Parenteral Medications
`VOIIIIIIB 1
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. Lieberman, and Leon lathmun
`
`
`
`
`
`SerumCOHEEFIIIBIIGH.|mJU;'r;|,-,3}
`
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`|nnoPharma Exhibit 1018.0001
`
`

`

`Pharmaceutical
`B05398 FIIIIIIS:
`
`Parenteral Medications
`VIIIIIIIIB 1
`Second Edition, Revised and Expanded
`
`Edited by
`
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. Lieberman
`
`H.H. Lieberman Associates, inc.
`Consultant Services
`
`Livingston, New Jersey
`
`leon luchman
`
`Lachman Consultant Services
`
`Westbur}; New York
`
`Marcel Dekker, Inc.
`
`New York 0 Basel 0 Hong Kong
`
`lnnoPharma Exhibit 10180002
`
`

`

`Library eaf Cengress Cataloging +~ in-« Pubzicatmn Bata
`
`§‘har:r:ac:eutir:aI iloaage 'f01‘i13§ , parenteral mestliestiona I edited by
`Kenneth
`Avia. Earhart A. Lieharnmn, and team Lamhmzln.
`rev. and expandeti.
`p.
`cm.
`.Im::1u£ies hiblimgraphieal refarences and index.
`ISBN i}-824’?~35’?$~2 (V. 1 : am. paper)
`1. Pamnte:-:aI aaiutimns. 2. Pharmaceutical tachnaioggg.
`Kenneth E.
`11. Lieberman, He:-rbart A.
`111.
`Igm;-hmaxn; Lawn.
`
`I. As,
`
`*~-
`
`ed. ,
`
`[}3NLM: 1. Infusistzms. Eiarenteral.
`WB 354 PESE}
`RS2{}1.P3’?P:iS 1992
`615‘. 19--£19.23
`£}Nt.iVZ rm..«:3
`
`for Lihrargr of Cczngress
`
`2. Technolagy. Pharmaceutical.
`
`EL «~ EEMS3
`(31?
`
`This back is printed an acid«free papa-gr.
`
`Capyright IQ 1992 55y MARC DEKKER, INC. All Rights Resmrvea
`
`Neither this book 11:}: any part may be repmdmzed er transmitted in my form
`at by any meanza. elactrenic «:3: machanisal, including phntacepying, micro-
`filming, and regarding, car by any informatixm smragz: and raztrievai system,
`without permissian in writing mm the puhiisher.
`
`MARCEL DEKKER, INC.
`2713 Maziimn Avenue, New Yark, New ‘(ark 515
`
`Current printing {last digit}:
`10 9 8 7 (3 5 4 3 2 I
`
`PRINTEB IN THE UNITED STATES OF AMERICA
`
`|nnoPharma Exhibit 1018.0003
`
`

`

`mam
`
`Prgfacé
`Centribnturs
`
`Pxmenteral Medicatinns,
`Gmntanta sf ilharmaeeuticai Ilmsage Fatwa:
`Secsmi Eciitisrm, Reviseé an-:1 Expanded, Volumes 2 and 3
`Tablets, Seczmzi Ecliiion.
`Cezmtaants of P‘]*:az~ma:::emicaI Ilasage Farms:
`Eiaxrised and Expanntieci, ‘W;-iumes 1-3
`isperse Systems.
`Contents sf P‘hm-maceutinzmi Bosage Farms:
`Vniumes 1 anti 2
`
`Chapter 1
`
`The Parenteral Beijsage Farm and. Its Histmical Develcapment
`Kenneth E. Avis
`
`1. The Imsage Farm
`11. Histsry of Parenteral Nledicatians
`Agpenéix A:
`iélassary of Terms
`Appendix B:
`Iiighiighis in 1:112 Hiatory af
`Pa,mm;e::°a1 Macizénatiorss
`Raferan-mes
`
`Chapter 2
`
`Pamntarai 11mg Aciminiaatratmn; Routes, Fracautinns,
`Problems, Somplieaiiona, and {Drug Belivraery Systems
`
`Richami J. Emma, Michagi J. Akerg, and
`Salvatore J. Turco
`
`Imrneimztion
`I. Genera} Indications for Efiarenteral
`
`3a:imin_ist:ra.tia:n :31‘ ffimgs
`Pharmaceutical Facmrs Affecting Parenteral
`Acimimstmtion
`
`Specific Fmutes :33? miminiatration
`Ifiistrihutian mi Parenteram; Aclministarefi Agants
`
`II .
`
`111.
`IV .
`
`iii
`xi
`
`XV
`
`xvii
`
`£a~b—'
`
`11$
`15
`
`1.’?
`
`1.7
`
`18
`
`19
`31
`39
`
`|nnoPharma Exhibit 1018.0004
`
`

