SEVENTH EDETION
`
`AND DRUG
`
`DELIVERY SYSTEMS
`
`PHARMACEUTICAL
`DOSAGE FORMS
`
`
`
`Howard C. Ansel
`
`Loyd V. Allen, Jr.
`
`Nicholas G. Popovich
`
`AstraZeneca Exhibit 2097 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00900
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01913
`
`

`

`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 2097 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 Exhibit 2097 p. 3
`
`

`

`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
`
`AstraZeneca Exhibit 2097 p. 4
`
`

`

`
`
`
`
`
`
` DISPERSE SYSTEMS
`
`Chapter at a Glance
`
`Susgaensims
`1232;130:715 far Suspenaians
`Fea mras Desired. in a Pharmaceutical
`
`Sustsim
`thaical Features @f the Disparsed Phase 0?
`a Suspensian Disparsian Medium
`Pragmatism GE Suspensigns
`Sustained—Releasa Suspensims
`Extempwaneaus Cumgxaundmg cfi
`Suspemians
`Fackaging and Starage mf Snspensmns
`Examples 0f Oral Suspensiang
`Arimca‘d Om»? Susyensians
`Amibfici‘afial Oral stpenséms
`Examples of {Ether Suspmmm
`any: Suwmsiws
`Racéaf Suspenfiififls
`[1132* Pawdars far Oral Suspensivn
`Emulsians
`
`Pumuse 53f Emulsians and of
`Emulsificatian
`Thearies 0f Emulsificatiun
`
`Preparation 2:3? Emulsians
`Emaalsifying Aggrxta
`The HLB S; stem"
`
`Mefhatis a 5:121:25 far: Przzpamtmn
`Caminmmi :3? Dr}; (Sam 3&3?th
`Eng-fish m Wat Gum Methmi
`Bsféfa (:1? Farms Battia £419:de
`
`Auxiliary Msihedg
`3?: Sim Snap mam
`Mimoemufiaiams
`
`Stabihty 0f Emulsions
`Aggregafian mini Caalasaeme
`Examples elf {3:211 Emulfiiom
`Ma‘ngmfi C33“! Emulsian
`(Samar Gaff Ermfigfian
`Simefhémne Ennis-3m
`
`346
`
`{3315 am? Magmas
`Cflfloifia} Dispfirfiiflns
`Termwlagy Reiateci tn Geis
`Cfasséfimtz‘m and Types {$13525
`Preparatim 6f Magmas awi Gels-
`Exampies of {Selling Agents
`Gel Farmulatiw Cmsidei‘atians
`
`Exampies 9f Magmas and Gels
`Esrgfmzém Magma; N2":
`fifumimém Hydraxide GEL LISP
`M53}: {Effie’lagrtgaiag LISP
`Srm'cfz Giggsefifa
`Lufze’fmiirzg $5133; Farmzda
`C2353? Lawsuit (3:23 with Bimgfhimfla
`staxame? G63 Base‘
`
`pl‘flpfill‘ Admflnisimtiun anti Use {:af
`Disparse Systems
`Aemmls
`
`Adm“ fages a? the Awasal Eaaage
`Farm
`
`The: Aerese§ Frincigle
`Agassi Systéms
`Timmpfmse Sgsfsms
`T}: reewpimsg 5335:2335
`Camwessed Gas Systems
`Ammo: Cantainezr and Valw Asgembly
`Cmmfrmrs
`
`Vilma Agfieméfgj
`Metered Base Mmlers (MUE‘s)
`Fifling Operatiims
`Cfifzi Fifiing
`233mm}? Ffliing
`“E‘s-sting fire §'£££Ez:£ Emma-sew
`Packagmg, Labeling! ami Sterage
`Prepay Acimmigfration am} Use 0%
`@harmacemical Aarosmls
`
`Tapicai Aerosnls
`Vaginal and Rectal Aeromla
`
`Astraleneca Exhibit 2097 13* 5
`
`

