SEVENTH EDETION
`
`AND DRUG
`
`DELIVERY SYSTEMS
`
`PHARMACEUTICAL
`DOSAGE FORMS
`
`
`
`Howard C. Ansel
`
`Loyd V. Allen, Jr.
`
`Nicholas G. Popovich
`
`AstraZeneca Exhibit 2096 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 2096 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 2096 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 2096 p. 4
`
`

`

`Secfimn V. Liquid Image” Farms
`
`
`
`SOLUTIONS
`
`
`
`Chapter at a Glance
`
`Soiubility
`Inning-mic Melaczdea
`{Jammie Malemles
`Same”: Salvmts Fm Liquiii Frézparatium
`Bistillfitimz Maikad
`
`{wanexdmflgg meffwd
`Ravage flszrwsis
`
`Fraparatéim 0f Saiutians
`Qtal Salutiom anti Freparatimxs {m Oral
`Smiutian
`
`{Dry Mixtur‘afifor Safuféon
`G7??? Saiufs‘mzs:
`
`Gm? Refrydmtiau Saiutms
`(33:45 (Salem‘s Max:236 Ssluffmz
`Magnesium Citmtra (3m! Sammy:
`33:17in Citrate and {Citric yam? €3er Salmfm
`
`Syrups
`Canapwents 0f Syrups
`Surmsa and Nemwfiuarase 335M Syrups
`Antimicméiia! Preserzmiw
`Flawmfif
`(Salaam
`
`I’repara kitten 0f Syrups
`nguéz'm’t with me Aid qflimt
`3:22an by Agitatisn withwfi Hie Aft? of
`Heat
`
`Adéftim mf Swarm-:3 to a; Medicafgé Limit? fir
`it: :2 Fitzmmd Liquid
`Percaiatém
`Elmira
`
`Preparatian 0f Elixirs
`Nammedicated Elixirs
`Medicated Eiixim
`Amihfstzmmw Elixirfi
`
`Barbimmtc? Egdaifmffiypmfis Eiixim
`Pizgnafiarbfml Elixir
`
`Qigexm Elixir
`Tinctures
`
`29f;
`
`mezr fidminiatratéan and Use mi Liquid
`Fererai Dasaga Farms
`Tupical Salutiws and Tinctures
`Tupicai Salutiam
`Sprays
`Numinum Amalia! Twigs}! Salutiw
`Aluminum Suhacemte Tammi
`Sahrfz'mz
`
`Cafcfuw Hydra-Ewe Tapimf Sfliutim
`{36:52} “I‘m“ Tapfmi Safufimz
`Hygimgan Pamxmfa Tapietal Salts: Hm:
`Chimhsxiding Gfucramzfe Salaam
`
`ngidonewfadéas Tapfcm‘ 501mm
`Tkimmml Twimf Salzetémz
`Vaginal and Renal 5011166113
`Vaginal Bauehes
`Retenfim Enema
`Evawaiimx 5113mm
`
`Tapical Tinctures
`{Ming Tincture
`
`Cflmpfli‘éfld Benzez‘n Tina‘im's:
`Thimsmsal Tine! 14:12
`
`Special Aypliitatian Salutiuns
`Nasal} Preparatians
`Nam! Begangesmr-zi Eafmfmfis
`Ifihzzlfiiz‘m Sainfimzs
`
`Examplzs qf Mefiimted Infzafmim
`Swariimm
`fimakmi‘g
`
`Amyl Mtfitg Inhaéazzt
`Pmmflhexedring Irzfmlamat
`Pram? Admfflfsfmtz‘m and Use quasm
`{3:133:15 anti fiprzzys
`Masai Rama f2)?“ Systgrmc Efi‘m‘fi
`Stir; Saluéimm
`
`Cammmfimmmg Sflfe‘ifiéfifls
`fimi‘wififiecrmm Antflz‘nflammmmy, and
`Airzniggfiic: Ear Pragmatism
`
`Astraleneca Exhibit 20961 S
`
`

`

`Emmi-{ms
`
`29?
`
`Ffexiéflg Cafiwiz‘afi
`
`Saficyéi‘c A3323 Caifaéfm:
`Extractien Mahads far Preparing
`Salufions
`Merhmis as? Eximctiiufi
`Macemtim
`E‘ezwimfm
`
`Preps." Adminfsfrmtian and Use: of (Diff:
`B‘mps
`Tapicai Ora} (Dentai) Salutiwns
`Miscallaneaus Salutiuns
`Ammatic Waters
`Diluted Acids;
`Spirits
`Naaaqueous Selutitms
`Linimenta
`Cullmiians
`Caliadima
`
`Exampie Reparatians Pregaresi by
`Extractim Prucesaes
`Fiuiciaxtracta
`Extracts
`
`I}: fiiwsxmflmm tafmsg mlutécns may be p11?
`pared him any cumbiraatiw GE saiid, liquid; am“!