`

`viii’
`
`Cirzmtenta
`
`1!.
`
`Preeauiimns, Pmlslaflza. Hmards. emd
`
`Ciampiicaimns Asaamiatmi with Parenterm Drug
`éLdministrati+‘:m
`
`V}. Meihuciss and Ijevicwas For Ilrugig Deiivszry Systems
`VII.
`Summary
`Referencvsas
`
`Ckmgmgr 3 Bicapharmaceuticfi at Injectmale Medications;
`
`SQ! MQIEBEQ
`
`‘I.
`
`II.
`
`Introrlmsticzan
`
`Plzyaimchemiwl and Pfzysieimgiam Eaciura
`Affeciing Brag Absarptirsn by injection: An
`Qvarariem
`
`IV.
`
`III. Apgaiieatimz -:31’ Pharmacnkiantias t.:::> £3ic:pi“za1:*m.a~
`cesutiz: Inwmatigaticms: Phsarmmmkinatic Morielsz
`Exaxnpies uf I3:Empham1:.mex.zt:£'a fP§':armacn5<i:1etie
`Frinrxipma
`ReguIatan1*;.r Clcansiciez-atismsa for Bimequivalenee
`Stndias
`
`V.
`
`VI. Eiaequivaiensaa Study @i€ Twa Injectégbie Forms
`af the Same Emma:
`Summary
`Referencézg
`
`VII.
`
`Chéagatar 4
`
`Prefarmumtmn Rasearch mi wranterai Mfiicatians
`
`SQ! Mmola nianfi Shmerwm N . Agftmrimr
`
`1.
`
`rratredueiinn
`
`11. Drug; Stzhatan-:.:s=.~ ‘Phgrsinanhamical Fmperiiea
`Ht Am:-relerateé Siatsiiity Evalnazian
`11?. General means at‘ Ifirug Dszgmdmman
`V.
`?m£m~n3u1atie:m Stuéies far Pretaina and I-‘aptiaes
`VI.
`Prafdrmulaticsn S-:::re+aning :21’ Parnarxteral
`Backaging ilmmponanm
`Summary
`VII .
`VIII . Prefarmuiatian Worksiiewat‘
`Rafarenmas
`
`Chptgr 5
`
`Fommiatian elf Sinai Vmume Jfifiargnteraia
`
`Ptrick P‘. eLuca and Jozzmea C. Eoyran
`
`I .
`
`intmfiumian
`
`11.
`III.
`
`IV.
`V.
`
`Pnrmnlaiian Pfinciplas
`fiontainaer Iiffeizsts on Farmulmian
`
`fitahiiity Evzziumierz
`Process Effects
`Fiaferancaaa
`
`£1
`
`@@
`SE
`5?
`
`59
`
`5%}
`
`60
`
`1'?
`
`138
`
`18%
`
`[B9
`111
`112
`
`115
`
`.115
`
`11%
`1%“
`15%?)
`153
`
`15%
`163
`153
`169
`
`173
`
`1'13
`
`1%
`22'!
`
`234
`2&6}
`245
`
`|nnoPharma Exhibit 1018.0005
`
`