`

`Disperse Sysiwas
`
`347
`
`as this smisrmésfi (iigifibuted samewhat unifmrmky
`thmugmut a "made m which the dmg embits a
`minimum degree cf mmbfléty. Same suspensiana
`an? amilabig in read‘iywtuvuse Enrmmthat is: alreaciy
`fiisfibuw‘i {Waugh a liquid vehicle with a: wi‘fhaut
`stabifizers and other phamaceufical additives (Fig.
`“131}. {Ether megawatts axe avaiiabie &5 dry paw—
`derg Mariam fur auspenaisna in liquid whieiesflais
`1:335 :31? graham: generauy ia a pawder Mime Chitin-
`taining the drug am suitabfie suapertztfing am digs»
`parsing 33mm which {spam dilufiwr: am agitafim
`with a apecifiad gummy a? vehicle {generafiy puri»
`flew} water} reswta in rim fwmatim at” a sugpenaim
`mitabiié far adminjsmitiam Figure “13.2 denies"
`mama the gmpwfim czf fl'fis {we eaf pmefiutt. Drugs
`that émi‘ unstabie if maintained 5:}: texts-mixed yefiacis
`{11ftime in me presemte cf an aquews vehicle {far 2&—
`ampiep mas}? azmbimic cimgfi} are “mat frequenfl}!
`mypiied as (Ry gawcier mixmres far xeczanstimtim
`a: aims: rim»: 9f disgensing. W135 type ca? prepamtian is
`fiagiguatad in this US? by a titia :3?” the farm“. .
`. fa:
`Gm} Suspemianf‘fiepamé suspensians mat requirv
`ing recanzxtimtéar at the time {bf dispeming are aim“
`piy designatad as". .
`. Oral Suspenaiflnf’
`
`Reasans far Suspensions
`
`Wham are Ewaai magma far preparing fitlfipfii’t-
`5mm. 3:}: {me {hing {:Efiaifi't dwgg axe chemiflafiy am"
`siabia when m Salaam hut stable? whert susgendeaei.
`k: insrames such as this! the auspensian insuma
`chemicai stability while: pen‘m‘t’tiag [ézguirj t§1arapy.f-‘m
`man}; pafiema, {1'18 Equid farm is: pmfvetrfid (we: the
`Mid {mm sf rim: Same. drug bacause vi {he ease mi
`swaflawing fiqtfiéfi ami {11E fleadbifi’ty in the admizfis«
`Imam {if a rmge {Elf dam. This is; yarficulaxly advanv
`tagems fur Mama chfidmn afici the: afidariyfiha dis—
`advantaage 3E 22 {fisagraeabia taste flf cextajn dfilgfi
`
`THIS WEE inducjes the: main @1395; 3f liquid
`preparafians containing uraciiswlvm Gr immiscibia
`drug distributed thmughaut a which. In these
`preparatianfi, the: gubatame {lifitfiblimti i5 referred
`ta as the dispsysaxf phase and the: vehizflra is termeti
`the: dzwersfng phasm m :fispersim: mflfium. Tcgfithen
`they graduate :51 éispersed system.
`The particles if the dispetfied phasa are usually
`595:1 mateflals that are 111501211313 in the dispersim
`metiium. In the cage {31: emxflsiflzm the dispersed
`phage is a Equid fiubsmnce wifith is neithat solubie
`m:- miacible with {he liquid :3? the fijspewing phase.
`The enufisifimtian precess. resuits in the disparsion emf
`fiqmd drug as fine drapiats thmughcmt Has: disparaing
`Fhafié, in the case a£ an aeragai, ma dispersed: phase
`may he air that is pres-am as; smail bubbles. {magma
`a sulutim :31“ an emfisimm Dispmiam alga mmisi’ 23f
`drag-glam (:f a liqxdd (3:311:53?! a? Suggerasiw} in air.
`The. yarficles of the dispersed phase vary widei‘y‘
`in aim frirum huge particiea visible: m the: naked eye
`dam m particies 05 mimid a} dimensicsm failing bev
`tween 1.41} rem and 121.5 gun in size. Disparsims mm
`mining 2:031:32 particles, uauafly iflmfii} pm in 531%,
`are referred ta as £36235 diggersiflns and inciude the
`gaspemz‘mza ami amalgam. Dispataiam mntaining
`particles af smaller size: are termazi fizze dispersicms
`{€3.5«10 114m); and, if the particfes aye in ma calleiciai
`range, sailfish! diapersimzs. Magnum and 3913 magma
`sent Such fine éiaperaians.
`Largely besause Sf the}: greater size, Ciisparsad
`particlea in a same «fiispergiw have a greatar {em
`£19m}: w separate mm the cilspe‘fwitm médium fixan
`dc: the Fm‘tie‘ées a? a fine. {£559ersizmw Most solids in
`disperaiun and In aettla ta the batmm (if the can»
`tame: because af their gI‘E‘atEf trierrssity than the 633*
`persicm medium, whfirzaas mast edesifiezi liquitis
`fem“ mai uae are ails and generally haw: a $223533? dew
`salty than the aqueous medium in which they am dism
`perseci and temi to ma mumd m in}: 0f the prepa-
`ratim. Cflmpkte and unifarm reéiambufim 3E the
`dispersad phase i5 essential m the germinate adminig-
`imam a? uniform 216535. R}: a pmperl}; prepared
`disperaion,
`this maxim be acmmpfifihed by the
`mafiarate agitation (If the camaimr.
`The farms emf this chapter i5 {3:1 dispersimm of
`dmgs administered orally at topicafiyfihe same ba—
`sic pharmaceutital charactemtics appky m 6:133:33 (ii?
`persim‘: systems admismmd by $581“ mates 3E afin
`mixfistratim. Included amang these are mphthalmir:
`suspensians, and gratile suspensima fer injection.
`
`Fig 131 Exampfg aafsome cmmmmfm‘ em! suspensimss.
`
`SuSpensions
`
`Suspénsicms may be (flame-d. as preparaticans cum
`raining firmly divided drug panties [referred t0
`
`Astraleneca Exhibit 2097 11 6
`
`