`gag, {ha three Emma of matter. Fm Examgfle, a sand
`salute way has: diswlveci in either: amthe: mks}, a
`liquid, at a gas, and with the same being true for a
`liquid Salute and far at gas, mime typés (Ki hflmaga»
`news mimwes are gossibla. In pharmacy hawaver,
`intereat in smiu rims i5 fear the mast part limited :2:
`prepaxatims of a amid; a éiquid, am less frequentiy
`a gas salute dissclmad in a liquid solvent.
`in pharmaceutical
`terms; safufz'mzs are "liquid
`preparaziana 2m: summit”: {me as more: chtamical
`substames dissalved in a suitable stalwart? (31* mix“
`
`tum af mutual} 1;; miscibia solvents“ {1). fiecama flfa
`pamcuiar pharmaceuticai sclutim"5 use, it may be
`Classified as an an?! salaarim an}: 5:39am, apkfhszfimic
`sflfutiflfi, a: reapim! 391%me Still mixer sniutiflna be~
`muse at" their mmpcnaitiun (Jr 115%,. may be dasaifiafi
`a3 {rather phamaceuficai fiasage Emma Em exam»
`plea. aqumus awlufiifims cantaining a 5ugar are: clam:
`aified as symys: fiwaetienad hydmaimhfllit (Gambia
`marinas if water and athaml} salutims are temxed
`3mm; summing 23f ammatic: materials are termed
`spirits: if the selves: is aimhalici a: amnmir: watm‘s if
`this advent is aquaaua. Salutiztms prapaz’sd by ex:-
`tratting active mmfimtmta Emm crude dmga are
`termed Es‘z-zctwss arflmzi 3x15113315; depending an {heir
`methmd of preparatian and their mmemratimi
`Tisrziémes may aim be soiutians 0f chemicai sub-
`Smmes dissmlved m almhml Ur 'm a hyiimalmhmk:
`whwt. (Imam animtimg prepareci to be steriie and
`gymgenwfma am} intended far parenteral admims»
`Haitian are dassified 51$ itzjeafz'mg. Almnugh Other
`exampmg cauld he cited; it is apparent that a 5:22qu
`titan; em a distifict type: if pharmazteutical praparw
`him, is much further defined than is the physicav
`chemical definition of the term gaézztim.
`
`{3:211 sniutianm amps, elixirs; Spirits ami tint--
`tux-es are prepared and maxi far the Spfifiififi effecta
`cf the medicinal agents present. In these prepara—
`tima, the medicinai agema are intended m pmfide
`
`systemic Effects‘fhe fattt that they are administeyeé
`in wiutian farm 1:51:33}? mama that their abserpv
`mm mm ma gastmintest‘inal twat? mm the sys«
`remit cimflatim may be expwtad ti: 0cm: maze
`rapiiily than fmm glispefisim m wiié siesage {Carma
`3f tha same madicMal agent»
`Sfliutes came: than the! medicinai agave: am am”
`aiiy prawn: in many aéafinistes‘ed aukutiwns. “1:133:52?
`additicsnal agents, uaually are includeci L0 muvide
`c0101; Sigma, meeirnessr tu- atahflity tn- the mlutizm.
`In furmulating a: cumgaunding a phamaceutécal
`saizstiam the ghamaem mm: utiiiza itfiamafiaa
`cm the saiuhiiiry and fitabjiity m? £31211 {If the aaiutea
`prawn}: with regazd {a the when? or advent sys
`tam empiwyeci. Cambinatmns cf medicinal m
`pharma-teutic agents that W111} raid? in chemiczal at
`physical intflactixma affecting the therapeutit quad ,
`it}? Q17 phmacmtin stability in? the pmfiwt £121.15be
`avaidgd1
`
`E333? singifiz—‘smuta suiufims and asgaecialiy {Qt
`multiplwwéute Silliutifit‘ifir the yhatmads? must be
`aware 9f the saiuaiiity chamctafisticfi :13? the wiufes
`anti the features 9f the mmmun phamaceutical
`suivxsnffi. Sash chamicai agent has m; awn whifiib
`it}: “1?: a givan mks-em. Fm many meéicinai agents...
`their sainbiiities in the £13133! sotvenm are stated in
`the: USP 52$ weli as; in ather reference beaks.
`
`Solubility
`Attractive farms between atams; 133:3 it) the fav
`matimn mg maiemles and iam; The intermaiemiar
`
`forcea‘ which are, éevelaped between like male~
`cakes, am- respufisible for the phyaiml Emit? (ix-2..
`safici, iéquid, m gag) 9f the subatame armies“ giwn
`mndifims, as tempexame and pregame. Under my .
`diam}: mmfiitimg. mast mganic mmpmnds! and
`thus mast drug gabstanms. farm molecdar mEidg.
`Men mmiecmes intaz‘act, attraciiw farceg. and re»
`pulsive 3:311:83 are 31 efftaca’fixe amacdw ffll‘tfifi cause
`the 111013211233 19:: whem whereag the xepuigiw.
