Parenteral Medications
`Volume 1
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. lieberman, and lean luthmun
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`AstraZeneca Exhibit 2103 p.
`InnoPhamia Licensing LLC v. AstraZeneca AB IPR20l7-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017—01910
`
`

`

`
`
`
`
`ParenterIal
`
`Sum Efiéfiimg “We mi Epndxnmfi
`
`KennAih E. AME
`
`The Univetsity of Tennessee
`Memphis, Tennessee
`
`
`’A As lIeernmu
`
`L @ 1.,
`
`'
`
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`
`5
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`
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`
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`
`K
`
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`
`H.H. Lieberman Associates, Inc.
`Consultant Services
`
`Livingston, New Jersey
`
`
`
`Lachman Consultant Services
`
`Westbum New York
`
`Marcel Dekker, inc.
`
`New Yen-k A Basel 9 Hang Knng
`
`AstraZeneca Exhibit 2103 p 2
`
`

`

`Library of Gangress Cataloging - in“ Publication Data
`
`Pharmafleutical dmsagfi Emma. pammeral medicatians / edited by
`Kenna/t1": E. Avis, Herbert A” Lieberman, and Leon Lachman. M 21163 ed. .
`rev, anti. expanded.
`En
`cm.
`
`Includes bibliographical references and index.
`ISBN 53-82%?85’E'fiv2 (v. 1 : all-t. papw)
`1. Parenteral salutians.
`2. i‘hm’maceuiical techmiugy‘
`Kenneth E.
`II. Lieberman, Barbara“: A.
`III.‘ Lachman, Leann.
`
`It Atria,
`
`[DNLMr 1* Infusimns, Pamnteral. 2. Technology, Pharmaceutical.
`WE 35:: P535}
`RSBBLPE’ENS 1932
`615’. Lia-"dew
`‘DN LEW 1’1}ij
`
`im- Library of Cungress
`
`91 »38053
`{ZIP
`
`This beak is printefi 0n acid-free paper.
`
`Cflpyright “@3 1992 by MARCEL IEKKER, INC. Ali Rights Reserved
`
`Neithar thii book my: any part may be repmfiucad m- irammittad in any farm
`(it by any means, algctmnic m mechanirsal, inclufiing phatompyingt micrw
`filming, and regarding, m by any infarmatiorz manage and retrievaf system,
`withom permissian in writing fmm the: pnhtishan
`
`MARCEL DEKKER, INC.
`2‘20 Madiscnn Avanue, NW Yen-k, New Yark 10016
`
`Current printing (last digit);
`10 9 8 7 6 5 4 3 2 I
`
`PRINTED IN THE UNITED STATES 0F AMERICA
`
`Astraleneca Exhibit 2103 p. 3
`
`

`

`Confiaemtg
`
`I’refaae
`Cantributora
`
`Cantams cf Phavmaeeutical hostage Emma: Parenteral Medicatians,
`Sewncfi Editiang Revisad and Expandad. Valumes 2 and 3
`Cantents 0f Pharmaceuticzal Bflaage: Farms: Tablets, 852mm: Editicm,
`Revised and Expanded. Valumes 1*3
`(laments af Pharmaceutical Baggage mes: DiSperse Systems,
`Vulumes 1 and 2
`
`iii
`xi
`
`xiii
`
`3W
`
`xvii
`
`Chapter 1
`
`The Parenteral Bewge Farm and 11:5 Hismricgtl Davelapmant
`
`1
`
`Kenneth E. Avis
`
`I. The Dasage Farm
`II. Histary Bf Parenterai Medicatians
`flippemfix A: Glossary of “Karma
`Agapandix 1E3: Highiigghts in the Rigatm‘y of
`‘Parentewl Meclicatians
`References
`
`Chapter 2
`
`Parenteral Ilrug; Adminigtratmn: Routes, Ereeautiuns,
`Emblems, Complications, and Brug flelivery Sygtamfi
`
`Richard J. Duma. Michael J. Akin-‘3. and
`Saivmare J. Tame;
`
`Intraductimz
`l. Generai lnciicatiana for Parenteral
`
`Administration :31" Drugs
`H . Pharmaceutical Factars Affecting Parenteral
`Administratifin
`
`UL Specific Relates of Administratiun
`IV. Distribution 63f Farenterally Administered Agents
`
`1
`4
`12
`
`1%
`15
`
`17
`
`1 7
`
`18
`
`19
`
`21
`3‘3
`
`vii
`
`Astraleneca Exhibit 2103 p* 4
`
`