`

`3518
`
`flismzse Syargms
`
`
`
`
`
`
`
`
`
`gartt suspensian. 15.1 aciditiém ta thatapautic efficacy;
`ahemicai stahifity {Jaf the. campsnnenta fixf the farmu a
`Emma, pennanency sf the Freparatiam and eatheric‘:
`appea} co? the prepaxatianmdefiirabifi qualities; in
`a1} pharmaceutical preparafiamwa few {Rhett fear
`tunes 3133313; mute spewificafly‘ m thsa pharm aceu flea}
`mspensim:
`
`
`
`1. A prwpwy prispariad phamamuficai suapension
`31mm same shawl}? 311d ghauiii be: readiiy redis-
`parsed 11pm the gentle shaking a? the cantanarfl
`
`2. The characteristics af the sufigganaiw 511mm be:
`
`such that file: particle size «:3? 3h? fiusgensaid m-
`
`mams fem}; canstant thrwghflut Lang periads
`
`:fi undisturbed standiag.
`
`3* The suspensim simuld palm reaciily and evamy
`
`from 115 container.
`
`
`
`
`Fig 13.2 Carrxmextifii emsfiaéstic lvawtém fizmmi assfipm»
`m3“: fiflmifig mmnfiimtfm with yargfigd 2mm: (3:: £233 {a}? is
`the dry wwdw mixture; and an the rigid the geesprzzwém: affair
`rwnstfwtim: wifi’: fizs spgi‘fiad arr-mun: afpmfiesf 2mm:
`
`when given in salutiw farm is avememe when the
`drug is agimimstezred as; undisaaiwd particles M an
`Cami atxgpemim. In fact, chemiaal forms of (remix:
`pmwtasting drugs have hem specificafl? éeveispad
`{01' their insaluhifity in a desireé vehicle far the $9116
`gamma :3? prepazing a palatabié liquid zinc-sags: farm.
`Fm example? {ha wataz‘eiusmluble 85m: farm Elf chit?»
`rampheraiml ci'ilmamphemwi galmiiata, was. deval»
`raped m prepare a pamtabie liquid {image farm {3f the
`shinrampheniwig fixes result being thé dweiagmam
`a? Chlmamphamml Paimitate {Sinai Suspénaim; US?
`By the creafian {If insoiub‘te farms 0:” drugs far 13513 in
`atmpensims, the ciifficujt taatemasking pmblems: flf
`devampmenmi phamacists are greatly minced, am
`the geiertian «13%? the fiawramg to be used in a given
`susptmfiicm may be baaed an tagta greference rather
`than cm a partimia; fiawmnfis ahfliry m arc: as a
`masking agent for an unplessmt taxing drug. PM the
`mus? gm: ma} maspemimxs am asgumua preparaiima
`with the vehicle {lama-ad and aweeirzmrd fm suit the
`
`anticipated mate preferences; af the intended patina-2m.
`
`Features fleshed in a
`
`i’hannaceutical Suspension
`
`There me many :ronsfideraiigns ifi the dgvemp-
`men: and preparation of a pharmaceutically ela-
`
`”Thaw main Eeaturas and? a susgenaicm which daa
`pend 0:: 12h? nature GE the dispersed phase! the dis—
`pexfiim wwaiiums anti pharmaceutita? adjuncra wiii
`be dismasad briefly.
`
`Sadimentatian Rate of the
`
`Farticles 0f 3 Suspension
`
`Wig “sariéxs fiwfars izwcflmd in the: was" Gffiflflflft}; 5f
`gstéliszg 3f {he pariigfas aft? suspwsiars are En-zbadfezi in
`532;: lawman nfStfikas‘Iawe zarhisk 2‘3 prfisenfw fr: IP35: m
`aarrzpmying szggssimf Pharmacy Cfipfiufe.
`Stokes‘ equatian was dwived far at: ideai situaw
`my; in which :mifonm ges'ifectiy Spherical partiflfefi
`in a very dihns maspemim’: settle.- withmt effecting
`mrbuiamze in their dwwzward course, witimut wk
`$151103 flf the: partides af the susgansmdhand with
`mt chemista} a}: phyaizzai attractimi ear affinity far the:
`dispersim’: mfiiium. {Evin-gush; Stakes’ equanon
`does {not appiy precisely til the usual ghat'maaeurk
`cal suspensim in which the guspmsaid is irregw
`iariy shaped; 3f uarimxs partide diametem and mm
`gpheristai, in mich the fall at" the particles {$313.5 re»
`an]: in bath fizrbtxlente and caiflsmm and aim in
`which mere may be a rmsenable ammunt of affin-
`ity of the parficieg; far the stxfipengmn iflfidimn. Haw—
`ever, the 133311: concepts mf the equation do give a
`valid inditatitm 3f the famterg that“ am imgmrtam t0
`the mgpensim {:af the particlea and a cine {a the gnaw
`sible adjusimmts tint can be made ta 3 farmulafim‘s
`m fiecreaae the rate a? particie éedimemastion.
`Pram the lemmings”: it i5 apparent that the veiatw
`ii}: of {a1} :st a Euspwded particie is greater far large:
`pariicles them i: is for Smaller pafliclég, 311 ether few
`furs remaining mnstant. By yachting the particle":
`size mf 1:113 dispgrsed phase; we can maem a simwer
`miss 3? fiescenmf aw: part-ides. A150; the greater the
`
`AstraZeneca Exhibit 2097 13* 7
`
`

