Parenteral Medications
`VOIIIIIIB 1
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. liebennnn, and lean luthmun
`
`
`
`E3
`
`:3"
`_E_E
`9
`'5
`:1I:
`a;u
`I:
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`E2
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`
`
`
`Time ihOurs]
`
`InnoPharma Exhibit 1018.0001
`
`

`

`Pharmaceutical
`”05390 Forms:
`
`Parenteral MEIIiBflliOIIS
`"IIIIIIIIB 1
`Second Edition, Revised and Expanded
`
`Edited by
`
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. liebermnn
`
`RH. Lieberman Associates, inc.
`Consultant Services
`
`Livingston, New Jersey
`
`leon lnrhmnn
`
`Lachman Consuitant Services
`
`Weather}; New York
`
`Marcel Dekker, Inc.
`
`New York 0 Base! 0 Hong Kong
`
`lnnoPharma Exhibit 1018.0002
`
`

`

`Library cf Cangress Cataloging « in~ Pubiicatmn Bata
`
`F‘harmaceufifzal $0ng faring , parenteral mediestmna I awaited by
`Kenneth E Afia. flerhert A. Liebarman, and Lean Lamhmzm. N am: ed. ,
`rev. and, expandeé.
`.
`can
`.Imféufies hiblmgraphigal rafamnces and index
`ISBN n-«azwsmwz (v: 1 : am. paper)
`1. Paranteral aaiutimns. 2. Pharmaceutical tachnaiogy,
`Kenneth E.
`1L Reberman, Earhart A.
`El. Lauhman; Laen.
`
`I‘ Avm,
`
`[BNLMz L Infusians. Farentaral.
`WB 354 P5363
`33231.193wés 1992
`615‘.
`lQHdQED
`mm mm
`
`far mhrary of Cungreas
`
`2. Technolagy. Pharmaceutical;
`
`BL « 33953
`(31?
`
`This back is printed on acid«free paper.
`
`Capyright @3 1992 fly MARC! BERKER. INC. All Rights Ream-veg!
`
`Neither this book 11:}: any part may be tepmfiaced m- ummified in my form
`:1: by my mama. alumna m machaniaal, handing phntacepying, micm
`filming, and regarding, m by any infermatian smmga and minim-{a} system,
`without parmisgisn in writing fmm the puhiisher‘
`
`MARCEL DEKKER, INC.
`2713 Martian-:11 Avenue, New ”Yen-1:, New Ymk {“165
`
`Current printing {last digit}:
`10 9 8 7 6 5 4 3 2 I
`
`PRINTEB IN THE UNITED STATES OF AMERICA
`
`InnoPharma Exhibit 1018.0003
`
`

`

`Cmfiemts
`
`Prgfaee-
`Cantribfimrs
`
`Gflntants in? ilharmaeeutinai Basage Fflma: Parenteral Madicatiana,
`Salami Efiitim, Rafigeé anti Expandeti, “5301115435 2 and 3
`Cements GI Iflmrmacemical Engage Farms: Tablets, 86mm} Efliiion,
`Revised and Expanrieci? Vommes b3
`Centants {sf Pharmaceutmai Dosage Farms:
`Iisperse Systems.
`VnXumes 1 anti 2
`
`Chapter 1
`
`The Parenteral Baggage I’m-m and. Its Histmical Develepment
`Kenneth E. Avis
`
`1. Tha Dasage Farm
`11. HiSmry of Parenteral Medicatians
`Agpenéix A:
`filassary of ”farms
`Appendix B: Highligms in {he Emma-3y 0f
`Parenteral Medications
`Raferenmas
`
`Chapter 2
`
`33:11:33, Pmcautmns:
`Parentami Drug Adminiatratim;
`Problems, Sampliczaiinnm and flmg Salivary Sysiams
`
`Richarfl J. mama, Minimal J. Akerg, and
`Salvatore J. Turco
`
`Immdmfiion
`I. Genera: intiirzatinns for {flarenteral
`
`II .
`
`gagiministration nf ffimgs
`Pharmaceutical Faemrs Affecting Parenteral
`Administration
`
`Specific Rmtes :33? exaministrmicm
`111,
`IV , Bismihutian mi Parenterafiy Administer—«sci Agents
`
`iii
`xi
`
`XV
`
`xvii
`
`gap—-
`
`111
`15
`
`1’?
`
`1.7
`
`18
`
`19
`31
`39
`
`InnoPharma Exhibit 1018.0004
`
`