`

`viii
`
`Cantrnts
`
`Vr
`
`Freeautiens, Prablems, Hazards, and
`
`Campiirations Associated with Parenteral Drug
`Afiministratian
`
`VI; Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`Raferencas
`
`Clzaptar 3 Bimpharmaceuties af Injectable Medicatians
`
`Seal Mamie
`
`I.
`
`II.
`
`Intrfiductifm
`
`Physiwchamica}. and Physiaiagieal Faewrs
`Afircting Drug Absmrptian by; Inferticm: An
`Overview
`
`IV.
`
`I11. Applicatinn 13f Pharmacakinafias to Biogharmw
`cautic: Investigations: Pharmacokinatic Madam
`Examgglas at" Bimpharmacautic{Pharmawkmetic
`Prinuigales
`V. Regulamry Consifierstians far Bioequivalenca
`Studies;
`
`VI; Biaequivalence Study @f Twm Inimitable Farmg
`0f the Same Drug
`Summary
`References
`
`VII.
`
`Chapter 63
`
`Prefarmulation Research 9f Parenteral Medicatians
`
`5'0? Mamie} and Shreeram N. Agharkar
`
`I.
`
`Intrudnctian
`
`II. Drug Substance: Phyaicachemiéal Properties
`III. Acuaieramd Stability Evaluatinn
`IV. Gangral Macias 0f Brag Degraflafiun
`V,
`Prefurmulation Studies fur Framing and Peptides
`VI.
`Prefarmuiation Screaming cf Parentrm]
`Packaging Compnnema
`Summary
`VII,
`VIII. Prefarmulatien Worksheet
`
`References
`
`Chapter 5
`
`Formulatian of Small Volume Parenterals
`
`Patrick P. DeLuca and James C. Boylcm
`
`I.
`
`introductian
`
`II.
`Farmulation Principles
`
`III. Cmntainer Effecta an Farmulmicm
`
`IV Stability Evaluatian
`V.
`Pracesa Effects
`Referéncas
`
`41
`
`49
`56
`5'?
`
`59
`
`59
`
`$0
`
`??
`
`993
`
`1138
`
`189
`111
`112
`
`115
`
`1 15
`
`118
`1%
`150
`1551
`
`1.58
`163
`1&3
`
`169
`
`1?3
`
`173
`
`1%
`22'?
`
`23%
`244
`245
`
`Astraleneca Exhibit 2 IO3 p. 5
`
`

`

`Contents
`
`ix
`
`Chapter 6
`
`Formulation of Large Volume Parenterels
`
`Levit J. Demorest and Jeffrey G. Hamilton
`
`I.
`II.
`III.
`IV.
`V.
`
`Introduction ‘
`
`Concepts of Formulation
`Formulation Development
`Solution Quality
`Summary
`References
`
`Chapter 7
`
`Parenteral Products of Peptides and Proteins
`
`YuHChong John Wong
`
`I.
`II.
`III.
`IV.
`
`V.
`
`Introduction
`
`
`Characteristics of Proteins and Peptides
`Formulation Principles
`Compatibility with Packaging Components and
`Infusion Sets
`Formulation of Market Products
`References
`
`Chapter 8
`
`Sterile
`
`Diagnostics
`
`Leif E.
`
`Olsen
`
`Introduction
`
`II.
`III.
`IV.
`
`VI.
`VII.
`
`Diagnostic Products Defined
`SteriIe Diagnostics
`Definitions
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9
`
`Glass Containers for Parenterals
`
`R. Poul Abendroth and Robert N. Clark
`
`1.
`II.
`III.
`
`IV .
`V .
`VI .
`VII.
`VIII.
`
`Introduction
`The Nature of Glass
`
`United States Pharmacopeia Glassware
`Classifications
`The Manufacture of Glass Containers
`Chemical Performance
`Mechanical Performance
`
`The Container and Closure as a System
`Quality Assurance
`References
`
`249
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321
`
`323.
`321
`322
`325
`330
`351
`359
`359
`
`351
`
`381
`381
`
`362
`369
`375
`380
`380
`382
`384
`
`AstraZeneca Exhibit 2103 p. 6
`
`

`

`:-
`
`Canlents
`
`Chapter If) 05% 0f Plasticg for Parentserafi Packaging?
`
`Jahn M. Ana's. Raher‘t S. N339‘ and
`Charms H, White
`
`Intmductimn
`I.
`Fundamentalg
`II .
`III. Fabricatian Pmcesses
`
`Imgortant Criteria {car Selectian 0i” Plastics
`IV.
`V. Plastics Used in Parenteral Packaging
`VI. Quality Assurance of Parentera? Contaiflew
`Raferences
`
`Chapter 11 Elaatameric Cifisures far Parenterals
`
`Edward J. Smith and Robert J. Nash
`
`I. Elagtomeric Parenteral Packaging Companents:
`A Physieai Descriptmn
`Phyaical Dessrigtion (sf Rubber
`II.
`III. Typas :35 Rubber Usaci in Parenteral Packaging
`IV‘ Ciasura Besign
`V. Rubber Campuunding
`V1. Vulcanizatinn Franzen
`VII. Closure: Manufaczture and Contra!
`
`{Ensure Eesigfi Qualifieatian
`VIII.
`1X . Regulatory Qansifietatims
`X .
`Intarantiun {if 13mg Farmmatiuns with
`Rubber Clasures
`
`XI. Cmntgmpm'ary Closure-Related Issues
`References
`
`Chapter 12 Pamnmra: Praducts in Hospital anefl Heme Care
`Fharmaey Practice
`
`Jam: W. Levchuk
`
`l.
`
`Introdumifin
`
`II. The Frepawfiinn {3f Sterile baggage Farms in the
`Haspita} and in Rama Care
`III. DiSpensing and Comgounding P‘mcessas
`IV. Tenhnolug’y 3f Sterile Cnmpaunfiing in the
`Hmspital thmaey
`V. Clinical: Supply and Use at“ Sterile product&
`VI. Qualify Assurance
`V11 . Canclusien
`
`Appendix: Abbreviated Sequence for Preparing 5-1
`Sraries of Extempomnmuglgr Campaunded LV.
`admixtures
`Refemnces
`
`~
`
`Index
`
`387
`
`38?
`. 339
`393
`
`($07
`422
`c139
`4&3
`
`1145
`
`445
`450
`451
`462
`483
`£170
`4'77
`
`€394
`583
`
`$05
`
`58‘?
`508
`
`513
`
`51 3
`
`513
`52%
`
`532
`547
`552
`5&2
`
`563
`56%
`
`569
`
`Astraleneca Exhibit 2103 p. 7
`
`