`
`Astraleneca Exhibit 2096 13* 6
`
`

`

`298
`
`Saius‘ium
`
`fumes prevent meiemkax interpenetratien and de—
`smmtien. When {he ametive and repuieiee force;
`me equals the leukemia} energy between {we mole
`eulee is minimum and the syetem is mes: Stable
`Dipelar meEeeuiee frequent? tenci m align
`rhemeelvee with ether dipeia: maieeules such that
`the negakive pefe ef ene melemie points towegd
`the peeitive peie 0f the ether. Large gmups ef web
`armies may be asseciated threuggh fheee week at-
`tractierts lemem as dieeledipeie :3: var: tier Waais
`Emcee. In additien ten the dieefier mteraetiene, ether
`attraetiene eeeer between paler and nenpelarmei—
`easier; and iene. These indude fen «dipeie ferces
`and hydrogen heading. lee ietter is sf eartieuia:
`ietereet‘ Beeause :35 email size and iarge elemestaw
`tie flee, the hydregee amen can Eflmi‘éi in time is an
`electrenegetiee 3mm femieg an eieetmetaiic Qrpe
`ef aeweiatien referred te as e eyeregen bend er 3’3?“
`dragm bn’cige Hydregen bending ineelvee strengly
`electrenegafiee meme as exygem nihmgem ami fle-
`eriue. Such a brand exists. if! water; represented by
`{he darted lines:
`
`f ”x
`H
`
`e
`
`f \
`:«1
`
`3
`
`WM!!!
`
`Hydi'egen bands; edge exjet bemeen same almiml
`ewlecuiee eeeere, eexbexylie acme, alniehydes, and
`Pefypeptidee.
`When a selufe ciievseives, the substanee’s inter“
`
`mefeeular Emcee- ef ettractiefi meet be averwme‘: b};
`fereee ex“ etirectien between the aebute and Saleem
`
`molecxdesfihie inveives breakmg the eoiutmsmmre
`fereee and the eeiventeselvem farms m achieve the
`selme—selveni emectim.
`
`The meeeey ef an agent in a particular advent
`indicates the maximum cententrafim to whim a
`
`eelutien may be prepared with the: agent and that
`eeivemt When e eelvent, at a given temperature,
`hes dieseiveci 3?} 0f the eelute it can) it is said 13:; be
`
`mfmzted. Te emphaeiee the pessibie variation in
`eelubility between Ewe chemical egantg emi them“
`fare in the ammmte e21? eaeh reqeirefi m prepare a
`eemrated saluting-1r Ewe effieiefi aqueeue eamrated
`seiutione are cited as examples; Caieium Hydmmde
`Teeieai Selmtien‘ USP; and Peteesiézm Eeflide Gee}
`Seiutiem USE? The first eemtiem prepared by agi—
`
`tating an excees element ef calcium heel-mid?! mm
`purified“ watee eontaim {ml}! abeut 14%?) mg e?" die
`seized eelute per KHZ! {EL :15 eeiutien at 25%;
`whereas the latter militia“ teeming emu: 100 g Qf
`mime per we ml of whimsy ever ”RUG times as
`much salute 3e present if! the ealeitm’x hydrezede
`{apical seiuticm. it is apparent 5mm this cemeasi—
`seen that the maximum pessibie mneentratiee re
`which a {ghamaeist may pregnant a selutien vafiee
`greatly 3111:3113 depeeciem, in part, an the chemise]
`censtitufien {3f the salute Threugh selectien of a
`eiifferem seiubiiieifig egaxt er a different ehemieai
`gait fem“; ef the medicinal agent! alteratien 0f the
`pH Die seiuh‘eng e: substitutien; in gait er in whale.
`Bf the sateen: a phermeeiet ear: in certain instances
`diasniee greater quantities 0!: a eelute than weuM
`otherwise be peseible. Far exernyflee ied’ine gran»
`mes ere eolubie in water £11113: Ice the extent GE 1 g
`in abeut 3080 mL 0% were: Using 0112}:
`these
`We agents}, the maximum ceneemratien peseible
`would be apgmiadmately BiB‘féa ef iedine in aquew
`ms selutien. Beware: threugh the use ef an eque»
`mus saiutiun 0f petessium 0r sedium ieeriide as; the
`sewenn much larger ameunts e? iedine may he die
`mined as the remit ef the femafien £1? a were:w
`
`salubie cemeiex with the iedicie seit.This reeetiee
`is taken advantage $35,. fer exempie, in iedine “reek
`cal Seiufieze U513; gi‘epaxed {0 contain abflut 2%. ef
`indine and 2.4% efmdium ieciide.
`
`Temgeramre is an impatient Seder in determin"
`ing the selubility ef e drug and in emparing its sew
`iufifln. Must chenuceis abserb heal" when they are
`dieseived and are said tea have a pesitiee Ewe: ef see
`Ecxtien, rewiring in increased soiubifity with an in-
`creeee in temperaflwe a few eheméeele have 31 Reg
`stifle? Reef 3;“ 332mm: and emibit a decrease in
`emlebfiiry wieh a rise in temyemture. (lithe: factors,
`in adeiitien m temperame, effect seiubilify. These
`inefude the verifies chemise} and ether physical
`preperfies of 3303:}. ”the? ee‘mte and the wheat, {seem
`{ere ref preemre, the aeidify er baeieity ef the (some
`tier; me state of eebdixesien of the salute. and fhé?