`

`viii
`
`(Immune
`
`V.
`
`Preeamimnsg thtams. Hazards, and
`
`Campiimzfisn$ Asammmd with Parenterm Drug
`ékdministratifln
`
`V’L
`VII‘
`
`{5533;170:155 and Devicaes For Urug Deiivsary Systrms
`Summary
`Refer-anew
`
`anagram 3 Biggharmaceuticfi (:2! Injectfame Medicationfl
`
`SQ! Mmgia
`
`’I.
`
`II.
`
`Introdnation
`
`Phyaimchssmma} and Physiezrmgicm Emmra
`Affecting 125mg: Abmrptmn by lnjmtion: An
`Qvarfiem
`
`In.
`
`apwieafim {1f Pharmacnkmmms m fiiuphamm
`mum: Immatigatitms: Pharmamkmetic Mariam
`IV. Exampies 13f Binphamnaeemiiz Immrmacnkinetie
`Frincipma
`V. Reguiamry Cansifieratims; for Bimquimlenne
`Sindias
`
`VI. Eiaaquivaiema Study m? Tim Injecta‘ble Forms
`af the Same 33mg:
`Summary
`Referenceg
`
`VII.
`
`Chagatar 4
`
`Prefmmukmmn Rasearch 0f @arantéral Evfiufiicmians
`
`$9! Mawla arm? Shmer‘am N. Aghmrkfir
`
`l.
`
`{ntmdueiim
`
`11. Drug Subatanm ‘Physimahamiaal Fmpefiies
`my Ameleratati Siahiiity Evalnaiien
`IV. General Macias 43f 13mg Degradmmn
`V. menrmulatim Stuaiea fnr Framing and Paptifies
`VI‘ Prafarmulatian Sareening 3f Pammaml
`Eackaging {Emmpnnmm
`Summary
`Prefflrmuiatmn erks’imm
`Rafarenms
`
`V11 .
`VIII .
`
`Chaptgar 5 Fomuiatign a? Small Valuing Farmtmaig
`
`Patrick F.
`
`leLucrg and Jamw C. Eoyran
`
`I .
`
`intmfiummn
`
`Parmnlmian Pm‘ncfiglas
`11.
`HI. Container Effems on Ie‘mmulmian
`
`IV. Etahiiity Evaiummn
`V.
`Process Effects.
`Rfiafaranms
`
`s31
`
`9%
`5E
`5?
`
`59
`
`59
`
`60
`
`1'?
`
`138
`
`19%
`
`[89
`111
`112
`
`115
`
`.115
`
`11%
`1%9
`"15%)
`15%
`
`15%
`163
`153
`169
`
`1‘33
`
`1'13
`
`1%
`22?
`
`23%
`2%
`245
`
`InnoPharma Exhibit 1018.0005
`
`

`

`Cuntents
`
`1'39
`
`Chapter 6
`
`Formulatien “of Large Volume 'Parenterals
`
`Levitl. Demomst and Jeffrey G. Hamilton
`
`Introduction ,
`1.
`II, Concepts of Formulation
`III.
`Formulation Development
`IV.
`Solutie'n Quality
`‘
`V.
`Summary
`References
`
`Chapter 7
`
`Parenteral Products of Peptides and Proteins
`
`Ymahang John wang
`
`I .
`
`‘ Introduction
`
`11. Charaeteristics of Proteins and Peptides
`III.
`Fayrmulatian Principles
`IV]. Campatibflity with Packaging Comp-wants and
`Infusian Sets
`Formulatien of Market Products
`
`V.
`
`Referénces
`
`Chapter 8
`
`Sterile Diagnostics
`
`,, Leif EQ Oisenx
`I.
`:Introduction
`
`II. Diagnostic Products Defined
`III .
`Stet-fie Diagnostics
`IV‘ Defirfitions \
`V. Asaptic Manufacturing Consideratibn’s
`VI.
`'Val‘idatien 'P re gram
`VII. Conclusion-
`References
`
`Chapter 9
`
`Glass _ Containers for Par-enterais
`
`R. Pam! A‘b'endroth and RObeH N. Clark
`
`__Intr0du«ction
`L.
`II. The Nature of Glass
`111. United States Pharmacoypeia Glassware
`Classification-s
`IV . The Manufacture of Glass Containers
`V. Chemical Perfarmance
`VI . Mechanical, Performance
`
`VII. The Cbntainerand Closure as a System
`VII}. Quaiity Assurance
`References
`
`249
`
`249
`250
`Z? 3
`280
`
`291
`281
`
`283
`
`283
`
`284
`3-02
`
`310
`312.
`317
`
`321.
`
`321
`321
`322
`325
`330
`351
`«359
`359
`
`.331
`
`7361
`3&1
`
`362'
`369
`375
`380
`
`380-
`382'
`384
`
`InnoPharma Exhibit 1018.0006
`
`

`

`x
`
`Conten ts
`
`Chaptiar 10 Use 9f Plaatics for Parentaral Elan-Raging
`
`John M. Aries. Rabar‘t S. Name, and
`Charles H. Whim
`
`Introductinn
`I .
`Fundamentals
`II .
`III. Fahricafinn i’rmesses
`
`Impar‘tam Criteria for Selectian m? Flaatics
`IV.
`V. wasting 1339:} in Parenteral Packaging
`V1, Quality assurance 4:)? Parenteral Cnntainers
`Refarencas
`
`Chapter 11 Eiastemeric Clgsures far Parenterals
`
`Phi-ward J. Smith and Rmbart J; Nam:
`
`I. Elasmmeric Faraflmral Paelmging Ccm§onamm
`A Flzysieai Bescripfion
`Physinai Bescripticm of Rubber
`11.
`III. Typeg {1f Rubhar 13990 in Paranteral Packaging
`1V3 Clnsum Dgsign
`V. Rubber Camgmmding
`VL
`chanizatim: 13326122333
`VII,
`(313mm Manufacmm and Cantml
`
`{fissure Design Qualificmmn
`V111
`IX. Eeguiamry’ Canaicieratimns
`X , mmmcfinn of Drug meulatinns with
`Rubble? Emaurea
`
`XI. Gantempnrary Clnsurvflelamci Issues
`References
`
`Chapter 12 Paranteral Products: in Haspital {and Home Care
`Pharmacy Practica
`
`John "W. Levchuk
`
`1 fl
`
`Immductian
`
`11‘ The Pregaration af‘ Sterile} Damage Forms in the
`Haspim} 9106 in Hams Exam
`III. Dispensing and Compaunfiing Prmesses
`IV. Technomgy at“ Stefim Campaumfing in the
`floggital Pimrmacy
`{:11an Supply and rise cf Stews: Pmdueta
`V .
`VI. Quality Afisumnce
`VII .
`(33119111332911
`
`Appendix; Abbreviated Sequence far Pregaring a
`Series at? Extemporammusly Compannded IN.
`admixtures
`Rafa-ences
`
`Indax
`
`387
`
`38?
`. 389
`308
`
`407
`£3522
`£130
`443
`
`4435
`
`4:15
`450
`451
`462
`453
`£5.10
`$7?
`
`494
`503
`
`505
`
`50'?
`508
`
`513
`
`513
`
`513
`5241
`
`532
`5%?
`552
`5%
`
`56 3
`566
`
`5% 9
`
`InnoPharma Exhibit 1018.0007
`
`