`

`Cantents
`
`ix
`
`Chapter 6
`
`Formulatien “of 'Large' Volume Pairenterals
`
`Levitl. %Demor:e1st1 and Jeffrey G. Hamilton
`I.
`
`II.“
`III.
`IV .
`
`AV .
`
`Introduction ,
`Concepts of Formulation
`Formulation Development
`Solutien Quality
`’
`Summary
`References
`
`Chapter 7
`
`Parentteral P1rodue1ts of Peptides and Proteims
`
`Yu-Chang John Wang
`
`1.
`11.1
`
`111.
`IV.
`
`V.
`
`L Introduction
`
`Characteristics 0f Proteins and [Peptides
`Formulatian Principles
`Campatibflity with Packaging Compunensts and
`Infusian Sets
`Formulaticsn of Market Products
`
`References
`
`Chapter 8
`
`Sterile
`
`Diagnostics
`
`. Leif E.
`
`Oisen1
`:Introducti<>n
`
`II .
`III.
`IV .
`
`V11.
`VII,
`
`Diagnostic Products Defined
`Sterfie 1DiaVginostiesV
`Defirfitioné \
`Aseptic Manufacturing Considerations
`1Va11id:ati=:>n 1P1*ogram1
`Conclusion
`Vfleferences
`
`Chapter 9
`
`G1ass1Containers for Parenterais
`
`R. Paul A‘b'end1"oth and Robert N. Clark‘
`
`1.
`11.
`
`111.
`
`Iv.
`v.
`VI.
`
`V11.
`V11}.
`
`1.In1tr0d_Vu«ction
`The Nature of Glass
`United Wstates Pharmacopeia G1ass1wa:t*e
`LC1«assjfic.-3tionLs
`The Manufacture of Glass 'Containers
`Chemical Performance
`Mechaniicm Performance
`
`The Cfontainex-and Closure as E SYSVS-m
`Quaiity Assurance
`References
`
`I249
`
`249
`250
`273
`290
`
`281
`12:31
`
`283
`
`283
`
`284
`302
`
`310
`3121
`1317
`
`321.
`
`321
`321
`322
`325
`330
`351
`.359
`359
`
`361
`
`361
`3&1
`
`362
`369
`7375
`380
`
`1380
`382
`384
`
`|nnoPharma Exhibit 1018.0006
`
`

`

`1‘
`
`Conten ts
`
`Chapter 16 Use cat‘ Plaatica for Parenteral Elrackfiaging
`
`John M. zines. Rabaswt 5. Name, and
`Charles H. ‘whim
`
`I .
`II .
`III.
`
`Intmductinn
`Fundamentals
`Fahricaiiezon 1‘»‘1*z::«*:»asses
`
`Impsrtant Criteria for Salactian sf Fiastics
`IV.
`E*1astim~; 1339:} in Parenterai Packaging
`V.
`VI. Quaiity Assurance sf.‘ Parenteral Cantainers
`Réfarencas
`
`Chapter 11 Eiastameric Clgsures fear .Paranterals
`
`Eaiwcxrci J. Smith and Rabear-t J. Ham:
`
`1. Elasmmeric Parameral Packaging €3<3m;>on:.=:nts:
`A Flzysieai Bescription
`Physiuai Bescriptinn of Rubber
`11.
`III. Typeg cf Ruhhar Usefl in Faranferal Packaging
`IV‘ Civasura Design
`X3’. Rubber Eamgmannciing
`VI. Vale:-anizatim: Psrcscess
`VII,
`(Ensure Manufaettzm and Centre-1
`
`fglnsure Design Qualifieatian
`‘REIT.
`IX. Reguiatcsry’ Cunaideraiimns
`X .
`Imemcfinn of Drug Ftsrmulations with
`Iiubézat {fissures
`
`XI. Clantempnrargg (310sure~Re1ame:i Issues
`References
`
`Clmpter 12 Parenteral Frmiueta in Haspital and Harm Care
`Pharmmrgg? Practice
`
`Jim "W. Levchuk
`
`1 .
`
`Intmcmctixsn
`
`11. The Iwegzaraticsn mf‘ Stariie Zflmaage Farms in the
`Hospital am: in Hams flare
`III. Bispensing and Gompmlnfiirzg Processes
`IV. Technology at“ Stefile C‘.:3mp::unr1ing*in the
`Eiosgital Plmrmacy
`V . Glinieal Supply and £339 cf $13:-iia Frodnata
`VI. Quality Assurance
`VII .
`C::m~:2lusim1
`
`Appendix; Abbreviated Sequence far P‘:-egaring a
`Series cf Extemporammusly Ciompounciecl I.V.
`admixtures
`Rafa:-ezxces
`
`Indax
`
`387
`
`38?
`. 339
`398
`
`407
`$22
`-43%
`-443
`
`445
`
`M5
`45!)
`451
`462
`4153
`£:,‘1'ifJ
`$7?
`
`494
`383
`
`585
`
`50'?
`508
`
`513
`
`513
`
`513
`524
`
`532
`5%‘?
`5352
`532
`
`56 3
`566
`
`56 9
`
`|nnoPharma Exhibit 1018.000?
`
`