`phyeieei agitation eppfietj ten the eelutien flaring
`the dissolving preeese‘ The eelu‘eility of a pure
`ehemiee} guestame at a given temperehme and
`pressure is emetent; hewever, ire We of sewage.
`that is, {the speed at which it dieeaivee, depends cm
`the particle size 9f the eubsieme and the extent ef
`agitafianfme fine: the pewden the greater the ear
`face area that memes in eenteet with the solvent;
`and the more raging the ciisecifing precese. Men, the
`greaiet me agitatien! the mere meaneetee eefvem
`passes ever the dmg, and the faster the formation
`ef the solution.
`
`Astraleneca Exhibit 2096 p* 7
`
`

`

`The. saiuhiiiiy 3f a substance in a given gslxsent
`may be determined by preparing; a saturatad saiw
`titan if it at a spacific tamparatum and deteminiflg
`by chemical analysis the ammm 0f chemical (iis«
`flawed in a given weight a? salufim. Egg 33mph: cab
`cuiat’iam the maxim: cf when: tequimd m dissolve
`the amuunt (Elf salute can be fietermineé‘me 5:;lew
`
`bifity may then he expreaseed a3 grams: :3? $011,319 disv
`salm‘ng in miililfters cf salvantmfa: examgakaffi g (33’
`gadium chlmicia dissalves in 23 ml. (3? warm."
`War: the»: exacrsaiubiiity has: nut bean determmea
`general expressions GE relative scalability may be
`med. Them terms; are {iefined in that US? as pre«
`flamed in Table: 13.1 (2}.
`3% great mamy cf the impurtanf: mg-anir: medicinai
`agents are either: weak acifis :3: weak bases: and
`their saiubilitj; is dapandeni till a Large measum an
`the pH {If the sulveantfhese drugs react eiiherwith
`Wang acids GE“ strang hams ix: farm wafarvsczlubie
`saute. For instanca the weak $33533; including many
`cf the alkaiuids {afropina mdeina arid m:‘24'ph1‘.t“vc3}a
`miihifitaxxflngs {diphenyhydxamme and tripalm—
`Examine}. ism! anesthetitis {magma panama, and
`muaaainex and ether impurtant drugs are: mt vary
`watetusoiuhha but they awe galubie in ciilure scflw
`firms GE arms” Phamxamufical manufacturers have
`
`pregarad many arid salts at” these arganic bases: is
`enable the preparatiatz {If aquzems salutiqns.
`ii
`must be rewgnizteci‘ hammer, that if me 53H {31‘ the
`aqumus saluticms {IE these safits is changed by the
`additim af alkaii, the free- bafie may sepamta 5mm
`sclutiun Hams; it has adequate sclubiliiy in water.
`Orgarzic medicinais that are weak acidfi inducia 2hr:
`haxbiturate drugs {as phembarbital and gentcbarm
`bitaifi anti the sulfanamides (as 513] Eadiazina and
`suifacetamide}. These and wither weak acidfi farm
`waiter-salubie salts in basis: minimum anti may 529$
`rate {mm saiutian by a {Qwaziflg {132‘ the pH. Table
`12.2 presents the camparatfve aaiubilitieg DE same
`grpical exampslefi <35 weak acids shad weak E33323 and
`their salts.
`
`Table 12:1,. Reiative Team m‘ Salubility :2)
`
`Parts qf Safamt Required
`
`fir." 2 PM: a)” Sainis
`Desmigthzss Tam:
`Very gamble
`Less than 1
`Freely salubie
`Farm 1 ti: ii}
`Saiuble
`Ram ‘16 its 3!}
`
`{3er 30 £22 mi!
`fiparingiy soluble
`Exam 103m 1006
`Siightiy gamble
`Fran: mm 1:; 1mm)
`Very alightly gamble
`mam} am} war
`Practicaliy infifliuhle
`(at insulutde
`
`Saiutions
`
`299
`
`Tabla ’12.; W322: and Alcahal Suiubitihies af Same
`Seiecmd Weak acids! Weak 3335334. and ”Thai: Salts
`
`Mummy 3fFEEL (2fSalaam
`Regsairad Ea fifmiw
`I 3:}; flag
`
`Drag
`
`Ampnmr
`Armgma suifam
`Cadeifle
`{imam Stfla’w
`Caéeine phusphatrs
`Marphine
`Mar? hing suiiate
`i’hembazbiw
`Fhanuharbizai Stadium
`Frucaine
`Framing aydmtifiméa
`Suifiadiazine
`Sadium mlfmiiaaine
`
`Miner
`
`455
`0.5
`1243
`3%}
`2.5
`5.0530
`16
`1,3823
`1
`230
`‘l
`33,860
`2
`
`Mafia?
`
`2
`5
`2
`13280
`325
`215.]