`

`Fowmulelle of Small
`
`E
`..
`Imee
`
`
`
`l'aelreeatme
`
`Patrick P. fileLuca
`
`University of Kentucky Callege of Pharmacy, Lexingmn, Kentucky
`
`James C. Eeylen
`
`ebbett Lnbmatm‘fes. Abbefi Fer-k. Illineie
`
`I.
`
`INTROQUCTION
`
`”Whereas a parenteral can be clefinerl as e sterile firing, eelutiom ear euepeneien
`that is packaged in a manner suitable for: administration by hypodermic: infiee
`lien, either in the farm preeerecl er fellewing the eedition of a euitehle eelw
`em er suspending agent [1} . the term email velume perememl (S???) has been
`effieielly defined by the United Statee Phermeeepeie (i331?) {21 ee ".
`.
`. en
`injeetmn that is packaged in eemeinere labeled as cementing 12m ml or leee."
`The {35513 eategefizes eterile preparefiene for parenteral use eemrfiing re the
`phyeieel etete of the preduet ae fellewre;
`
`1. Selafiem e1- emuleieee ei medieemente suitable fer injeetien
`2. Dry solids er liquid eeneenteetee eonteining he additives wlfieh, upon
`the edditien of euitahle eemen’te yielci eelutiene eoni‘erming in all
`reepeete to requiremente fer infieefiene
`3, Peeperetmne the eeme ee eeeefibed in eleee 2 he: centaining (me er
`more eflditienel euheteneee
`
`4. Seepeneiene of senile in a suitable meéimn which are not be be injected
`intravenously or irate the epinel eolumn
`firs; eelide which, new we edditien of eniteeie Vehicles, become
`sterile euepeneione
`
`5.
`
`filtheugh the term sterile pharmeeemieele is epplieehle m an injeetiene (realm
`phemeeeutieele inelufiecl} , egmheimie preparetiene, enfi irrigating eeletiene,
`this chapter empheefiees the farmuletien ef injecteble deeege forms.
`The eueeeeeiul fermuletien of an inimitable preparetlen requires e tamed
`knewleaige of ellyeieel, chemical, eml biological principles ee well ee expertise
`in the epyfieetien at these erineiplee. Such knowledge and expertiee are re
`quired te effeet netienel fieeieiene regerfiing the selection Elf:
`(1} e suitable
`
`17"3
`
`InnoPharma Exhibit 1018.0008
`
`

`

`N4
`
`IeLuce anti Ieylen
`
`vehicle tequeoee, neztequeous, er easement); (2} eeeee euhs'taneee {ante
`mierebiefi agents, entiexiéeme. buffer-e. eheieting egente! and tenieity com
`tributom}: end (3) the eppmpriete eentainer and centeiner components. 1m
`here-sit in the ebeee deeieiene is the ehiigetery eetieern fer pmfiuet safety.
`effeetivenese. stability. and reliability. This chapter feeeeee en the physical-
`chemieal eepeete ef preparing a stable precinct in a euiteble mnteiner teenage
`nizitig that safety must he eeteb‘iiehecfil thmugh evaluation of toxicity, tissue
`tolerance, pyregenicity, eiex’ifityt emi temeity. anti efficacy muet he demam
`sire-ten} through mntmiied» clinical ineeetigetiene.
`The majority ei parenteral pmdnete are aqueous eeiutiene, preferred bee
`eeuee of their phyeielegie compatibility em} versatility with regard te mute
`ef admirfietretion. However; eeeelvente or nenequeoue eubeteneee are after:
`tequired te effeet eeltttien or etehiiity, Furthermem. the desired prepertiee
`are sometimes attained threugh the nee :3? e euepeneien or an emuleitm. A1-
`theugh each 0? theee deeege farms: have dietineiive chereeteflsfics and fermw
`latter: requiremente. certain phyeieaiwehemieel Qi‘ineiplee ere eemmmi. These
`eemmen principles will be fiiemeeefi in a genera: manner and the differences
`distinctive of each system win he empheeieetit
`it is imeerteet te recognize
`that the gharmeeeutieel terminate defiveti from bieteehneiegy ere on the ire
`ereeee anti the fei‘muietien m" theee predtmte requires eeme animus: skills emit
`navel appreeeiiee. An attempt will be made to cover same of the formulation
`eppreeei‘xee fer metering anti peptidee.
`
`
`It. FORMULATION PRINCIPLES
`
`A.
`
`influence 5f the R23th 0f fidministration
`
`Since parenteral preparetiene ere intredueeti direetiy iete the Entree my extre
`eeiiuier fluid tempertmente. the lymphatic system. or the bloom the nature
`015‘ the product anti titre desired pliermeeemtgieel eetien are teeters tietermining;
`the particuier route at“ administrefien te be emgteyed. The deeirefi mute 0f
`administration. in turn. pieces certain requimmente and iimitetinns 0n the
`fermuietions as well as the fievieee used for adminietefing the damage farms.
`Ceneequently, a variety ef routes; ef administration {eee Ghats, 2) are cur
`rent}? ueeti fer parenterei pron-insist
`fine at the meet important mneideretiene in fermelating e parenteral prom
`uet ie the epprepriete velume inte which the £1ng shame he incerpereted.
`The intravenous mute is the only route by trifle}: large volumes (Len. greater
`that; 1!} m1} cert be administered, eithmigh the rate at adminietretien must be
`eerefuily eeetrolled. Volumes up te 10 mi can he etiministered intreepineny,
`white the iniremueemer mute ie nermeily limited to 3 m1, eubeutenenue m 2
`m1 anti intrefiermal te fi.2 ml.
`
`The cheiee cf the eehrent Bystem er vehicle its directiy related to the 2211-»
`temieti mute of efiminietretinn of the predtmt.
`intravenous and intreepinel
`injectiene are generally reetrieteti ’te tiiiute at; itemize eolutiene, winereae :3in
`mlutiens, memivent eolutiene, eeepensiene, and emuieimze can be injected
`Intramuscular-1y anti euhmteneeuely.
`Ieotenieity is another factor that tenet be taken intt; eeneitieretieni AI-
`theugh ientnnic eeiut'iena are ieee irritating, nausea Ease infinity and eliminate
`the eeeeihility {if namelyeie! it ie not eeeeniiel that an injectiene he ientenie.
`In feet, for euheeteneeue end intremueenier injectiene hypertenie eelutiene
`
`InnoPharma Exhibit 1018.0009
`
`