`

` : Regeaha‘c @JE
`
`Pemmierai Medaictims
`
`Sof Motula*
`
`White-hail Labar'mflrias, Hammanmn. New Jersey
`
`Shreerarn N. Agharkar
`
`Bristal-Myers Squibb Campany, Syracuse. New Yark
`
`i.
`
`lNTRODUCTlON
`
`Pl’ejgi‘nzuiggul‘l research reiatea m pharmaceutical and analytical investigmimig
`
`
`farms. Exgmmmen s are designad tr.) ganemm s: a characterizing spec): 1c,
`yharmaaeutieaiiy impurtamz physicocimmiea} graperties If the thug substance
`and its wmbinatien with selemaci salvents, excipients. and packaging mmw
`pennants. These studies: am carriad {mt 1131:1851? stressad canditians a? temperw
`tare, light, humidity, and oxygen in :31?er ta acceierata and detect yutential
`teactium. Taking mm accuunt aariy pharmacalmgicfil rand hiagharmaceutieal
`data? yrefwrmulaiian studieg yield key infermatian necfissary ta guide the farm'-
`ulator and analyst tuward the daveiepment Elf an alagant, stahla éasag‘a farm
`
`with gal-3:3 biaavaiiabilityi Friar t0 devalngsment m? the clirfical and markaiafi
`{lasagna form, prefcrmulaticn atudiefi yielri basic kmwlafige mammary ta: de»
`velop suitable farmulatians for toxisnlsgical use.
`Due to important research Mafia in a highly fiampatitive field, rainid pra-
`gresa is esaential, and clinical stuciies shauld he initiated a3 30mm 35.: gmsaible.
`T111113 an expeditimus preformulation program (he. , one typically taking: 6 t0
`13 weeks; to complete) is generaiiy requireci.
`If clinicai grogram ameleration
`is desired, it may ha neceasary to streamline studies and devalap crucial tie~
`amen—«making data in mortar time perimis. Shauna interim results indicate
`that a mere stable car mare soluble cirug form ia neededs expamsion of the
`original program will be necessary. Additimnafly, areas of particular interest
`may arise, suah as the elucidatian 0f .51 reacticin machanism or the investigaiion
`of unusual solubility phenamena‘ Such studias may be m? prime impartance
`and are often addregsed either initiaiiy or as semnciuphaae prafmmulatian
`stuiies, depending an their gotaniial impact an tha overafl program.
`
`*Current affiliatian: Wyeth-Ayerst Laboratories, Rafimr, Pennsylvmfia
`
`115
`
`Astraleneca Exhibit 2103 p 8
`
`

`

`115
`
`Morale} and A gharkar
`
`
`The? gamma! subject 0:“ prefmrmulmicm resemch has been daescribed in 616*
`tail by several investigatm‘s {145} am} is in wide use thmughout the phat-ma»
`seminal industry. Them? pmsamations have daait mainly with studies tiesig‘maci
`for solid dcsage farms. Some aggecific flpglicatiams have been made to certain
`areas 0f parenteral intereat [63?] . The abjective 9f this chaptar is 1:0 mutline
`methnds used in develnping yrefwmulatmn data necessary t0 characterize
`significant physicmhamical QI‘QQeI‘tiQS 0f new drugs impartant ta :3 pgmn»
`{areal fm‘mulation fievelopment pragram.
`
`
`H. DRUG SUBSTANCE PHYSICQCHEMICRL PRGPERTiES
`
`Typical physicachemieal pmgerties {11" drug substances that either characterize
`or may exert significant influence cm the develepment Df 51 parenteral farmulw
`tian are listed in Table 1.
`
`
`A. MaleCuiar Structure and Weight
`
`These are the mast basic: characteristicg {1f :3 €31ng substance and are amang
`the first items to: be 3-310sz Fran: the moleeuiar awuctum the invastigatm
`can make initial judgmgms regarding patsntial pmprartiea and functianal gmup
`reactivities, m; described in Sectimn IV.
`
`8 . Color
`
`Calor is genera-11y a function of a drug's inherent chemical atruetura ralating' 1:0
`a certain level of unsaturatimn. Calm intensity relates to the extent af canjw
`gated unsaturation as well as the presence of chromaphnraa such as ~NH3. «@833!
`and 430* (ketane) , which intensify calm. Some compaunds may appear to have
`calm altheugh atructurally saturated. Such a phenomenmn can aften be due t0
`the presence of minute traces ef highly unsaturaéed, intensaly adored impurities
`antiwar degradatmn pmducts. These substances may be prone t0 inc-reamed
`calm: formation under stress ccnflitions 0f heat, exygen. and light. A signifi»
`cant cahr change can become a limiting f‘acmr to the shelf life nf a parenteral
`pmduct even Mime :3 Significant change in chemical stability is mated.
`
`Table 1 Physicochemical Preperties 0f Drug Subfitémces
`
`Malecular structure and weight
`
`Saiubility
`
`Color
`
`Odm'
`
`138 scalability pmfim
`
`Pelymorphism patential
`
`Melting paint
`
`Salvate formatian
`
`Thermal analytical profile
`
`Absrbance spectra
`
`Particle size and. Bhape
`
`Light stahiiity
`
`Hygroscapicity patential
`
`Thermal stability
`
`mmzaticm constant
`
`pH stability pmffle
`
`Optical activity
`
`Astraleneca Exhibit 2103 13* 9
`
`