`5&5
`8
`10
`winbiez
`Iii
`sparing}? SQIubIe
`slightly saiubie
`
`Aikhmgi‘a them are m exact NIES fa: predicting
`naming}? 2m» winbility a? a Eitamicai agent in a
`gartimlar Hazard;
`axpezfienced‘ pharmaceuticai
`thflfifistfi can agtimate the general saiubifity Bf a
`chemist-223 wmgatmd baaed an its; maiemlar stmv
`rare ami fimstima? grngsfhe infamaticm gath-
`eared em a gram: number cf imiividual chemicai
`mmmundg has. {Ed in the characterigafian 0f tint-:-
`miubiiities <3? gmuya 9f Campuuzzds, anti ihflugh
`there may be as: actasianai in acwmcy with respfsct
`in an individua? member af a gym}; a! mmpuurzds—n‘
`the gameraiizatims mnethelass same a usefué
`functian. A5 demfinstrated by the {Liam in‘mbie ‘11:?
`and what similar Slates; salts caf mganiz: campmmda
`am imam saiubia in water than are the tafiewaad»
`Eng argaflia: bases. Cmvexaalga the urganic: haw: am
`mare miubisé in urgamc wivems, including 31501101,
`man are the Cafiespanding Salt farms. Perhaps the
`m& written gmcielme fer the predictim {pf sain-
`hiiity is thai‘fiM diagoives erfmeanmg that a 3:31-
`vent heaving a mammal Structure mast simfiar ta
`aha: {23’ the: intssndeci mime Mil be most magi}; ta
`ciiamiw it"l'hus‘ mganic campaunfis are EH93??? sai-
`ubie in mganic garments than in water. Organifi
`mmpaumis may, hawevea be gamewhafi wvatérw
`mlnhie if they cantain palm groups mpabie of
`farming hygimge‘n hands with water. In £act,
`the:
`greater the number af @6223; groups prawn-i; the
`gceamr WEI} iikeiy be the argamjc campmnd’s 50h:-
`bifii}; in waiez. [30123; gruupa include (314., {EEC}.
`ESQH, CHQH‘ CHEQH. (IGOR; Ni)? CC}; NH;
`and 303%. The inimiiudimn a? halagen atflsms mm
`
`Astraleneca Exhibit 2096 13* 8
`
`

`

`353E!
`
`Swimimrs
`
`a maieculeé tends tats decrease watersmubiiity be~
`frame Of an inctease in the maietulat' waight 3f the
`mmpeumi witimut a prapartiunate increase in pew
`1mity.fimincsease in the maieaulaz Weight csf an 01%
`gawk: campwnd wii-hmt a change in {admit}: ram
`suits in decxeafiad mlubility in warm. T3313 123?;
`filemwsrrazea same if mega generalititzs thmugh
`the 1.153 m specifi: chemical examgles.
`As with mganjs wrapaunds, the pharmacist is
`aware a? same general patterns“; (3f mlufiiiity that
`appiy w imrganic mmpuundst Fm: insmme, mast
`aaéta sf mmwalant writing such 3:23 smiimm, gnu-33v
`3mm and ammwium are": ware? wiumm whereas
`
`the: divalent safisns 11kg cakéumg magnesium, and
`barium usauafiy {mm water-soluble mmpmmia
`with nitrate, acetate, and shim-ids: anims but met
`with tazbwnateg piwwhata a: hyfimxide animafic:
`be: aura there are certain cambiaatims sf animn
`and mum that: wmulci seem ta he Sim {131* in make»
`
`up but that dc: mt have simiia: salubiiii}; characten
`istic‘s. Fm: instartca‘ magwesium auifaw {Epsam salt}
`is aahabie: but caicium suifata is {ml}: slightly Balm
`Ede; barium sulfate :5 very insaiuble {I gdissmvas in
`333qu éBQfiGQ 3111; WE water} am? is wad as an
`agaque media far x—ray abaewatiw {35 the intesti—
`nal tract: but barium suifide and barium sulfite :5:th
`mat as; imam b163, and their meal use: can maul! in poi-
`sm‘ziag; mezcuwus chiaridxa: Mara) is insmiubie and
`was farmerly used as a cafiwartim b2“ marina: $35110»
`ride {Hng} is; gamble in water: and ii; a daadiy pm“
`aim if taken internaliy. Thaw are ma my imtanms in
`which salubilifiea €16 certain drugs and their cfiffer»
`entiaticm {mm ether drugs are crimes} to the phat»
`macist in tamer that he: or aha migm avoid cam»
`pmmding fafiuwsa m therapeutie fiigasterfi,
`
`Table 12.3. SmubiIEties uf Sac-chad Grganix:
`Campnunds ire Water as a Demamirafion of
`
`Chemical Siruct‘umfitflubfliiy Relatisnship
`
`Pm mgania: as well 33 far inmganic salutes; the
`ability at‘ a saivam tea ciissniva them degendg an
`its effaetivsness ii”: matwming the electmniv:
`fartea {hat E10112? :hsa atuma a? tha salute tugathe:
`am the mrmspmding lack {mi resaluta (m the.