`

`Fermuletien ef Small Vetume @arentemls
`
`175
`
`are often need he feeflitete etaeueptiee ref erug due in Ieeel effueien of tieeue
`fluids. With intraveneue eelutieee ieetenieity heeemee fiveee impertent as long
`as administration ie slew eneegh “to permit fiflutiflfl or ediuetment in the bleed-
`Hewever, inteeepinel irxjeetiene must be ieetenic because 01’ ewe; circulation
`ef the eerebmepfinal “fluid in which eerupt changes ef earn-stirs: pressure ear:
`gi‘ee rise to eeveee side effeete.
`New estates of efimimeteetien include inteeertieuiere directly into the 33mm
`vial fluid for rheemeteidel dieeeeee em: even intreeigitel; between the finger-eg
`in Greer t0 better :erget the lymphatic-e. The eeeenterel remee of admire?
`teatime wilt influence the design (if navel {image farms and fleug fleh‘eery eyee
`teme especially ee mere patent agents from bieteehnelegy ere develepefl.
`
`I. Seiection ef the Vehicie
`
`{3hemiaeedrya the high dielee~
`Meet peeenteeee preduete ere aqueous eeletiene.
`trie eenetent ef water makes it peeeible m dissolve innieahle electrelytee and
`tie hydmgenebending patential facilitates the seletien ef elmhmle, aldehyéee,
`Remneeg ene emineet Water fer Injectiem {3813, ie the eeixrent er“ eheiee fer
`making perentereis.
`It must he prepared feeeh by fiietifletien at by rave-rec
`oemeeie emf! eentein tee exit-def} substance. When it is net peeeible to use a
`when}; equeeue eelutien fer ehye’ieai er ehemieel reeeene, the edditien Of
`eeiuhfliemg ageme or easements may be neeeeeex‘yt Fer inetenee, nemeeler
`eubeteneee Cine, , alkaloids} bases} peeeeee limited solubility in water and it
`is neeeeeery to mid e eeeeivem eeeh ee glycerin, emanate, prepylene glyeel
`or pefiyethjelene glyeele
`In other eeeee, to prevent chemical eegredatien {Lee ,
`hyfiml'yeie, exidetiom fiecerbexyletian, m: reeemieetiun) water may have to
`be eliminatee peetiefly er tetafly, Meet proteins and peetieee remfire an
`equeeue environment, amt the efiflitien ef salt, buffer, er other eeditieee fee
`seluhility purpneee eften leads to eenfermet‘ienal changes- Ceneequently,
`perenterel precinct feemulemre ehee‘ld be aware 01? net: only the nature 231’ "the
`eeleem ens? salute in paeenteeeie but eleo the eelvenb salute intereetiene and
`the route ef edminfietretien
`
`Selubility and Seiubitizetian
`
`The solubility of e embetenee at e given temperetuee ie flefined quantitatively
`ee the eeeeentretien of the dieeoierefl salute in a saturated eelutimt (Le. ., the
`diesehrefl eeiute pheee}. Generally, {huge ere geeeem in eeluticm et unsatu-
`rated er eebeetureted eaneentretiene; etherwiee, eweteilieetien of the ewe;
`can eeeee ee e ream}: ef ehengee in pH er temperature er by seeding from
`other ingredients er particulates in the eelutimn. Te enhance the eelubflity
`0f drags. in addition ta using (at-genie eelvente that are mieeible with water
`as: emeerieenteF other techniques can he empieyee. These imfiede eelt ferme-
`130m and pmdrege, which? altheugh capable of greetiy enhancing solubility.
`canetitute new entitiee requiring efiditionel clinical etuéieet {Ether substances
`need as eeluhilieere inemee the eurfieee-eetive and. eemplexing egente.
`Surfeeev-eetive agents. by virtue of their eeeeeietiee temieneiee in eolu-
`ticm emit the ability in mien: mm mneentreted paler and nonpeler eentere
`{mieellee3 , have been ueefi to eeluhitiee druge ene ether eubeteneee eueh ee
`eitemme, heemenee, eutfmemidee, eyee, resins. and veletiie pile. Theee
`eurfeetente ere pawerfe! wetting egente and farm eelleidal dieperstene that
`have the eppeerenee ef e true eelutien.
`
`InnoPharma Exhibit 1018.0010
`
`