`

`Pro formulation Research
`
`1 1 7
`
`The drug substances color should he recorded by on subjective description,
`as well as by an objective means such as by comparison with standard color
`chips [8] , or by spectrophotometric analysis if the compound‘s color intensity
`in solution is proportional to concentration. The American Public Health Asset“
`ciation (APHA) color standards [9} can be used effectively to quantitate
`changes in solution color with time. Visible absorbsnce of APHA color stand-
`ards (diluted appropriately) can be measured spectrophotometrically {10]
`to
`
`monitor more accurately the color of solution test samples. An example plot
`
`is shown in figure 1.
`
`C. Odor
`
`The odor of a new drug substance should be examined by cautiously smelling
`the heedspace of the drug container which has been previously closed to allow
`volatiles to concentrate. The presence and description of any odor should he
`recorded. The substance may exhibit an inherent odor characteristic of major
`functional groups present (i.e. , sulfurous or garlic—like for sulfides, sulfoxides,
`or sulfhydryl-containing compounds, or ammoniscsl as for amines). Alternaw
`tively, a drug may be void of characteristic odor or it may have an odor of
`residual solvent. The presence of a solvent odor should be reviewod with the
`synthesis chemist to determine whether the sample has been edeouately dried.
`
`D. Particle Size, Shape, and Crystallinity
`
`The particle size of a weter~soluble drug is not of concern unless it exists in
`large aggregates and an increase in rate of solution is desired to reduce menu-
`factoring time. Under such circumstances milling through on appropriate size
`sieve [11] may be sufficient.
`
`soc
`
`37.5
`
`b
`'U
`I
`D
`
`o
`250 s
`fl
`
`U’
`o
`
`"
`
`125
`
`D
`
`2O
`
`4O
`
`60
`
`BO
`
`100
`
`is Certified APHA Color Standard (500 units)
`
`or:
`
`0.3
`
`EC
`
`Q g
`
`..
`a:
`.-..
`E
`
`"j
`v 02
`8
`
`5e
`
`D
`
`3 0.1
`q
`
`0
`
`0
`
`
`Figure 1 Typical visible absorbence readings at 400 nm for certified APHA
`color standard (500 units) at various dilutions versus APHA color number.
`
`AstraZeneca Exhibit 2103 p. 10
`
`

`

`11 5‘
`
`Motclc amt! A ghcrkm’
`
`Particle size and Shape charactericticc can lac determined by micrcsccyic
`cvcluaticn using either an aptical micrcsccyek grcfcrably with pclariging at
`tachmcntc, cc by a scanning electron microscope. The film‘phciagical characw
`tcricticc cf the drug substance should bc rcccrdcci either by a sketch or,
`mare accur‘atcly, by a phctomicrcgraph which acts c3 #21 permanent recard fur
`campaciscn with future batches. A gccci estimate cf particle size and particle;
`size range can be chtcincd ”by Viewing sever-cl ficlcc (31' a rcprcccntctfivc samw
`plc cf circg substancc‘
`A calcrizing‘ micrcsccpc is E11513?! used tc determine- whether a ccmpcunc is
`crystafiinc 0r amcrphcus. Crystalline maicriéfic rcfract palm-iced light and are
`thus; visible when cciarization attachments in the ocular and ccjccfivc are
`
`crossed at c 9%” angle (cmssccl polars), whcrcas amcrphcus m glassy cub—
`stcnccs became invisible.
`
`Optical micrcsccpcs usually cpemtc at uscfifl magnificaticns cf up t0 1900’s
`with a rcsclcticn limit in the vicinity cf 1 mm. The cccnning clcctmn micccw
`cccpc prcvidcc magflificatiuns up tc Zflflflflflx with a rcsciuticn cf ayprcximatc»
`by 25 3. to determine detaflcc particle Surface mcrphclcgy as well as individ_
`ual {Daniela surface characteristics. Whereas thc cgticcl micrcsccpc previdcs
`unly c twc‘dimcncicnal View, the scanning clcctmn micmsccpc 843633 the dimcnm
`sicn cf depth by tilting thc stage t0 scvcm} angfics cf View during- ape-ration-
`Thus what may appear tc 13c a ccmbination cf acicuiar and p1ctc~shcpcd struc~
`
`turec under a colarizing micmsupe cculfi in reality 0:113! be a field cf flat
`plates cf varicus sizes with came an cciggc, as shcwn in Figure 2. This ability
`
`tc rescivc various shapes helps the investigatcr deter-mine w’dcther a sample
`is marphclcg‘ically homagenccus. Mixturca cf mcrphclcgiccl forms either within
`a sampic (21* between scmples cculfl indicate: the existcncc cf hydrates. culvctcc,
`cr pclymcrphic farms which mum later significantly affect properties such as
`sciubility, stability, and biccvcilability.
`
`
`E . Mclting Pcint
`
`The melting pcict cf a substance is thcrmcdyncmically dcfincd as the tcmpcrw
`turc at which the cclid and liquid phases are in cquifibrium as described in
`Equaticn (1).
`
`Samid r“: SEQ Hid.
`
`( I )
`
`A melting~goini dctermination ig c gccd first indicaticn cf purity since the
`presence of relatively small amounts of impurity can be detected by a lowering
`as Well as widening in thc mcltingwpcint range. Methcds for dctcrmining the
`Inching range or temperature are dcscribcfi in cictul for various ccmgacuncis
`[12] . Any peculiar hehavicr 01" a substance unficrgcing: Inciting, such as; fill-w
`mafia change in volume, Inciting and rccrystaflicaticn, gas evalmicn, cclcr
`change, 01" cthcr physical change, shank} 33c rcccrcicd and, inwstigatcd fur-
`ther. Such bchcficr mule} be infiicatiVQ 03? significant changes! such as a
`pclymcrphic transition, decnlmration, oxidation, cm dccarhcxylaticn.
`
`F. Thermal Analytical Prcfflc
`
`Durifig cynthesis anti isolai’icn, a samplc may havc bccn exposed ’54:: changes
`in the temccra’turc encircnment which may be cxhibitcc} as a thermal prafilc
`
`AstraZeneca Exhibit 2103 p. '11
`
`