`part 02‘ the arm-ms themszfives ta waist the advent
`atrium. Busing the dissafut-iw garages; the meta
`cakes m‘
`the SGIVQflt and than soiute became:
`
`unifmmly mixed and cohesive fwrces a? the awms
`3:3 mgéacézci by QEW farms due to the attraction
`of the mime and solvent molecules £01: (me
`marker.
`
`The student may firm? the €13} iawing gfinéfai M123
`0? swiubfiit}; useful.
`
`Inmganic Moieculas
`L [E bath the cafian and anim {if an 16:15:: mm
`
`$0
`
`3.
`
`paumi are magma-2:, me salute-salute aura»
`five farceg am usually aasily Werwma am
`therefma; these campaunda are gmaraily water
`gamma. {Exac:rzpie&, Natl 1381: KL WfiNflfi
`warms)
`If unify am if the Ewen Earns iv: an ionic cram-
`pmmd is mammfimt the saiutwsaiute migrant“
`titans are @1336 usuafiy easily :wermme and the
`mmpaunds axe avatar saluble,
`(Examples:
`Baiiig, MEIR, NazSGag Nagififlgfi
`If £133}? {ha its-1mm and amen are muftszém, the
`mmmasufime intamctian may be ten great m be
`warccrme b5;
`the suiute~suivent
`immasztiun
`and the mmyaum may have got}: water 301w
`biiity. (Exampies:
`("15:31:34, BaSCZ‘é, 83130;; Ex“
`septima‘: 395(2),? Fefiflflj
`4. Canmmn saks (1!? aika'fi mats-ls {Na R“; Li, C5?
`Rb) are: usuafly water gamble {Excegwticw
`UQCQE)
`5. Ammcnium arid quaternary amnmnium Salts;
`am water suiubie‘
`f’r. Nitraim, magma acemfm. chlmates, and law
`
`Cmqmmnf
`
`menda
`
`Eenmne
`Emma: mid
`Benjy? alwhui
`£3113sz
`Wacatedml
`Fymgaflal
`Carma tetrafihksride
`Chlamémm
`Methylenez chlaridve
`
`CfiHfi
`CgHfiCCJQH
`Cfif‘fgCHgOfi
`Ca SSH
`Cfifig {OH};
`CéHg'iimmg
`GEL:
`CHCia
`(ZZZI‘IQQ2
`
`M‘mfier nfmi
`23f Wafer
`Realism fa
`mmsm I g; sf
`Campsimif
`
`14%
`“2%?5
`2E:
`15
`23
`1.7
`2.00%
`200
`50
`
`rams; am? generafiy warm swimmer. {Exmptimsr
`silver and mermmug acetate}
`2?. Suifaies, guifitas; and ihimsulfates am generahy
`water salable. (Exceptions: aralcmm and ham
`Sum Saks}
`S. Chlmides. bmmides, and indideg are water
`amiable. {Excapfimsr saits {pf sflver and mer~
`mmus 3mm)
`9. Mini salts cmasgmmiing ta an msmlubie sea}?
`will be mare water gamble than the original
`salt.
`
`‘10‘ Hydrmideg and oxidea a? mmpmmis tithe?!
`than alkssii metafi caficmfi and the ammcmium
`
`Em an: genarafiy water insaluble.
`
`Astraleneca Exhibit 2096 p 9
`
`

`

`11. Suifidrzg are water inwmhie remap”! {air their
`aflcaii meta] saita.
`
`12‘ Phwsyhatem :arbcanaraa siiicarasi bmrares, and
`iiwrbchlorires are water inseiuble except: Em
`their alkali metal gait; arid ammrmium wits.
`
`Oigmflfc Maiecules
`
`‘1. Muiewles; having me prfiar funcrirmai gram}
`arr: usuaiiy soluble m trimi chain ifingths of firm
`tafbr‘mfi.
`‘
`
`2i Maiewier herring branchrid chains are mere
`Sfiiuble than the crirreaiwmiirrg stmigiiiwhain
`mmpriurirlr
`3. Water suitability decreases wirii arr inrrraare in
`maiecuizrr weight
`é? fricti'easeri armature] aimilazii}! bsrween smiute
`and smivrarzr is acmmparrieri by increaseci soiw
`bilit’y.
`
`Ii: ii; the gharmaaisr‘s kmwiedge sir” rim chemical
`characteristica rif drugs that permits the 3:31:32an rif
`the prairie: advent fer a garriwlar mini-a Hmwrwn
`in additirm tr: the factora rif fioiubiiirga the «salesman
`is baaed rm such additirmai scalverit characifiristirs
`
`as; ciariry, law imam fiscusityf campatibiiity with
`(ii-her iarmuiatiw irrgrediants: themirzal inertmass,
`palatabiiiw, rider, whiz; and rscawmy. in mass: in—
`EtaIiCE-S‘ and especially far saiiitians; rt: 53$ taken
`areal}; used righti'zalrniralifi Cir inferred“ water is the
`prei'errari Summit because it CGETXES stirrer in meat—
`ing the majority (if the abaw critaria than this: grim:
`avaiiahie garments. In marry iiiararicras, when water
`is tired as the primary warrant, an auxiiiary when?