`

`
`
`Sedimentation Rate 3; Stakas’ Equation
`
`Physical Pharmacy Camille 13.1
`
`Bispme System:
`
`349
`
`Stakas‘ Equafiéfln;
`
`whafié
`
`£25, x dz
`Cit
`
`~ w as:
`15311
`
`..
`
`dxg‘df is tha rate af aartiéng,
`ti is ma cfiamafer a? flag parrisla-s,
`p; is the: demify a? the partida
`pa 3:; the density a? the madman,
`g is the gruvimtiaan canshnt, and
`1”; is {he visccssigy a? ma maéium,
`
`A numher cf {news-s can he udiusa‘ad m ambiance the physimi stabiiiy a? c: suspensimn, including #119 di«
`amater a? ihe {gametes and fhe dansiky and viscasit}; :3? {ha madiumr [ha affect @f changing “1959 is iiiusv
`:mfed in the: Faiicwing Exampie‘
`mpg i
`
`A puwdar has a density a? 1.3 gg’cz‘: and is avuifahfe as a pawdgr with an average pufiicée diameter of
`2§ micmns {assuming five: particies m be spheraih Accmrdmg k3 Smke’s Equmiwn, this powder wilt sat-
`fie in watar {Viacmiiy 3F 1 cps. assumgd) :31 :1 mm 6?:
`
`32.5 3% 10432513 .., LGH‘?B€}§
`18 x Chm
`
`z;
`
`«4;
`1.02 x K)
`
`cm/sec
`
`If the yarficie siza a? fhe pawder is reduced fa $125 1.1. and wmtéar is sfifl used as thé dispersian medium;
`the pawdar wiii new same of a rare 0!:
`
`gas x 1043233 —- mime} m
`18 X 3.02
`
`w
`L02 x 1C)
`
`cm/sec
`
`As is evident. a decrease in particiaa size by a Fade-3r {if 10 (@514ng in £3 reduction in the rota a? settling by
`a Emcmr an? 1011 This enhancaé affect is a resuh an? Ihaa “d“ Factor in Smite-«:5 Equafian being squared.
`
`Now: if a different disperséan meciium, such as géychrin, is issued in glaze of Water, c: furiher decrease in
`583$!ng wit! :asult. Glycerin 11:13 :3 density a? 125 3ft}: and a whammy {if 403 cps.
`
`The iarger parfide size pawder {2.5 9.4.} win saflfe at c: rate 0?:
`“am
`3
`l
`2‘5 “k: 10
`118::
`3'25 Q83 x $25 x1043 era/sac
`
`m
`
`E
`
`The smufier particie Sim (C125 {4.} pmwder WEN “0W same at a rate of:
`“52
`..
`3 {1.3
`18x4
`
`{2‘5 x 30
`
`1.239%} m 4.25 x IQ-Wcm/sec
`
`A summcnry @f these results is Shawn in tha Ballwwing fabia:
`
`familiar?
`
`Rate of Sefifirig {cmfsec}
`
`215 3; powder in water
`825 LL pmwder in water
`2,5 9;, infier in giycerin
`£3.25 “powder in glynerin
`
`1.32 :2: 10‘“!
`1.62 24:: mfli‘
`4.23 K ”14:3“3
`«1.25 x 10””
`
`As is evitianf from this habits; a change in dispersion medium resvifs En tha greatest chaage in 513 we of
`sefiiing emf pmticies. Fmticfe size reducfim also can cmnrrimge significanfly m suspensim smhiiity. These
`facfars are imporfam in the karmalmimn a? physimfiy sfobte suspemians.
`
`Astraleneca Exhibit 2097 11 8
`
`