`

`176
`
`Dance and 330116111;
`
`Ethylenechamme isresumed in 11m1110ph3r11meImectmnstomamtam the
`theoghylline in solution smce amihephylhne is a salt. that ionizes into its can“
`,stituent 10115 theophyllzneand ethylenedlamme.
`
`:Amimphyflline 1»
`
`atheophynine— +,ethy1en,aeiamin92+
`
`Ethy1ened13mme,3 strengly 3111523111113 3111351231133 is volatile and if it eseapes,
`the pH will be lewered, causing, theoglhylhhe 14:11 16 be converted t1) free their
`1111;711:1113 {pKa "u 8. 8) whmh15 01111; slightly soluble in Water (8 m 3/1111)
`
`’Theophfllihe"
`
`4,14 11+ 4?
`
`theophynine (free)
`
`Creatinine, niacinamide, and 19231111;have beenusedfor solublhzmg steroids
`infile free 3113017101farm. The 1159 0f the Shit Or 93th of these stermds 01'
`Vitamins eliminates the need t0 use eemhflizere but requiree etheradditives
`te ensure stabmty.
`10211111313111: 3319311113 the best solvent 01- egeht te evercomé dlfflculhes that
`arise inthe preparetien of pharmaceutical dosageforms centaining pearly
`soluble druga With parenterals, the drug 31111 Other dissolved subetances
`311011161 remain 50111111112113 thruughout the shelfdife of thepmduct.
`
`Soiubiltty Expressiens. Saiuhihty 0111substance can he expressed in a
`number (if Ways Generany, the wheentration is expressed as percent: (w Iv) ,_
`that 15, grams per 1118 m1 of 51311111311 but 1113131113 and 11101121113;have 133311
`'
`used [11913th is defined as the number of melee per 1008 m1 of solution.
`,Mdlality is the number of 11131313 of salute per 111% g0f sol-113111 end therefere,
`being ”a weightrelationship, is mt mflueneed bytemperature. The USP lists
`I'selubzlity 111 terms at the number of milliliters hf solvent required to hisselve
`1 g 01‘Substance. If exact soluhflitiesare net knew-11 the USP 1311111111133 gen“
`6131 terms 19 (1331111113 3 given range These deseriptire tern-133113 heted 111
`Table 1
`
`Table!- 1 EXprassions fer Approximate Solubility:
`
`Solvent to dissolve
` Temp 1 part; of salute
`
`
`Relative amount at
`
`Very "301111119
`Freely 3011111113
`8111111119.
`
`:Sparingly- 3111111316:
`
`Slightly 301111112
`
`1
`
`L
`
`L
`
`V L
`
`L
`
`1
`
`<1
`19111
`10— 30
`
`310411.01
`
`1131]? 11100
`
`vary 31193111137 soluble
`
`
`10:30 11,101
`Prectic3l‘lyinsoluble or 1115011113113 >111;,GU{}
`
`InnoPharma Exhibit 1018.0011
`
`

`

`Fammtufmn 13f Smrm Vatume vantm'ais
`
`1??
`
`3513111on for dgtermming the anluhfliiy af drug sub“
`Measuring Solubiiity.
`magma in varians golvents have been described {3.81. The ghase mlubizity
`taflhmque is eggeeiafly applicable to datarmining “the 39111131131123: cf pare swam
`stances and film dfitecting the presemze of impurities [6} .
`In this meflmd,
`succegaively largar partinns 0f that submanm are afified m the same volume
`af advent in guitable containers which are agitatact at canstant temgeratures;
`generally 3!} i I}. 196.
`In £11033 cantainers in which exce3$ drug is present
`(unfligsmveflh samples mf the suparnatant am withflramz and assayed until
`the concentratmn is constant {idih , the ayatem has mashed equilibrium). PM
`a pure campannd, a phase sambility diagram is cana‘tructefi 33 flown in Fig
`um 13‘ The gambifity is reacting fietaminafi by extrapmafing tha line with
`a 31mm nf mm to the y axiai.
`If an impurity axiats in aha substance, 3:: 931389:
`sulubifity éiggram as shawn in Figure 11:; resulta. which shows an infiectim
`in the ascenfii‘ng line? Extragalatian cf the harimnml line gives the aoluhib
`it}; Bf the substance £311.13 me impurity {3f the substance an the ram-s, while
`estrapalatinn sf thc asmnfling line gima the aolubility cf the impurity.
`
`Bnnfiing Forces. For a substance to tiissalve. the far-mas Of attractian that
`mail the maiecuieg together must he avermme by the annivem, The miuhflity
`will he determined by the ralative binding fames within the substance; (smut?
`soiute interactmna) anal hams-en the substance and tha vehicle (snlufa~ garment
`intermions) .
`If an environment similar to that 3f the crystal structure can
`be provided by the solvent then the greater the solubility ($.22. , "like {3113*
`solves 11kg“).
`Ionic mmpaunds dismlve more readily in water by virtua of
`ion~dipola interactions, whereas hydrophmbic substances {fissahre more easily
`in organitz saivems 33 a rasult Inf dipole (31‘ indueed £1ng1%: interaetmm (van
`«tier 52433313. Eganfinn m:- Eeb‘y’e forces) *
`
`
`
`
`Undssmhw mm»?
`begins; amassing
`
`mg SOLUTEfm!
`
`fiQL‘JENT
`
` Sfliflhdiif ni :mpugiw
`mg 501.111: [mi swam
`
`Figure I Phage solubility diagrams for: a pure subgtance (a) and 3 Substance
`cantaining an imparity {13) 1k
`
`InnoPharma Exhibit 1018.0012
`
` 3mmEflflflmgfmé
`
`SULESTECGNC.mg1‘mI
`
`
`
`wwwwwwww‘
`warm” (2? gunman am: mgmag
`
`
`
`