`

`Frufiafifim f I
`
`
`
`rmtmg
`
`Patrick P. £JeLuca
`
`I-'nivem1'ty of Kemtucky Gouge of Pharmacy, Leacingmn, Kentuclcy
`
`James C. Eayian
`
`fibbatt Lmhoratwies. Abiisatt Fm-k. Iliincwis
`
`E.
`
`INTROIEUCTIN
`
`631' suspensicm
`Whareas a par'anta2rcz1 can be ciefiineri as a sterile cirug, salution,
`that is packaged in a manner suitable for administration by hypodermic infiam
`tion, either in the farm prepared or fcallmazing the aciditicm of a suitame sob.»
`em 61* suspending agent {1} . the tarm smaii vaiume pszmnrercxi (SW?) has been
`nffieiaiiy defined by the United States Pharmacopeia (US?) {21 as '”.
`.
`. an
`injeetien that is packaged in czantainers labeled aa ccmmirzing 153 mi or iess."
`The USP catagnrizes sterile p1*eparation3 for pamntera} use aecarciing It} the
`phgraioal state: of the pmduct as fmlowss
`
`1. Soluticma or emulsiona of medicamenta suitable for injecrtimz
`2. Dry solids er liquid enncsantratas 2;-soniaining no asiditivas which, upn
`the addition of suitable solvents‘ yielfi solutions confirming in all
`respescateae ta requirements far infections
`3. Preparations. the same as éemribed in class 2 Erin: cantaining 011% car
`more additianal suhaztan-ms
`
`4. Snap-anflana of solirls in a suitable meéimn which are not to be injected
`imravennusly or into the spinal aolumn
`5. Ery solids which, apan {he aiicliticen of suitahia Vehicles, mgcome
`sterile suspensions
`
`Althnugh the term stsrtxe pharmaceuticals is applicsahm ‘m an injectimls {raflim
`pharmaceuticals inciuiiecl} , xzghthaimic p:nepa1*att2:3ns, anfi irrigating soltiticens,
`this rt.-hapitgr emp313$i2as the farmulatian ezsf injectabla cicsaaga forms.
`The suczcaesaful fnrmuiation of an injactahle pregnaratian requires 3 tarmac}
`knowledge of ghyaical, chemical, anti biolngical principles as well as expertise:
`in the applieatimn of these inrincipiea. Such knowledge and expertise are re--
`quired to effergt natinnal rcierfisizms “regarsiing the selection 61$:
`{1} a suitable
`
`l?3
`
`|nnoPharma Exhibit 1018.0008
`
`