`

`350
`
`Disperse Swtmm
`
`denaity cf 31% particles, the greatar the ram GE 36*
`seem, pmfiéed the density af thE‘ which is am a1»
`wreak Became aqueaus vehirles am used in £31m:-
`macwticai aral ausgensimm the dansity 3f the
`partickea is generafiy greater than that Bf the whim
`618‘ a desirable: faamreg far if the particles were 3883
`dense: than {ha vamde, they would {anti 1:: flaat,
`and flaatingparfides waukd be quite difficult: to siis»
`m‘hute unfinnniy in the? vehiclex The raw mi seed}?
`mentafism may be appreciab 11,: reduceti by mamas»
`mg the wiacaaity GE the diaparsian maciium, and
`within limits :31” pracfizaiiry this may be dune. Haw
`ever; a yroduct having tam high a. vismsiiy i3 mm
`generafly desirable, becausg it paws mm diffifluity
`and it is squall}; difficult to tedisparse thfif guspam
`mi dfhcamfma if the Vimugity {3f 21 suspwsian is: in w
`greased, it is time :30 {31113: ta 5; mafiwt extent m
`maid them difficuzties.
`
`The: figcasity characteristici; (xi 3 3133;359:1316“ may
`be altered mi ml}; by the whim used; buff 313:3 by
`the swag cement. 2315 the prupmtim Bf mh‘d partiw
`ales is increased in a auspensim, 5:3 is thé viswsim
`Tm: fiscaaity GE 31 phamaceuticai preparatim may
`
`Synchramus {“9er “a
`
`Speed sefiectcnf mu m“X
`
`anuffmafiaswitch“a \\r
`
`Clutch Ewe:
`
`,
`
`V
`
`be detanniaed ti‘mugh the use uf a Ewekfiehfifig—
`swimmer, which measures viscosity by the farce re-
`quizeci m mats-1&2 a spiraifie in the MM bang tested
`{Fig "33.3;
`Fm Lhe magi parts the phyaical ambiiity at" a may
`mammal Suspensiua appears ta he must appa~
`pflateéy aéjuszad b} at: alteratian in the {iispemeé
`12321352? rather than Waugh great chafigas in aha diam
`gamma medium In {£16591 imtames‘ the dispersim
`medium is suppartiw m the adgusred éisyergeé
`phasza. Thaw: acijustmanzs mam}; are macemesi
`with yarticfg size! unifwrmfify‘ 0f particle met arid
`sagax‘atian :10: the patticiea 5:: that they are net filial}:
`n: became graatl; marge? :3? t2: farm a saw cake on
`standing
`
`Physical Features (if the Dispersed
`i’hasa (if a Suspensifln
`
`Pmbahfi the must impartant simgle aansidemtian
`in a ciimssion {bf ampeasiws is the aige 0f the: drug
`partidag. in [mm gem? pharmaceutical} auspemtiws.
`the particle ciiamatm i5 bemgefl 1 and 58 gm.
`
`saw-- Gear {rain
`
`gm Sim-war
`‘
`mama lavai
`
`gm ma:
`
`W»- flamed fiut
`
`
`Haws
`
`FuinfarW/
`
`Jewe¥ bearing suppém MM“
`Spinaje mingling nu:W]
` “n.
`imméraiun mark
`
`Spindia bady ~—-—«~m.>
`
`E:
`u
`
`“N ”m Gafihratad
`m
`spirai naming
`“a“ Umar shaét
`
`Pivm pm:
`
`WM flammable
`spindle guam
`
`
`contafiner
`
`Fig. 13.3 Schemazic drawing 9f :Eze Emakfieid Vismme:e:z rCmmcsy erwkfiafld Enginemng whammy-I‘m.)
`
`AstraZeneca Exhibit 2097 13* 9
`
`