`

`178
`
`DeLuca and [Dylan
`
`The anlubflity of the £1ng substance 13 due in large part tn the palarity
`cat“ the advent. after; axpresseci in terms turf {Sigma mnmem, which is related
`ta the fiieleetric canstant.
`31311351113 with high flielectfic mnstsnts dissmima
`imam campmnda and are water salable, whereas salvants with law fiielectrir:
`constants are mi: water gamma and d0 not disanlve ionic: mmpounds. Tm
`former are classifier} as polar mlvents (@.g. , water, {gynerim and malignant
`while the latter are amp-13m:- {eg‘ , «chm.mzpt‘ctsrmg benzene, and the oils}.
`801*
`vents with infermadiate diaiectric mnatams (tang. , acetone and hutanal) are
`classifieéi a3 semipmar. The dielectric: constants 13f mast gharmamuiiea} 331*
`vents are known nus} am} Wilma 1‘03:
`:3 number czf “binary and tertiary ”Manda
`have been rapnriefi :9} am}, if not regormfi. {3311 be maxim astimatmi {1G}.
`Table 2 is:
`{2 Eating 63f the dieiactmc anngtants (sf game: liquids; used in pharma-
`aeutical syatema;
`The gambiiity fireflies 0f 9. number {22‘ pharmaceutimm m; a function of
`tiialactr’ic (gunman: have been reparted by Parnta anti enmworkers and gathers
`{1143?} , By determning the smuhility 231’ a substance in a system at «marinas
`dielectric constants. a graph Euflh ass that shown in figure 2 can “be mnstructeé
`to detarmine the, dielectric constant that will prmflfle the required soiuhifity.
`As can be men from the mm, m abtain the maximum mneentrafion a dielec—
`tric mnstant ed" arounfl am is requireti. m1 a1: mixtures will Show a maximum;
`but such a plat illuatrates the requireci fiielectric congtant to obtain the de~
`sireri mncentratiun‘ Far example? if? a dielectric eonsmnt {chm} mi‘ 66 was
`gamma, 3 mixture {31‘ water (tide, ?B.5), polyethylene glyem (PEG) £06
`
`Tame 1 Dielectric Congtants of 51731119 Selventa an 2590
`
`301mm
`
`Water-'31
`
`Glfircering‘
`
`
`
`
`N . N~Bimethy1acetamiu ea
`
`Dielactric canatant
`
`78. 5
`
`40. 1
`
`37 . a
`
`Pmpylene glyccila
`
`32. (31 (310)
`
`3191;118:101
`
`Ethmolfi
`
`N—Pmpanal
`
`Acemne
`
`Remy! {31:363th
`
`Pglyathylene glycol 4mg
`
`Cottnnseagad 05113
`
`Benzene
`
`max {SIRE
`
`E’JLScylvrentB used in parental-.2313
`
`31 . 5
`
`24. 3
`
`20K 1
`
`19. 1
`
`1.3. I
`
`12* 5
`
`3. fl
`
`2 . 3
`
`2 , 2
`
`InnoPharma Exhibit 1018.0013
`
`