`

`IN
`
`eLu.cea and asylum
`
`vahicle (aqueous, nonaqueous, or casement): {2} mined substances ijantim
`mimrobéal agents. auxin:-miants. buffers. chelating agents, and tunic-ity com
`tribumra}; and (3) the appmpriate container am’: container compcvnentg.
`In~
`ha:-ant in the abmra clacisiatns is the ah1ig*atnry csmcern far pmriuazt safety.
`effectivenesa. stability. and miiabilzitgy. This chapter focxssers on time: physical-
`ehemiaal aszpeet-s af pmgsaring a stable pmtimzt in a auitablvez mntain-ear re:m;:sg-
`nizing that safety must he eatabiished thmugh avaluation of toxicity, tissue
`toieranae, pyrngeznicity, stexiiity. ami tonicity. ami efficacy muat he damizzrr
`strated through rmntmlieci. clinical investigations.
`The majority M paranterai pmdmsts are aqueous aolmtiansz, preferred I:m—~
`cause of their physiologic: compatibility ant} versatility with regard ts rczrute
`sf aciministrmgion. However, czmmlvents or nanaqueous saubstanees are Izaften
`mquired to effect mlution or amhility. Furthermm-e. the desired prapeszrties
`are sometimes attained thrmngh the use mi‘ .3 suspensian or an emulsion. A1-
`thmlgh each :3? these dcmage farms: havé cliaatinciive c§1.a11's.act£;=zxtistic5 and farmir
`Iation requirements. caezrtairz ph_~;sica1-chemicsal gerineiples are ~:mmmm1. Thease
`msmmmn principles will be disrrusseci in a generai manner and the differences
`disatinetivev of each aystem will be emphaaiaa-:1.
`it is imgnnrtmzt to mrmogrxim
`that the gmarmaeeutical gmciue-Es dariveti from biateehnomgy are on the in»
`crease anti the fc32*m111Vati:,:n of theae prmlmzzm zrequirers game nhiiiguta skills; and
`nmrel apprmaches. An aitempt will he made to nzover same of tha formulation
`appmaeims Em? prateins and peptides.
`
`IE. FORMULATION PRINCIPLES
`
`A.
`
`{nfluence cf the Route Qf Jkdministration
`
`Sinae parenteral preparatinns are introduaeei dire.-mi}; int-:3 the im:ra~ can «E;x¥;ra«
`cailular fluid mmpartmants. the lymphatic system. or the hioofi. the 11amm
`of the product anti the desired pizarmar,-omgieal aamticm are famtors determining;
`the particuiar route cf administrati-zan ice be emgioyed. The desirefi mute of
`administration. in turn. places certain requirements and limitations on the
`formuiations as well 3:5 the ciexrices used for administarixzg the clczsage forms.
`Uansecguently, a variety of routes; cef administration {age Chap, 2) am cut~
`rent}?! used for parrenterai products.
`fine ::»f the most important cnnsideraticms in fmrmmating 3 parenteral pmfifl
`um; is the appropriate velume imsts which the cirug should be incarpcsrated.
`The intravenous mum is the only route by whieh large volumes (i.e.., greater
`than 1!} ml) can be administered, althmxgh the rate nf adminmtratian must be
`em-efully mmrolled. Volumes up in 3.0 ml can 13% administared intraspinally,
`while the intmmusisular mufize ix nmvmalljg limited to 3 ml, subczutanenus ta 2
`ml and intrariermal ta m2 ml.
`
`The Chaim of the aalvent system :3? vehicle £3 dim»:-*mf:Zy related to the 2211*
`tanfled mute of afimimstratmn of the pradmat.
`Intravenous and intraspinal
`injeetiana are genaraily mmrietad tats {mute aq uemaa mlufimns, wizereas nil?
`soiuticms, msmizrent solutions, suspesnsinns, and emuisirms can be injected
`Intramusctumrly and suhmitanemusly.
`Isotnnicity is another factor that must be taken intrza cunsiciaration. AI-
`thaugh issntnnic sczviuticzna are mass irritszciing‘, causae 233$ tcrxirrity and eliminate
`the gmssibiliiry inf hemcclysis. it is not ass:-zxniiai that an injections he isnmnic.
`In fact, for subcutanexrma and intramuacular injacticuns hypartanic solutions
`
`|nnoPharma Exhibit 1018.0009
`
`