`

`Particle size reduetmn is; generally ecmmpllshecl
`by dxyvamillingwier h: the incexperatien {3f the (lie
`parsed phase ime the dispeteien medium Cine cf
`the meet raged, eefiveniene emé inexpensiee methv
`eds ef preducjmg fine drug pewéeze DE elem}: 18 [Cl
`59 gm size is: mimpzdeerizeflera. Mifleyulverieere
`are highs-peed; attriliee or Emmet: mills which are
`efficient in reducing eewders if: the size amegtebie
`fer mast ezel and tepicei susgensz‘ens. For still fine:
`gertieles, wider 1% pm, the preeeee effieézf merge
`grinding eemetimes referred m as jelemz‘lfmg :3: mi~
`creaking is quite effective. Eff {hie precess,
`the
`eheering EtCliiGfl ef high velecjty mmpressetl air
`streams are the gel-tides in a eenfined space per
`(laces; the desired ultrafine es: micwnieed particles.
`The particles ti} be micreeieed are sweep: mm vie~
`lem twhulenee by the semi: we eupemmic valet-
`ity elf the air streeme The particles are aceelereted
`mm high eeleeifiee em miller: with we enmher.
`resulting in fragmentefien em a decrease in the
`size ef the pertmlesffl'lie methed may be emgaleyed
`in inefenees in which the parades are intended fee
`parenteeel er ephtheimie suepeneiensl Parfielee 3f
`exfi‘emely smell dimensiens may else be predeceéi
`by spew-drying techniques. A spray fiiyer £3 a cane”
`shame! piece ef aepezatus irate whieh a seletien ef
`a drug is epxeyed and rapidly dried by e curren‘: ef
`warned. dry air eirculating ie the coneThe reeuih
`ing dry pewder is than celieeteci. It is net gussible
`fer a eemmunity pharmacist fie achieve {he same
`degree at" partieleesiee :‘eduetiefi with 23ml“: simple
`eemmfmitmg equipment as the marker anti pesiley
`Hawevee maxi}! miemnieed druge are mamma-
`eiellg; available eed when needezi may he imp--
`chewed by the phermaciet in hull: quantities”
`es. Slime: by Stokes“ eqeafien, {he reductien in
`the peeticle size ef e suapeneeid is beneficial m the
`stability ef the aeepensien in that the rate {31:33:33-
`mentatien e? the mild particles is reduced as; the
`partieles are decreased in size, The :‘edumen in
`eertiele size presences stew, mere uniferm rates {pf
`settling, Hewevee me mum amid reducing the
`garfide size m tee gem a degree :3? fimnese; aims:
`fine parmclee haw e tendency in farm a mammal
`mice :4er settling to the hettom m“ the mmamer‘
`The resell may be that the cake resists breakup
`upem making; and Emmi; rigid aggregalee 35‘ party
`files which are ef larger: fiimemim and less sass?
`pendeble than the miginel euemnseidffhe particle
`ehepe 0f the suspensoid can elm affeet raking and
`preduet stability, It has. been Shawn that symmetrim
`cal barrel-shaped particles of calcium carbmete
`pmdueed mere stable mega-mime them did 333x213»
`menieel meedlewshapee particles 0f the same agent.
`
`Dispme Systems
`
`351
`
`The needlewshaped partielee farmed e tenacieus
`seclimenbeake en standing which meld net be new
`distributed whereas the barrel eheped partielee did
`not cake en standing {1}»
`Te 5mm the fennatien {if a take, measures ewe:
`
`be taken is gratin: the ag lemeratien ef the part5 ~
`ales lute lexger crystals a: slate masses One eema
`mm metiwcl 43f yrevemtieg the rigid eehesier; {if
`small particles of a suspensien ‘15 Waugh the in-
`Eentienai femalien ei“ a less rigid er lease aggrege v
`rim 3f the particles nee tegether by eemperetieeiy
`weal: perfielevzewpartide benefiting Emcee, finch an
`aggregatim 13f particles is temreei afiec er a fieeeacle
`were fleeeuiateel partieles forming a type 0f lattice
`structure that eeeiste templete settling {altheugh
`Ewe se {tie mere rapidly then fine: imlz'vi clue? parli-
`clee} anal thus are less prene {e eempactien than
`unlimeulatezi gerfieleel The fiance settle le farm a
`higher sediment eelume than unfleccuiated {early
`sleet the lease stmefure e-f whieh permits the ag~
`gregatee m break: up eaeily and distribute reetiiiy
`with a small ameunt (3f agitatien.
`There are several methecie ell prepafieg flee—
`mleteei
`suspeneiensa
`the melee
`depemiing
`an the We {3? émg imaived and the type 9f pmduet
`desisedl Fer instance:
`in the prepareiicm ef an
`oral suspensim ef a. drug: clays such as :iiluted knew
`tonne magma are eemmenly empleyed as the.
`flacwlatlng agent, The struttme (If the bentenite
`magma and Hf talker clays used far We puweee else
`essays the suspemsien by “Helping tr} eeppcm‘ fhe flee
`enee farmed. When eieye are unsuitable as: agents; as
`in a parenteral suspenséem Ez'equently 3 flex: ef the
`diseased phase fen be greeuced By an elterefiee in
`the g8 (:35 the emperetien {generally til the regime ef
`minimum drug seluhility}. Eleetreiytsee em else act
`as fifictuialing agents, apparently by reducing the
`eleeificel barrier behveen flue pertieiee at” the see
`peneuid and farming a bridge as as m link them m.
`gether.’1“he eazeielly fietemed emeentmtien 0f
`melanin end innit: ewfeeeeactiw agente (surfer-
`tamte} tan elm induce the fieeafiefien ef particles in
`extspemiun am; increase the gedimematjm velmne
`
`.Dispersim: Medium
`
`Qfienfimes, a5 with highi}; Eleccuiated suepenw
`Sims, the particles sf 3 suspensien settle tee rapidly
`in be eemiaian’c with what might be flamed e fill-{51“
`maceufimlly elegant prepafa lien» The rapid eettling
`hindere the accurate meaeurement ef damage and
`fmm an aesthetic paint at“ mew premiums tee 1.1m
`313ml}? 3; mpemetant layer. In many of the can-{men
`rial suspensims, eugeending agents are allied
`
`AstraZeneca Exhibit 2097 pl 10
`
`