`

`Preformula lion Research
`
`I I 9
`
`when the sample is hsstsd lsstwssn ambient tsmpsrsture and its melting palm.
`When new thermal history exists. the ssmgale will neither ssssrb new give eff
`hast grim“ t0 its melting paint. The basis tsslmiqus ussc‘l ts study this plus“
`ssmsssn is ssllscl differential thermal analysis (DTA). Essentially, the ssmglis
`is hsstsfi in the presence sf a sensitive thermscoupls while: a sssarlstlS balanced
`thsrmscsupls slsstrlsslly ssnnsstsrfil in series spyssitisn is heatstl st ills same
`rats in the presences sf an inert reference materials The reference substance
`is ans that tines not undergfi {harms} transitian within the range sf tsmsers»
`turss in las ssscis The data are platted. on rectilinear pspsr with the ordinate
`squad 1:0 this cliffsrsnss in ismpsrsturs between ssmglls ant} rsfsrsncs, tilT,
`sud tbs slsssisss squsl ts “thus tsmpsrsturs '33. Altl‘mugh {liffsrsmss in csnvsn»
`lisn exist, this trsstmsmt will indicate sxsthsrmis rssstions shave: snfi 921610"
`
`If s fist signal results, ns diffsrsstisl
`thermic sessilons sslsw the bssslins.
`shsngs in tsmpssstuss {AT} securrsfil hstwssn sample and ssfisrsses. When s
`ssmyls shsws a defined ssathsrm (best libsrsiiss} as snfisthsrm {hast slassrp»
`titan} I'ssulting frsm shysicsl m: clasmical. changes ss s function sf tempsraturs.
`these phenomena are indicative {3f phase trsnsitisnsl Examples sf character
`istis snclsthsrmic trsnsitisss that can is; detected by this technique srs:
`fus
`sitar: as melting, csys‘tsllins structure changes such as yslymoz’phis tssnsitisns,
`sublimstmm bsiling, and desslvstion. An sxnthsrmis affect is seen when crys»
`tsllisstisn sssurs. Examples sf thermsl analysis pmfilss sf mslts with and
`without clsssmpssitisn srs shown in Figurss 3 and s. Dsssmgxssitisn spun msltm
`mg is rusted when tbs signal {ix-09s bslsw the Grig'inal bssslins fallowisg the
`melting snelsthsrm.
`A similar ymssss which examines this phsnsmsns is called differential
`scanning sslsrimszry (DEC). With this technique, the srss uncles ths sutput
`curve is direstly Erspsstisnsl ts the tats’l smsum sf energy {(3} sbsssbsd m?
`liberated frsm the ssmglsl The abscissa is pmpostisnsl is the rate sf best
`transfsr (tic; hit} at ssy given time. The lass of surface msisturs smi s as»
`sompssitisn mslt is ssidsnt in the DSC curves shown in “figure 5‘.
`The thermal snslwissl mammal used ts detect tbs existence and stability
`0f sslvstsd drug; mslsculss is called thsrmsgmvimstrés analysis (TGA).
`In
`this tsshniqus rslstiss weight loss is studies between the ssmglls and s refers
`encs during the heating cycle, The reference chosen is ans knswn mat ts
`undsrgs Weight lsss sever the tsmgsraturs rsngs dssirsd. Weight less can
`seam as s result sf the lsss sf sample surfscs msisturs or by mslssslss dsssl»
`vstisr: er fisssmpssitisn.‘ Combined ETA and TBA curves fsr smishstsrisin
`showing intermedists phsss transitisns (ETA) , weight less, sud dsesmsssi»
`tisn CTGA) are shown in Figure 6. An overview of thermal snaiyticsl methods
`described above is available for further inf'srmstisn [17].
`
`G. Hygroswpicity
`
`A csmpsund is hygroscopic: if it picks up s significant amount sf moisture
`under a specific conditian sf "temperature and humiciityl A high degree of
`hygrosmpieity may adversely affect the physical and chemical inrogerties of
`a drug substsnes, making it either pharmaceuticslly fiiffimfil: as unsatisfscwry
`to mark with.
`
`Hygmscspicity studies are usually carried sat aver a rssgs sf humility
`conditisns relevant ts the gensral laboratory snfi manmfseturing areas as well
`as unasstmllsd stsrsgs snsimnmsm‘ A law-humidity csnfiitiorz can he uses
`
`AstraZeneca Exhibit 2103 p. 12
`
`