`

`Fmrmuletican ef Srmzil Velume Parerztemls
`
`175
`
`we often need to feefiiteie atseurpiieuii mi’ ihirug nine in 1:31:31 effueinn of tissue
`fluifls. with inieeeeneiie e<:iIui'i:‘me ieetcmieiiy heeemee Ieee impertent ae leng
`ee edminietretien is elm»: enengih ie permit diiutien er eciiueimeni in the bleed-
`However, int:-eepinel injeetione must be ieetenie because ef elves; circulation
`ef the eerebmepinal fluid in which elm-upt changes ef eemetie pressure can
`give ‘rise to servresse side effeete.
`New routes ef 3fimiI‘1i£tI'a‘1_iiQn include intreeriieuiar, directly inm the synm
`vial fixed for rsheumeteidel dieeasee am: even inire-nzligitel, between the fingers:
`in errier to better tergei the lymphatics. The eerenterel :2:-mzztee of e<im:mie~
`treiien will influence ihe design (if navel dneege farms and flrug rleiriirery eggsw
`teme especially as mere patent agents from bieieehnelegy are zievelnpezii.
`
`. Seiection ef the Vehicie
`
`Meet perenterei preduete ere aqueous eemtiztme. Chemically, the high ciie1ee—
`tric: eensiant ef water makes it peeeible in dissolve icmieahle electrelyiee and
`its hydmgenmanding potential facilitates the selmien mi‘ elecihels, aliiehyéee,
`Ieemnee, ens: amines. water ice» Injection, 8817-‘, ie the eeixrent ef eheiee fer
`making pereniereis.
`It must he prepared fresh by riieiilleiinn war by rev:-.-rec
`osmosis amfi eeniein he eéciefi substance. when it is net peesible to use a
`wheily equeeue eelution fer gnhyeieai er chemical reaeene, the addition «if
`eeiuhiiieing ageme or easements may he neeeeeary. Fer inetenee, neiigelar
`eubeieneee tji.e. , alkaloids} heees} peeeese limited eelubilitgr in water and it
`ie necessary to exit: 3 eeeeivent $11311 es glyeeiin, etheneli preeylene giyeel
`or peiyeihgrlene gigreel.
`In other eases, to prevent enemies} eegz-satiation (illfit .
`hyfirelyeie, exicietion, cieeerbexyietian, e1* recemieetiun} water may have to
`be eliminated peetiaiiy er teteiiyn. Meet proteins and peptitiee require an
`ecguerme environment, end ihe edziitien ef salt, buffer, or other additives fer
`seluhsilityr purpneee efien leads to eenformetienal changes- Ceneequently,
`parenteral peeciuei fee-muleiere eheeld be aware ef net only the nature ef ‘the
`eeieeni emf‘. salute in pare-e;nteea"£e but also the sszulvenv ealute intereetiene and
`the route of edininietzeetien
`
`Sglubility and Seiuhitizetion
`
`The solubility’ of a eebetenee at a given iremperetuee is riefined quantitatively
`es the eezmenizmiien of ‘the dieeoiireci eemie in a saturated eeiuiieii {i.e. , the
`diesehrefi eeiute phase}.
`fienerellgr, dmgge ere gureeem; in eeluiicm ei unsatu-
`rated are eubsetureied eeneentretiene; ethezewiee, eryeiailieeiion of the ewe
`ean eeem: ee e resuit of ehengee in 131% or temperature er by seeding from
`other ingredients er pariiculetes in the eeiutirm. Te enhance the seiubility
`sf drugs, in aciélition in using @i-genie eelvente that are miscible with water
`ee eeeelvente, other techniques can he empieyee. These ineimie eeit ferme-
`and ;pm{i1‘*11g*e, which? although capable of greatiy enhancing solubility,
`ccmstitute new entities requziring efiditionai clinical stuéiee. {Ether substances
`ueeci as eeluhilieere §.l.‘1C?:313<3.&‘: the eurfieee-active and eemplexing agents.
`Surfeeev-eeiive egeme, by virtue of their eeeoeietien temieneiee in salu-
`tion anti the ability in in-ient imzrsz oaneentreted palm‘ and nonpcaier eentere
`rfimieellee) , have been ueexi to eelubiliee drugs emi other eubeteneee eueh ee
`eitemine, hermeriee, euifmiemiciee, eyes, resins, and imletiie pile. These
`eurfectenie are powerfn} wetting agents and form eelieidel diejpersiens that
`have the appeerenee ef e true eemtien.
`
`|nnoPharma Exhibit 1018.001O
`
`