`

`352
`
`Disperse Systems
`
`pee. whereas ether packages have the deep eapahfl»
`it}; built mm the centemer. C313”: adefinieeetien the
`drape may he pIeeed direcfiy inte the infant’s meuth
`e: mixeci with a areal} pee-tier: ef feed. Beeeuee many
`ef the Suspeneiens ef amibietie drugs Needed fer
`peejetzic use are prepared in a highiy fiaeeree,
`sweetened, eeiefed base, were are frequentiyrefeneei
`he by their manufaeturere and else pepxflexly ee
`"syrups,"even theugh in fact they are seepeneiem.
`
`Preparation 0f Suspensiens
`
`to the eiepereien medium te Lend it a smcture ta
`aegis;
`in the eeepensien ef the zi‘iepereed geese.
`Cerbmmethyleeihflese‘ methyleefiuleseg Mumme—
`tefline eelluieee, peiyvinyl pjmmiitiene eeefhan
`gum anti heme-mite are a few ef the agents en»
`eieyed te thicker: the dispersien medium wet beige
`euepend the eusgeneeid. When pelymeeie seem
`steneee anti hydrephilic cefleéds are need as sus»
`pending agents: appreptiete tests meet be per
`farmed m shew that the agent flees mt interfere
`with the evaiiebiiity Ear
`therapeutic reflects a?
`the eueeensien‘s medicinal subetenee.Theee mate
`rials can bind certain medicinal agents, ramming
`them unavailable er mere elem}: availabie fer ”their
`theeepeutic funetien. else, the emeum ef the 31mm
`eending agent must net be such it: render the sets»
`Fen-Leisure tea Vietnam ta agitate {to dietflbute the
`eeeeee‘zeez‘zé} er t0 pen: The study {35 the flue: «theirw
`acteristiee is termed :heelegy‘ A gammery ef the
`caneeets ef rheeiegy is feunai in she aeeempenying
`Physica’i Pharmacy Capsule 13.2
`Suppert 0f ti’xe euepeeecrid by the ciispereien
`medium may depend {m several feetere: the density
`ef the euspeeeeici; whether it its fleeeuéeted‘. and the
`amount (:1? materiei requieing suppmrt.
`The eelici cement ef e euweeeien interlaced fer
`erel edmeetretien may waxy eeneidereeiyg eiepemiw
`ieg en the deee at" the drug re be edminieeered, the
`meme ef peeduct deeireci re be aziminietered, we
`ekse en the ability ef the dispeieien medium ‘ce eupv
`putt the eeneentretiee ef dang while meimainmg
`deeirebie features ef \rieeeeiiy and flew. The usage}
`admit are} euseeeeien {e feequeetiy designed he 3qu
`3:31}? the ease. ef the perfieuiax time in a eezwenient
`meeeefe ef 3 mL er ens-1e teeepeeafiiifi Fedietrie £1.13“
`peneiene are {emulated te deliver the eppmpr‘iate
`time u? drug by ecimieietering a eeeeeeefibgated
`number 01‘ drape. Figure 13.4 ShCBWS eemmenly
`packaged are} sespeneicns edmirfietemd 23$ pediatric
`drape. Semi-2 are aeeempenied by a ealibrated {impm
`
`
`
`In the peepaxetien GE 51 suepeneien‘. the 3921me
`we: must be aeqeeinted with the eheraeterietiee ef
`bath the interadeei dieperseci @heee anci the cfiepev
`sion medium.
`in same ineteflees the eiepeesed
`phase has an affimlty far the vehicle ta be emyleyed
`and is reexfiilfiwetted”byit ape“ ite edeitien. (Ether
`mugs are net penetraeeti eeefly by the eel‘nieie and
`have a residency re clump tegether at ten fleet gm tap
`of the eehieie. In the iatier case, the pewder must
`first be wetted by a seweeiiee "waiting agent“ re
`make the eeweer mere penetreble by the tiifipflfe
`siim meziiumm gimme gigs-tin: and ether hygre-
`seem»: lieuifis axe empleyezi as wetting agents when
`an equeeue vebieie ie m be used ee the diepereien
`phase. They feetfien by displacing the air in flee
`crevices 0f the parades, diepetsieg the particles,
`anti subsequentiy aflewing the eenetxefieu ef ciise
`premier: medium mm the eewd ea: In the iarge-seaie
`preparetien ef suepensiens the wetting agents. are
`mixed with the particles by an apparatus such as a
`ceileid mill; en a email scale in the eharmeey; fixey
`ere flexed with a mafia! and peetie. Geese the pew!
`deg ie weirtexcie the diepez‘eien medium {tee which have
`been ecicied a2! 0f the femwei‘iun’e eaiubie campe-
`nente mach as migrants: fleeerants: and preserve»
`twee} is added 31 eertieee fire the peweer, and the
`mixture is thereuglfly blended befere subsequent
`adfiifiens ef Whittle. A partiee 0f the vehicie ie need
`to wash the mixing equipment free ef eeepeneeidl
`and this parting is used tea bring the euepension be
`fine} volume arid meme that the euepefleien may
`tains the desired enncentmfien GE seiid matter.The
`
`fine} product is finer: passed thmugh e eefleid mm er
`ether bienfier er mixing device he insure unifermityr
`Whenever eppmprieta seitahie preeemefivee
`Should be inflmied in the {emmatien 1:35 Suspeneiens
`m preserve agea‘rst bacterial and meld cemteminefim.
`An example fermuia fer an erai maepeneien fob
`laws (2). In the exempief the suspenseizi is the
`entaeici aluminum hydrexide, the preservetivee are
`methyipaxaben and prepylpaxaben,‘ with amp and
`serbimi selufim prefiding the \riseczaeity as we}: as
`the sweetness.
`
`AstraZeneca Exhibit 2097 33* l l
`
`Fig. 13.4 Exammes ef met meme sespensims sizmieg
`geekege designs efe haiétde keeper smite and a miier’eteti
`{mapper emmzpmxyéng the mefiimfim cmueiner:
`
`