`

`120
`
`Morale and Aghorkcr
`
`
`
`Figure 2 Microscopic examination of an experimental drug. Views thrOugh
`an optical microscope (a) and a scanning electron microscope (b) at various
`stage angles as noted.
`(Courtesy of E. B. Vadas, Merck Frosst Canada. Inc. .
`Pointe Claire-Dowel, Quebec, Canada.)
`
`to determine whether a hydrate will lose water under such storage. Saturated
`solutions of certain salts stored in sealed containers , such as desiccators,
`
`are used to establish well- defined humidity conditions; examples are shown
`in Table 2.
`
`To carry out a study. samples of compound are accurately weighed into
`tared containers and placed at various humidity conditions for periods up to
`2 Weeks. Weight gain or loss is measured at predetermined intervals until
`equilibrium is reached. An assessment is made regarding the relative weight
`gain as well as color and general flowability. Chemical analysis is often per-
`formed shOuld physical change indicate possible chemical degradation. A hy-
`groscopicity classification is shown in Table 3. Thus from hygroscopicity
`studies the investigator can determine environmental humidity conditions neces-
`sary to maintain initial properties.
`If the drug is very hygroscopic or deter-
`mined tc be unstable in the presence of moisture, the drug would have to be
`stored under dry conditions and worked with under low humidity. Close ex-
`amination of the quantity of moisture gained during these experiments is imr
`portant in determining whether hydrate formation is occurring.
`
`AstraZencca Exhibit 2103 p. 13
`
`

`

`
`
`Figure 2
`
`(continued)
`
`121
`
`AstraZeneca Exhibit 2103 p. 14
`
`

`

`I22
`
`MGtQIfiI and Agrharkar
`
`{Him«a.
`
`Ha com ~— cmcag
`”
`Emma
`
`a mcas
`
`14
`
`
`
`HC- my:
`IE
`Hewcogfi
`
`4—130
`
`WMMMWMWW
`SQ
`1‘5
`It?)
`125
`150
`175
`EEG
`225
`a
`
`C
`
`Figure 3 Structure and differential thermal analysis scan of ergonawine maleata
`with tiecumpusitiun {USP reférence standard, lat L).
`(Fr-mm Ref. 13.)
`
`E.”
`
`0‘23”“
`NH
`
`m
`
`is:
`i
`
`k;
`
`g E;
`
`Figure- fl Structurg and differential then-mm analysia scan of ketamine.
`Ref. 14.)
`
`(Pram
`
`AstraZeneca Exhibit 2103 11 15
`
`

`

`Prefarmulatien Research
`
`123
`
`magma,
`0
`
`0
`
`NH?
`
`NH?
`
`/§Z;§/NH:2
`
`H0
`
`0
`
`0
`
`TEMPERATURE
`
`
`
`
`
`ENDOTHERM._A—a-EXOTHERM
`
`U
`
`100
`
`200
`
`300
`
`400
`
`TEMPERATURE, DC
`
`Figure 5 Structure and differential scanning calorimetry scan 0f gentamicin
`sulfate (USP reference standard).
`(From Ref. 15.)
`
`maul/“sec
`
`
`
`tom/z
`
`---I—--
`
`'
`
`I
`210
`
`90%
`
`TGA
`
`0
`
`AMPHQTERICtN B
`
`d0
`
`80
`
`3 20
`
`160
`
`203
`
`240
`
`280
`
`TEMPERATURE -.
`
`“C
`
`Figure 5 Structure, differential thermal analysis, and thermegrevimetrie fine}
`ysis scan of amphotericin 13.
`(From Ref. 16.)
`
`AstraZeneca Exhibit 2103 p. 16
`
`

`

`1 24
`
`Mo tote and A gh crkcr
`
`Table 2 Saturated Salt Solutions for Humidity Control
`
`Percent relative
`Temperature
`
`humidity
`(00)
`
`Potassium acetate, K02H302
`
`Calcium chloride, CsClz-GHZO
`Potassium thiocyenete, KSCN
`
`Sodium nitrite, NeN02
`
`Sodium acetate, Ne02H302-3H20
`
`20
`
`31
`47
`
`56
`
`76
`
`20
`
`24,5
`20
`
`20
`
`20
`
`
`
`90Zinc sulfate, AnSOét'YHZO 20
`
`
`
`Source: Ref. 18.
`
`H . Absorbence Spectra
`
`Molecules with structural unseturation are able to absorb light within a spe~
`cific frequency range. As mentioned previously, the degree of unsaturation
`coupled with the presence of chrcmophores will influence the extent of absorp-
`tion and whether ultraviolet (409-190 nm) or visible (800400 nm) light will
`be absorbed. The ultraviolet and Visible spectre of compounds in soiution
`are not highly specific; however, they are very suitable for quantitative ans“
`lyticsl work and serve as additional information for compound identification.
`The ultraviolet or visible spectrum can be determined by placing approximate-
`ly a 10 to 20 pg ml“1 solution of the compound in a 1 cm cell, and recording
`the spectrum versus the appropriate solvent blank in the spectral range 190
`to 800 nm. An example of the ultraviolet spectrum of chlorothiazide is shown
`in Figure 7. Absorbsnce maxima are evident at 228, 292, and 31!] nm.
`
`Table 3 Hygroscopicity Classification
`
`Class ImNonhygroscopic: Essentially no moisture increases occur at relative
`humidities below 90%. Furthermore, the increase in moisture content after
`storage for 1 week above 90% relative humidity (RH) is less than 20%.
`
`Class IIwSltghtly hygroscopic: Essentially no moisture increases occur at
`relative humidities below 80%. The increase in moisture content after storage
`for 1 week above 80% RH is less than 40%.
`
`Class Iilwlltodcrctely hygroscopic: Moisture content does not increase above
`5% after storage at relative humidities below 60%. The increase in moisture
`content after storage for 1 week above 80% RH is less than 50%.
`
`Class I V-nVer-y hygroscopic: Moisture increase may occur at relative humidi—
`ties as low as 40 to 50“. The increase in moisture content after storage for
`1 week above 90% RH may exceed 30%.
`
`Source: Ref. 1 9.
`
`AstraZeneca Exhibit 2103 p. 17
`
`