`is else: emplcyed rt: augment the wheat artimn 31‘
`water car is: warribuie it”; a prariuct‘s cherrrira} a:
`physical stability Aimhrii, glycerin; and prflpyierié
`giywi, Perhaps the most usari auxiliary garments,
`have been quire effective it"; trinrriburing tr) the rite»
`sired characteristics (if pharmaceutical sniurirmr
`and in maintaining their stabiiiry.
`(Either Saifi’efl‘ffi, web as aretma ethyl amide, and
`mngrapyi aictrhoi, are triri taxis: tr; be permitted in
`pharmaceutical prepararims m bra taken internal};
`bur they are ugefui a5 reagent solvents in mgarrir
`chemistry and in rhe preparamrgr stages rsf rimg Cir?“
`relopmerir. as iri thr: artraciiinn mt rmmvai {if “active
`ccmfimenrs fmrri medicinal giants. Fm grammes
`such as; rim rerrairr $011.92“an are riffitiaiiy rermgnizeri
`in the campendiar A number a? fixed c3133., smith 33
`mm rail: mmmeed 01L pea-nut mi; aria? sesame xiii,
`serve useful smivrsni functianr particularly in the
`preparation of crieagimmr injerrirms and are recmg-
`nixed in the affirm} compendia far this gimme.
`
`Solutirins
`
`3E3”!
`
`Same 331%an Far
`
`Liquid Preparatinns
`
`Tin? fflliriwing agents; find use as fiflivezms in thfi
`prepamfirm aismiuriaris.
`
`$260893; USP {Effiyi AICUKQI,
`Etirrzrwi, CZJHSQHJ
`Nari {<3 mm; alcohui is the meat useful ashram
`in pharmacy. Sr is used as a primary when? fur
`mart}? cargarrir crimpcrimis. Tagather with water ii:
`{arms a irydrusiwi’zriii: mixture iiiar dissaivas bath
`almhniaaiuizia arid waterwsaiuble substanceg, a
`feature esprecigiiy usafiri in the extrartririn Gf actives
`wrismrrenrs fmm crude drugs. By raging tirr: 53m»
`partifln 9E that? raw agents? the active wastimenrs
`may biz seirzctiiraiy dissvired anti extracted or a}-
`irrewrsd :0 remain hehinri acwrdirig try their garriwu
`iar sfliubiiiry chararterisrirs it“: the menstrumri. iii»
`miraL USE is 943 m §§.U% CEHEGH by wiumr
`{Em WV} whiz-a detrarmiried at 1556?, the LLS.
`Gavemmenr’s stamiarri temyerame far aicaimi
`derrrrninatiflnsi Dehyrimfad Akfififlh USE wrirairra
`rim i333 than 99.3% Cgfififlfi by wimrra and ifi uti—
`iizeri in insiames in which an asaerriiaiiy waiter-w Erase
`aim‘nrzi is dfifiilfi‘d.
`
`3mm: i233 been weii remgrrized % a advent
`arid excigianr in the furmuiatiarr GE arai pharma-
`reuiirai pmriuctsi Certain drugs are insriiubira ira.
`water and must be dissalvreci in arr airemate rem“
`
`+21%. Aimhrii ii aftarr preferred bataLIS-E cf its misciv
`biiity wirii warar and its abiiity tr: dismive many
`waterwinwiuhie ingredients! inciuciing drug subw
`mamas; flamrarirs: and arriimirrabiai preservatives:
`Aiwirrri is fraquaritiy used with mixer warrants, as
`giymis arid glycerin m redraw? the ammriif: a? sim—
`hrii requireszi it 21159 is tigeri in liquid pruducta a5 arr
`antimicmbiai preservative fiiifiiné‘. €11” as a rmpresew—
`grime with paraianfi, benmares, remakes! and rather
`agents”
`Hawever; aside} fmm its ribmmareriric advanr
`tages as a mirent and pmmrvativreg cmmrn has
`been axgrewefi we: the unriesireri pharmamiagic
`and gamma} taxis: affectg {If aimhrii Wham ingested
`in pirammrzeutirai pmdrrctr particulariy i3}: rhiid»
`ren.‘i’i:r:35,, the f-‘mx has pmprisfld that manufarrup
`era r2! OTC Kira} drug praducfs regtricr, insciar
`are garribie, the rim- af alcchai anti inciurie apprm
`prime warnings in the wheeling, Far QTC era} pm‘ifiir
`acts intanxtiad Err ahiiiirem wider Er year‘s firf aga, the
`remrnmenrieri aiceimi-mmem limit
`is {15%; Ear
`
`marinas intenried fur chiirirrm fr tr: 122 gram at? age;
`the remmmendrri limit is 23%; arrd far products;
`
`AstraZeneca Exhibit 20% p. 10
`
`

`

`332
`
`Solutions
`
`rectum memied fa: chfldzen (we: 12 ways (3f age and
`fur adults? rim mwmmmdw Eimii: i=5 13%.