`

`
`
`
`
`Bispgrse 55391125
`
`353
`
`
`
`Physicai Pharmacy Capsule Ii? Rheolagy
`
`Ehaaiagy is the mud}; a? flaw and invaives file viamsity characterisfics af ;:.av::m'datrst fluids; and semiwfids.
`Mafezflaia are ziivided ink: MC: gamma? ccmgqrias ciapanciing 2529:: their Haw charccmrisfics: Nawmnicn
`anci nafi‘NawmnEm. Nawfanim flaw is chamelarizad by a ccnfitms- viamsim ragurdiess a? the aha-or
`rare: appiied. Nan-Newmnian flaw is characterize—3d by a chunga if! viacasity characfarisiics with in«
`flaming shear rates. NonNewfcmiun flow inciwiaas pigskin psaudapfiaatic and difmunf flow.
`
`Newfan‘s Law 05 Flaw reiotes pamfief bay/era {35: iiquixzii with tha bmmm byer fixed, when at: game 35 phased
`an 3th {up imam“ amt the: map grime: mums at constant vaianfiy and each {ewes bigger maves with c1 vaiw
`My direcfiy praparfimafi ta ifs distance Foam the. szufimary barmm layer. The vaiacity graéiam, a: safe a?
`shear idvftir}, ha rhea diz‘fas‘afice a? when): civ bewaan Mo pianes r2? iiquid aepamted by fine eiésmnce d:
`The Fame {VIA} appiiad m me tap Myer {314:}! is {squirted to remit in flaw {rare 9f shear, i3) is caflad fha
`shaming stress: {F}. The ramfimshm czar: b6 axpraswd‘
`
`£1 .,.
`A
`
`5%:
`11 air
`
`where n is thé} viscmity ccwafficienra or viscssily. This reimtionship is when written
`
`a f,
`G
`
`whayeF 4;- F‘Mx and CE m tiw’dr. The: higher fin-s: vkacesity a? E! Eiquiée the gamer the shearing was}: re~
`wired k2: madam t: certain me at)? sham. A p33? 93‘ ¥ vs {3 3:533:35 C: rheagmm. A Newtonian Fluid w?” plat
`as. {a straéghi‘ tine with the skspea a“)? rim fine beiflg *1. Thai: unit a? viscwity is. the guise, which ia the sham
`Eng Mme requirerfi k; pmduce C5 veiaciy of T cmx’se: beMaw Mo pamfieT flaws a? “quid, each 1 cm2
`in mac: and swarmed by a distance: as? 1 cm. The mask mummies: uni? to usa is 153 canfipaisa, w cp
`{aquiwiem {a £131 mime}.
`
`These basic cancapm can be ilfuatmtgd in the fofigwing ham grmfihs.
`
`Rake0fShear
`
`EXAMpLE I
`
`Viscosity
`
`Sheafing Stress
`
`Shear Hate
`
`What is the shear mm when an 013 is rubbefi We» the skin wah r: reiafiva r019 0F moticnn between the Pine»
`gets and the skin of about '30 cmfsac and #513 Mm fhicknass is {35:31}? 002 cm?
`
`(3 =1 Wlfigggsec * 580 sac"i
`
`AstraZeneca Exhibit 2097 p 12
`
`

`

`35!:L
`
`Bispme Systems
`
`
`
`Rhealagy (Cmnfinued)
`
`Tha viscosity a? Newanim matemis can be easiiy determined using a capiéfiary viscmmeter, such as he
`GsMalti Pipe-t, and tha fwflawing ralufienship:
`
`n“ a ktd
`
`whew 11’1“: viscoaiky,
`k 2-": a ccefficient. inciuding such Facters as the radius and Ién'th (3F the capillary, 3&3?qu Q? the
`Eiqwd flawing‘ pressure henna W,
`t w timakcnd
`d a density a? die material.
`
`The aficiai