`

`meuimian of Small Valuma Parenterala
`
`179
`
`Am: Salafir‘firy
`
`f
`
`SGLUEELETY
`
`("£3 Wam M}
`
`
`m 2:3
`3:} m 3::
`5:} m
`DiELECTRtC CGNSTQN?
`
`Figure :2 Hypothetical p113: 9f salubifity mf a subatanca versus melemtric mn—
`stant in various mixtures m‘ diexane am: watexn
`
`(dun. 12.5} and ethaml (tic, 2&3) could ha use-cl. Selecting an ammmt of
`311mm: necessary m dismlve the drug (agu 18%). the percentages, sf PEG
`4m} and water can ha calculated as follows:
`
`(10) (24.3) + (X) (78.5) 4- (Qfl - X) (12.5) 3 (10%)
`
`(ED)
`
`Wham X is the gamamage mf wgier‘ requirefil and is ealeuiamd m be 73*5%.
`Thcerefnre. the vehicle it: prmflfie a fiieleetric: {213313th m“ at} will have the fab
`lowing campnsitiom
`
`Ethanol
`Pm 5m:
`
`5-123
`
`10%
`16.5%
`
`73. 5%
`
`Since fifeieflzfie censtam is a measura m“, the pelarim‘bility and dipole mn-
`mam: Df 21 campaanm several researchars hava explnmé others pammaters am}
`pniarity man-ems [18} which are included by melecular volume. salvem amt
`salute interamianm and specific interactiona mm}: as hydrogen homiing.
`Hilfiebrand and. Strait [3] intmduc-eci solnhifity parameters t0 prefiet 331w
`bfiity Bf regular salutians; Since pharmaceufiea‘l systems deviate from regular
`my ideal 801131333385 Martin anti m-wnrkem 119} madified the Hfldebrané ap~
`preach to include hydmgen- bonding and flipaiar interantians. The muieaular
`Eflrfafie area of the solute anti interfaciai tension between 5:31th and solvent
`
`were used by Amidst: {211} ami Yalkuwsky {213 to prams}: solubility. These
`apamaches ware especiafiy applicable to: sysmms in whigh the imamolgcuiar
`forces between 3011252111: and mime were different. Figure :3 shows we 501w
`biliij? as a functian 0f sobrgnt mnaemmtmm The 310m; of the fine is a measA
`ure of the activity in file semen: anti was fauna to be mlatefi m swam} param—
`eters of solubility inmuding interrfacial tensinn and hydrogen banding: [18,22] .
`fiydrogan handing, the strangest type cf dimmw {imam interactim, is
`
`characterizefi by a pmsitive center in the hydrogen awn: {prawn annex-L Be“
`cause sf its 3mm} size, mg hydrogen atom nan appmach “the negative gamer
`(electmn éonar} 3f 3 neighharmg {119312 more aim-12132 than any anther atom.
`As a result of this 51:31:13: manauvemhiiity, both intramfilecular banding Cine. .
`
`InnoPharma Exhibit 1018.0014
`
`

`

`18E?
`
`n30
`
`Debuca and; Baylan
`
`flames/l
`
`SGLUBiLITY,
`
`10$
`
`203
`
`a
`
`an
`so
`an
`m
`PROPYLENE GLYCOL. ‘3?)
`
`100
`
`Figure 3 nag-linear mluhility rezatinmhip far a series of alkyl p«aminobenm~
`ates~g3ycel~water. {me Yamowaky. S. 3. , Flynn. G.
`I... . and Amman, G.
`I“, J; Pharm. Sat. 53:933 (19%).}
`
`3“
`CafiswflmH-~~Q\
`
`H
`
`‘i‘
`{5:3
`(a
`
`Qwfi
`
`intermolecular H handbag
`
`intramalecnlar H band mg
`
`InnoPharma Exhibit 1018.0015
`
`

`

`Formulatmn cf Small VCJIILME Parenteralsx
`
`181
`
`between groups within a single maleeule) and the intermalr-zcular type (14% ,
`ammng mniatmles} can mam“. The latter is responsible for assaciatimn in mast
`saments am} dissolutim of mast druga.
`Generally, the proton is dammed by a carbaxyl, hyflmxyl, amine mt amifle
`gram}. The hydmgen fmm 8-H (31‘ {ii—*3 can alga farm hydmg‘en bnnfls, but
`generally ma bow-1:15 are weak, The meter: attached to a haiogen is: generally
`quite aative. HF farms strong hyémgen bands. Tygical eleetmn cantri‘bu»
`tar-s are. nxygen, mitmgan and balsam: 31an 333111113 in 5311213131331 gathers, alfiew
`hyclas, ketxmea, amide anti Nwhetemcyeiic campaunds. Same examples of kw
`{imam handing with water follow:
`
`3?
`*1“!
`:3
`$~~~H-~D~ «H-flv ~>~H-E€~w
`R
`H
`
`alcoml
`
`?
`*1.
`Rucaau ~HwaH“ .omm—H
`
`ketone
`
`amine
`
`Hf
`
`RanwH-flv ”NR3
`
`Aicmkmis digs-vulva in water by hydruggn bonding, up in an alkyl chain
`length of five carbon mama. Phenols diSS®1VQ in wamr and aimhol 311451, as
`the numbar 0f hydmxyl groups increaae, the water scalability is enhancad
`hacaufia m“ the itmraased apgurmnity far hyfimgen humming. Mast mamatic
`marbaxylm maids. stamifis! am} 3121?de glycoaidea are mat waiar saluble "but
`aismme in 31001101, giycerin, m glyecflg by hydmgen harming.
`Since.» the
`averali canformation nf pmtams; is most influencefi by hydrogen banding,
`waterwthe solvent 13f minim fer mam gmmms—«mmribmea m the hydmggn
`bonding and, themiare. can have a strnng influence on protein cenfarma’tim.
`13133131234031 intaractisns are respnnsible far the digsalution 9f ionic swam}!
`line snhmanaas in palar soivents {11.2. . water or 31301131}. Kong in museums
`59111111231. are generally hydratefi (fissurroumied by was? molecules) by as man};
`waiver malecxfles as can spafiaily fit meant} the ion. The attributeg @f a gmd
`when: far elemmlytes inclufia:
`(1) a highficiipola mamant; (2) a 3mm} mailer:—
`ular aim; and {3:1 a high dielemrie canstam to mange tha force {21’ attracticxn
`between the @9931to charged ions in the crystal. Water pass-{asses an of
`mesa eharacterisfim and is. tharefnra, a gem! graham far electml‘fies. The
`catian m? the electmlyte is attractefi m the negativafi oxygen atom, while the
`anion attracts the hydrogen atmma m the flipolar water molecules.
`Generally, when eiaetmlytas; dissolve in water, Thea? is generated because
`the iamciipoie inierac’tion energy exceecm the gum 9f the Stamina interacfinm
`energy of the 30mm and the fiipolwdipme interactinn enargy cf the aaivenf.
`Examples 9f 51 negative heat 9f anlutior: am anhydmua magnasium sulfate and
`sodium hydrnxide. Where the innwgiipole energy is has than the gum of the
`energias naming: the 3321.319 and solvent 123013311183 together, heat is absorbed
`fmm the anrmunfiing area tn make up far the energy fieficits Electmlytas
`shmwing a pasitive best an? salutixm inclmia patassfium inflicie and 39mm bmu
`
`InnoPharma Exhibit 1018.0016
`
`