`

`I76
`
`Lfiegbuw and Boyian:
`
`aminaphsrlihne ;inié¢fi0,r1sfLhe
`VEifh¥1EtiediaminLeLis L[1‘¥?‘?l11i1i'F3‘31
`U1€OQh’y‘11inB'5:n‘S01l1'CiC}I1 sinca aminephylline is a salt» thzlt ionzizes intoritsi curr-
`stituenLtLio1L1Lsj theoph3r1liné;a:1Ld ethjrlenediamine;
`
`Aminophylline 4+
`
`2Lt;h?eoLphLy11ine' + ,eth3i1en?;ediVamine2*
`
`eseapées ,
`strcngly Lalkaliné Lm1bsLtaIme,LLis: Lvolatilé arid
`?E:thy1er51ediaLmi»ne,
`JtheipLH[wi1é1Vbe ltawered, causing t1ie>0§h§*IIir:esa
`it: be cQnVerfe§1.tvt3Vfree: their
`phy1fineLC1?K“a; W 8.8), w2hic:h isVVun1yLs2ight1yLso1ub1e in water (8 mg/m1l).L
`
`‘TLhe0ph3f11ir1e'"
`
`4} H'’ + theopliyllinej (fréei
`
`L Creatinine’ , niacinamide , and 1Leei=thin«haVe hesan»usec1».for :s0LLlubi}iziL‘Lng‘: steroids
`fin fthé free a1echa1f£r:»rm.;
`frtihe use ofVt::1e Vsazt csrjestez-g oi tLhe$e ste;-¢:)i::1s:§:r
`:\ritamins~ e1iminates‘VVthe need jtca use acxlubilizers but requires “<:>ther~additives
`-toaensure stability.
`A ‘brief Ldéeséripticn rfifthe gjhencmelnatx Lfiif s011f1bitity?Lwil1 béi helgful to Lftiie
`Lfcufmulatorin Lse1eVcti%ng*the best solvent or agent “cm overcome difficulties that
`arise in -the p1‘epara’tic2n of pharmacraéutical. dosageforms —c‘CmtLainin.g' pzmrly.
`soluble drugs. with parentenals, the drug and other dissolved substances
`.sh.i:-um rejmifn solmzilized Lthruughout the Lshelf-life Lcsf the,»pI'C,L}du_ct
`
`su%)stanc:e= can be expressed in a
`’S<2IubiIi;ty}of
`:S:o¥~uLb§ litgy Expre1ssi::sns .L
`Vnumber of ways. Generally ,. the cehcentération is?expr5essedasJpercen1: (wlv) ,
`zfhati is; :3:-areas. ipeir —1/U9 T1‘I11[IT1f .s?o1uti%cLm $7 blit malsfifsr HnVdM:f:o1a1it:rLIha%re been]
`V
`VuLsedL.M Malarity is definediam the number of ?m«:;1gsf gen l0D?Bm;1 c2ff solution;
`Mdlalityis the number ofLm:31esLof solute pier. 1i}(1£1%}gJ0f scalvent and, th.e1*ef<1>re=,L
`being 29. ‘wjezigjhi *re1’ationshi;p, 55
`ihfl11eflt313’d':Lf:-3? “temperature; The“ USP 1iL‘st.S"
`=sc:»1ub i1ity
`terms of the number/ofimi11iIiVters cf solvent required to dissealve
`I1 gLGf;,SLL1bEiaDce.v If Lexact seluhilitiesare notLkna;wi11;, the USP Lproviflés. gen-«V
`LLera1V%teVrmsjL[m iflesctibei a g:i1re:nV range. These desgriptiire tejrm{s‘arVa listieii in
`,LTa3::1e, 1;
`
`Table! 1 Expressions for Approximate; LS-o1 u‘I:oi1ityr
`
`tTLem11=
`
`Ve1iy"S01'LL1h1e
`~;LFreé1§Lr s0iLLibL1e
`Sflluble
`
`:SLp%aring1Lyj soluble
`
`Slighfly 301111318”
`
`ive:-y Slightly isoxutsle
`
`Rielafiw amofint af L
`Vsoljventxto dissolve
`“1 part} ’oVfL salute
`
`L
`
`L
`
`L
`
`L
`
`L
`
`L
`
`«:1
`~1F1(§L
`10-39
`
`3LE!-1£:Dl
`
`L160‘ 1000
`
`1Vas3»o~1aL,e3oo“ L
`
`fPt'§c-Jti-calily in soluble V or inscyluble
`
`>1 3}, 0 DE?’
`
`|nnoPharma Exhibit 1018.0011
`
`