`
`Diluted fllcghal, NF
`
`Dimted News}, NF, is gregared by mixihg equal
`Wilma. af Mmml. U38 and Pufifieé Water; USE
`The final \rmiume <33? Silifih mixhlres is mt the mm M
`
`the hidits’idual wimmes of the m0 mmganenm. but
`due m {tantracfiw {if the liquids upsm mixing the fi—*
`flat Mama 5:; generafly abeut 3% 1353 than what
`wauid maximally ha ewecteciflima Wham 513 mil in?
`each campsmeat is cambmtai {ha {6513:5113 pmtiuct
`measureg appraximafely ‘31? mL. It is for this reamn
`that the strength crf Diluted $133113}! N13, i3 nm e»
`emfiy haif that Elf €118 mare saucentmred almhai, but
`sfightiy greatet; aggprmdmateiy é9°§L Ufiutafi almhcfl
`5:51 a use-3M hydmaicahulic $31th in various 13th
`maceuu‘cai meESS-Ea and praparafims.
`
`111091101, Rubhing
`
`Rubbingfixlmiwl cantains abmt ”33% 42f Ethyi al~
`mm! by miumef the? remainéer cansisting m3“ wax--
`ten denamrams with at Mihsut calm adciitiwes 311d
`perfume MS; and stahflizfifi. {I1 flack 1C“?! mL, it,
`must contain 11m 1:255 than 355 mg 13$ suztmae 9b
`taacetate or 1.4 mg flif denatwium benmam bitter
`substances that fisccurage accéciemal m abusive
`ma} ingeafian. The denamrants ampimyed in mbw
`hing almhwi are awarding t0 the Ifltemal Revenua
`Senéce, U3. 'fi'easure Eapamnsm, meula: 23-«FL
`which is mmpased Elf 8 mm by vfliuma 0f acemna,
`1.53 part3 b3: miuma of methyl isabutjfl kemna, anci
`105 parts by mlume 0f aim} almhoi.Tha use: Bf this
`fianaturam mixture makes {ha separatim 13E ethyl
`aiwhi’fi fmm {ha damturani’s a Virtually impassible
`tatak with animals}? cfistfllafim apparatus. This dig-a
`flauragea the mega} remavai am} we as a beverage?
`43f the aimholic content drubbing 3112131101.
`The precinct is valatfle anti flammable and sham
`he starred in tight flaw-airways {Emma fi’fim fire. It is
`empioyed as a mbeafaciemt externally and as a math-
`mg mb for hedfidafien patients, a gemficicle far mm
`sfmmtafl is: and a Skin deamm prim m injectim. It is
`aka mad as a vehicle fa}: {mica} preparatimns.
`Symnym: Macaw] Rubbing Cmmpflumi.
`
`Glycerin; USP {GchemI},
`CHZGHCHQH‘CHZQK
`
`Giycen’n is a clear amp}! quLLid with a sweet
`mafia. It 33 miscible bath wiih water am afimiml. A5
`
`a graham. it is; mmpamhie with 31mm but bemuge
`
`is}? its vismsitgg; salutes are 51:2wa salubie in it 111112333
`it is remixed 19:35 mamas by heating. Glycefin hag
`presewatiw qualitieS and is; after: wad as; a stain;-
`Iiaer and as an amliazy when? in canjumfitm with
`water car aicahci. It is used in many intramaf wepa-
`Gamma
`
`Isapmpyl Rubbing Alcaha!
`
`Iswpmpy} Rubbing Alcahal is abwt 333% by 230%
`name isrz‘gwpyi aicahui. the remaimie: {smashing {sf
`water with m” Militant cum}: adciitivea. stabifizers,
`and pexfilme fiifia It is used. extamafly as: a mbefa~
`dent and soothing rub am as; a axe-hide: far tnpicai
`pmfiucm This greparafiw and a mmmerciafiy
`avaiiabie @123 iwptapyi almhtal stalwart are amm-
`mnnly ampiceyed by ciiabetic patients“ in preparing
`needles and syringes; far hypcdemajc injectians <31?
`£9.5an and far disinfecting the skin
`
`Pfepyfene nycal‘, USP,
`CI:3CH(OH}CHEGH
`
`ngylene giyccd, a mwus liquid. is ram—ibis:
`with make: arid almhal. it is a useful wivem with a
`
`wide range af applicatiuna and is frequently substfi
`mas-2d Em gfiycerin in matiem pharmamutical farm
`muiatim‘us.
`
`Purified Warez», USP, H2.
`
`Niammliy {3:111:17ng wa tar exerts its wheat Effect
`cm mast substances it cam-acts and thug is impure
`and mmainfi varying amaunts :3? dissaheed inm—
`gemic gala usually sudium patasaium Gait-Mm
`magnesium. and item: Chiarides‘ suifatesfi and him
`cmbflnatesg as well as dissawed ami Lmdisscriwd
`mganic maths: and micrwr