`

`182
`
`BeLuca and Baymn
`
`with. Hyfirateé salts gamerally show a paaifiva heat of 50111121011. Citric acid,
`smrbital, am} “Laramie: have 1519331111112 heats: of aniutimn at: film during magma“
`titan the smuticn hemmera (33:31. When remnsiitziting dry pmdzmm mntajning
`huge amounts of théSQ aubstancaaa, which 13 quite mmmm in fmezewdried
`pmfimts. it is; mammary 11:} be aware: cf mm phenomenal-1 and warm the sam-
`tism grim- to injectien.
`many campiexea regult because m an iflnfii‘flduead dipole interaatian. Far
`example. incline is saluhflizeri in a amnion of pntassium iodide in the follnwing
`mannm:
`
`+~
`[£44111
`
`+-~
`+ K13
`
`Althaugh the maxim moiecule is electrically neutral, a temporary poiariiy may
`remit from aleatmnic mmements within the molecule. Such mavemams finance
`
`flipniaa in neighbnring maiemuim anti are mspmnsime for maintaining benzene
`and aarbcm tetrachloride in the 111313.11} state.
`’I‘ha imiicie mmpiex forms 12:5:-
`cause the ginseng alantrimai £13m 9f the Emmi-amiss in aoiufian induces a (31903:?
`in the palarigahle incline mommies. Benzene is; a neutral malecule that is; remb
`fly pnlafizable ma mlume in 310mm},
`Symmetrical molecules“ guch as 13311321112 and max-135m tetrachmrifia, 139331333
`3 mm dipole mamnant and are nflnyolar. Solubility of 311cm molecules or their
`existenca in a Imam state is {1116 in: van der 11123313 forces.,
`“II: 12123 manner claw
`mrihed earIier, an inductim affect scam-5 in them: electricaliy neutral male-
`mules? and the maleculas orient; ’t‘hemselves with surmnnding malecules an that
`mgative and pasitive 1303313 are tngether. Sash orientation is rafermfi w 3:3
`mamfing fmm indumd ciigmlednducgfi dipoie interammm. Theme very weak
`attraciians are sematimea called Landon fflrflES, hacmme they were: first deov
`saribac} by Lonfimn in 1931}. They are magmnsible far diasolution waif hydmphm
`hie 51113313111393 in mnpmar solvents Dag. , wax in carbqn tetrachmmcle and
`paraffin 3m petraleum bmzin}.
`1f the 3:11th and 3011:3111: in nangalar systems
`are aimflar in size aha structure. may can be mixed witham any apprmiame
`heat 9f selutien.
`1f the heat of 5911311911 is zero, the minim}: is referred to
`as an iéaa] 311110131911.
`
`Anather “£pr 0f van (ital? Waals farm is that resulting“ fmm induced dipole-
`fiipuie interactims , aim {23111213 thye interactians.
`“In this case, a dipmar
`malecule is capabia of infiuaing an eiectrical dipole in a nonpclar malecule.
`A mnlmuie that mmnatag, 52th as benmne, E331 be pnlarizefi by a ciipuiar
`31.112131;an such as methyl 313031121. ether examples; of such interaetians iii-1:111:19
`mixtures of ckdarai hyfimte in carban tatrachlmide and phenul in mineral 123:1.
`Examglsa sf :3ng marketed in watermiacible systems "31113111613 fiigitoxin,
`ghenytoin, and (11:229me T111386 injecticms are farmmmeti in a water-3133011313
`Eys‘cem cantaining glymlg and 31th} and afljua‘ted m a suitahla pH, chér
`cascalvents used in parenterals inclmie glycerin in fieglannsiée, dimathylmetaw
`midi: in mserpine and dimethylsuifofide in ahemetharapeutic aants 1.121113%?“
`@13ng 1231311111231 testing Propylene glymi :3 123m: moat frmuently as a comb
`mm. generally in connemmfions of 411% However, one product (mrazepam)
`uses a campiem nasalment gygmm:
`811% propylene glycmi and 20% palyethyiene
`glyoczlg the! latter twca ligaments; have L039 giggnificamly higher that: we ether
`solvents mentionad, althmugh tissue irritatian has ham implicatefi with a1:
`
`InnoPharma Exhibit 1018.0017
`
`

`

`Fgmulmian at“ Smelt Vniume Parenterals
`
`183
`
`the masnlvents when adminiatered in high cancemratiana via the intramtzscm—
`132* am} subcutaneous mutem Aithnugh such aystams are stable in individtml
`mntainem; exam} must he axemisad upturn administrafian. For example, pheny-
`tccin is diasnhrea E38 the stadium gait in a vehicte nontaining em pmpylene glycol
`and 1H% ethazml and adjuster?! m a pH M 12 with saflium hydraxifla. Bowman
`if this; mintmn is addgci ta 3 large volume intravenmus sotutim and the pH i3
`inwemd to a "value close to the pitta o