`

`Prefermulatian Research
`
`125
`
`AESGRBANCE
`
`
`
`11.0%»W
`
`2213
`
`260
`
`3013
`
`3613
`
`
`WAVE LENGTH. nr‘
`
`Figure 3' Structure anéi ultravialet abswrbance spectrum 01’ chlmwthazifle.
`{Frfim Ref. 21.}
`
`Relatianghipa used ta 23:21pr and quantitate wtraviciet and visible atr-
`scarbance GEE campounda in salutiun are Shfl’efii‘fl in Equatimns (2) and (3).
`
`- A
`a"
`
`A
`“a“;
`
`(2)
`
`(33‘
`
`In Equatian (2) , the quantity a, {23133:} absorptivity, is related ta the absorp-
`tian :3? a comyguné mt“ cementraiiun '2 (in gflfim} m1} thmugh a sample cell «:yf
`13 centimeters and thus has the unitg 11mm per grmnmentimeter. When the
`concentration is expresseci in males par liter. the abaurptivity bewmes malar
`ahaarptivity a, and is expressed in Eaters per mania aantimeter.
`F011
`"Bath values shmuld be recerded “far aach galvanic saystem 0f interest.
`quantitative use, either a or a is determined. Far 3 mmpoumi in aolutinn the
`malar mneentrafion :31? an unknszzwn quantity {3f the same drug can be detew
`minacfl by knawing the abgarbanca at the: wavelength arm} the can path iength.
`Rearranging Equatinn (3) yields Equation (Mm
`
`“é.
`cwba
`
`(£3)
`
`The infrareé (IR) apeetrum {run between 2.5 mm: 15 um) is highly specific
`for each chemical structure, with 3mm} structural differences rasuifing in
`significant spectral changes. Sampms can he greparefi as a saluting, as a
`disparsion in mineral {3i} (Nujol mull) , or as a pmassium bmmicie (KEI') penet.
`
`AstraZeneca Exhibit 2103 13* 18
`
`

`

`128
`
`Mama (ma? Aghm‘kflr
`
`2.5
`
`3.633
`
`M}
`
`5.8
`
`6.8
`
`7.8
`
`8.5! 3.310
`
`12
`
`14
`
`micmns
`
`Transmittance
`
`
`
`Sf}
`
`{'50
`
`4G
`
`2‘3
`
`U
`
`N a
`H u
`3 KEY]
`S
`
`NflfiH;
`N
`H
`G
`
`(3
`
`5
`
`N
`
`x’
`
`0
`3!
`CHQQCCHE‘
`
`($93943
`
`
`
`.5;
`
`‘3
`
`‘3
`
`h
`
`4000
`
`3535}
`
`3:390
`
`2538
`
`2QQ€3
`
`1800
`
`160C]!
`
`IQIQ 1280 W300
`
`8&8 359
`
`Wavenumber tom")
`
`Figure 8 Structure and infrared Spactrum {3f cefmaxime in K131“ with peaks 31‘
`several functianal groups identified.
`(Adapted fruit“: Ref. 22.)
`
`afzer “gunning a spactrum § significant 1:33am; relating ta maxim functiansa; (gr-01.1138
`are identified; sgaetra of subsequent samples 01‘ the same campaund are com“
`parefl with the Griginal.
`If IR spectra] differences are fauna. the reamn far
`and games: cf“ change shmfld be investigatad. This technique is used t0 de~
`tact batch-tumbatch variatiens. as an identity test , and fur the detection 0?
`poiymsrphs and. sulvates. KEI‘ and Nujal mull spectra cf cefmtaximg acid am
`Shawn in Figures 8 and 9. respectively. Peaks carrespaflding m variants fume“
`tienal grouys are iaentified by 1612mm gas—j an the KBr spectrum with assigned
`fraqueneies listeii in Table 61.
`
`I. Selubiiity
`
`Saiubility is 531‘ prime imyartance far develuping saiutians that can be injecteci
`either mmavenausly 0r intramuscularly In ganeral, soiuhility is a functian
`of chemical structure; saitg of acids m bases mpresent the class D? drugs
`having {he best chance 01‘ attaining the fiegree: 9f water aalubifity desired.
`Other campvunfi classes, either neutral maleeuies {arr very weak acid and bases
`which cannot be“: solubifised in wamr within the desimd pH range, may require
`the use of nenaquemus sulvents. A list 13f 31m}; saivems used far aniumlity
`studies as well as eventual use in §mdmts is shown in Table 5.
`
`Salubilfty Measurement
`
`The analytical methad usafi in thaining‘ smiubility measurements may vary
`according to th@ drug moiety.
`If the drug¥g structure has unsaturatei cgnjw
`gamma enabling it tr: absmrb visible 01* ultravimei fight, spectmphatametric
`analysis can be gerfarmem A predaterminad exnass af drug: ES planed inm
`suitable ampuls {or flasks) cmntaining a smafl volume {3—5 m2) for each saslvent
`
`AstraZeneca Exhibit 2103 11 19
`
`

