`NC}, 25,, FEE: Blues: N0. 1
`
`Capsule Qpaquant: Titanium diuflde
`
`Acgtaminapkefi with (fascism: Capsuées
`Aztiw ingredients:
`fiaemnfinupfiem 325 mg
`Cmdeifie phfisphahz; 3E} mg
`Sadium starch giymlam
`Diaintegrant:
`Lubricanh’giiciams: Magnesium 5161331“an staafic
`acid
`
`Capsule coiorants:
`
`{Raff “@1le N0» 10, Edible
`Ink; FD£2C Blue NQ 1
`{FDSzC {Green ND. 3 and
`13'8ng Red Na. 1&0}
`
`{Diphefihydmmme Hydracizfamie CQQSQIQS
`Active ingmdient:
`Uiphenhydramine HQ,
`50 mg
`Canfectimer’s 53?.ngst
`Fiiler:
`Lubficantsfgfidams: Tait. callaida} siiimn dioxide
`Wetfiflg agent:
`Stadium laurgl sulfata
`Capauie calarants:
`FDéaC‘ 8qu N0, 1,: FDSQC Rafi
`N91 3
`
`Capsule opaquant; Zitanjum dimidre
`
`Filling Hard Capsule Shells
`
`When filling a smafl number Qf mpmlas in the
`pharmacy the pharmacisf: uses thefipumch”meth0d‘
`In this method, the pharmacist {aims the precise
`number sf empty capauleg m be filled {mm his
`stock camainer, E31 counting the capsules as the 1m}
`tial ates; rather than taking a capsuie {mm fitmk a3
`each me is filial: the pharmacisf guards; against
`filling an extensions number 0f capguieg and amicis
`cantaminaring the stack cantmner with drug pow—
`dmx The pdeer #33 he encapwlated is placed an a
`sheet GE clean paper at an a giass oz parcel-air: piata
`Using the spatula; the pawder mi}: is farmed mm a
`cake having a depth cf agapmnmateiy mewfcurth
`tQ onewthir