`

`microns
`
`1
`
`6.0
`7““
`
`7.0
`1
`
`8.0 9.010
`‘1“"1'7
`
`12
`
`14
`
`2.5
`100
`
`3.0
`
`4.0
`-r-—-
`
`5.0
`“1—“
`
`
`
`Transmittance
`
`4000
`
`3500
`
`3000
`
`2500
`
`2000 1000
`
`1600
`
`1400
`
`1200
`
`1000
`
`800 650
`
`Wavenumber (cm“)
`
`Figure 9
`22.)
`
`Infrared spectrum 0f eefotaxime in Nujol mull.
`
`(Adapted from Ref.
`
`Table 1} Infrared Frequency Assignments for Cefotaxime
`
` Frequency (cm'l)
`
`Assignment
`
`0
`
`b
`c
`
`d
`
`0
`
`f
`
`g
`
`11
`i
`
`j
`
`3420
`
`wNHZ
`
`3340 (broad)
`
`—NH, —NI—I2
`
`2940
`1760
`
`1730
`
`1650
`
`1620
`
`1540
`
`“SHOE-12
`—C=O lactam
`
`0
`
`"CEO carboxylie, OwngHB
`
`O
`
`—P3--NH2
`
`O
`—ngH, owN—, "Crac—
`0
`—g—-N—
`
`13851355
`1180
`
`—O-C0-—CH3
`0:0 in ester
`
`CwO stretching
`1050
`
`Adapted from Ref. 22.
`
`127
`
`AstraZeneca Exhibit 2103 p. 20
`
`

`

`128
`
`Mamie and Agharkm
`
`Table 5 Examples {If Nanaqumus
`vaemg Usad in the Paranttaral
`Profium Farmulafinn
`
`Polyethylene glyml 4630 and 600
`
`Pmpylene glyccll
`
`Glycerin
`
`Ethyl Bluebell
`
`Fixed ails
`
`Ethyl Gleam
`
`Benzyl henzaate
`
`Sew-ca: Ref. 20.
`
`tested. The ampuls are sealed and placed cm a suitable shakér or I‘Qtzltflr at «a
`centralled temperature {ca-g. . 25 or 3790) far several (lays ta attain equilib*
`rium. At selected time intervals samgtles are withdrawn by an appmpriate
`means (syringe, gipeth filtered thmugh a small micmmeterwsize (example,
`£3. iii-0.45 um) filtw. and analyzed far firug‘ in solutizm using the agapmpriate
`ultraviolet {it}? visible assay methodalugy. Fm: exgmmh the ahsarbance is read
`versus a salvent blank at a preéatermmea wavelangth, Uging the appropriate
`Beer‘s law reference: curve as shown in Figura If}, the cancentmtian is either
`estimatad fmm the aurve m' can be calculated using a previmusly determined
`molecular absurptivity.
`Salubility determination 13f campsuncls that dc nut absurh ultravialet or
`Visible light can he attempted by transferring ffltarad aliauot sslutiuns Cantu
`yreviausly tared Weighing gains; evaparating the acivent, and (Ewing :0 can—
`stant weight under lawdamperatum conditiens.
`Due ta limits: in the amflum of new drugs available at the first stages {If
`preformulatign studies. it is sufficient ta determine: agpmximata salubility
`values far highly scalable mmpounds.
`In such 03.338 5 minimal valume mi 3531‘!"
`cant is used and fixed amaun‘ts flf drug adcled file. , 15$} mg~1 ml 017‘ advent).
`Shauld this still yield an unsaturated salufiun, a value (fig: , 131%} will be
`
`guffieient to denote high solubility at this Stagel
`Iquilibrium solubility can ha
`determined when mare compafind is available, if imgormm fur a gaariicular
`aulvent.
`
`It is Elsa very imyortant to run smiubflity dgtarminationa at refrigeration
`temperature (2«8°C) using salvents demonstrating a high gotential far use in
`farmulation studies. Thig is dam; to establish the range sf concentration usable
`within the range 2 ta 2590 withaut risking mmmtian and crystal growth aim“
`wing stability stmfliesl
`
`pH-Smluhility meile
`
`Campaunds with either acidic er basic functianfility will Shaw differences in
`smlubility characteristias with changes in smiutinn gal-1 in accorii with their igni-
`gatinn constants. These differennas are after: large anti impartant in attaining
`
`AstraZeneca Exhibit 2103 p. 21
`
`

`

`Prefomulotion Research
`
`129
`
`1.0
`
`0.8
`
`0.6
`
`Absorbence 0.4
`
`0.2
`
`
`
`Absorbance of sample
`
`
`
`_
`
`Concentration of ssnpie
`
`
`
`0
`
`0,2
`
`8.4
`
`0.6
`
`0.8
`
`1.0
`
`Concentration
`
`Figure 10 Hypothetical Beer's law curve