`

`Fmwnututian af Smmi Vcztunxe Pr.;1r*emer*ais
`
`1??
`
`Measuring Solubiiity. Wtmhotis for rmtermixfismg the 3:2.-luhiiiiy af drug sub“
`stanrses in trmriczns saolvents have been described f3- S]. The phase scslubizity
`technique is esgeeially applicable to determining the snlubility of pure s11b-
`stszntzea and aim detecting the presensze nf impurities [33 .
`In this meflmci,
`succesaivelgs larger pczrtions cxf that substance are aaifieci to the same volume
`csf solvent in amiable mzmtsainers which are agitatazi at canstant temperatures,
`generally 35 i 1:1. 1°13.
`In those cuntainers in which excess drug is present
`(umiissslved), samples mi’ the sugar-natant am withfirmsrn and assayed until
`the congeniratimn is constant {Lee , the fifzstem has reached equilibrium). Far
`:21 pure compound, a phase snlnbility diagram is cmrzstx-ucteci as shown in E~‘ig~
`are 13‘ The scsiuhiizlty is reacting cietarminmi by extrapniating the line with
`a slope mf zero to the 3: afiéiifi.
`If an impurity exiats in the substance, a phase
`suluhifify diagrarn as shawn in Figure 11:» results, which shows an inflectian
`in the ascenniing line. Ram:-apezlaticon cf the harimntal line gives the aa1uI::+iI—~
`it}; mi‘ the substance plug me impurity of the substance an the 3r~zz:-miss, while
`esztmpolatinn sf thc asmcnfling line: gives the aolubility of the impurity.
`
`Bamcfing Forces. For a substance to tiissalve. the forms sf anti:-acticm that
`hcalri the mcfiecuies together must be msermme by the anivent, The aoiuhilitgar
`will be determined by the ralative binding ftrzmes within the substance (saint?
`soiute intuaractiana) and between the substance and the: vehicle (ss:e1u’::s:- snhrent
`interactions) .
`If an environment similar to that sf the crystal stzmzzmre can
`be provided by the solvent. then the gmater the solubility ($.22. . "like r1is~
`solves i:i.ke"}.
`Ionic crzrnpauzmir» dis:-:a1ve more readily in water by virtue: of
`ionwiipola interactions, whereas hydrophenbic substances ziissrzlxre more easily
`in ozrganivs senivents as: 9. result of dipole our induced digole interaetions (van
`der 5233315. Lnmion my 13::-zbjsve forces) *
`
`
`
`Undsss-alwcs mute
`beqéng amassing
`
`mg SOLUTE!mI
`
`’SOL‘«’E?\3'f
`
`w..«..«w...«..«....‘«~
`smmaam cs? sunssanar am: r.m;;ur}:g
`
`
`
` Sniubaiiig of xmpugiry
`mg SDLUTE Jmé SQLVENT
`
`soum€£}NC.mgfmé
`
`sown“:CC’?NC.mq/ml
`
`Figure I Phage solubility diagrams for: a pure subgtance (a) and at aubstzrzncc
`enntaining an impnrity (1:1) 1*
`
`|nnoPharma Exhibit 1018.0012
`
`

`

`178
`
`£3@Luca and Hymn
`
`The snlubility of the (1.:-izg substance is due in large part tn the palarity
`@f the solvent. eften expraase-ti in terms taef tiiggnie mmment, which is related
`tea the ssiielmztric canstant. Servants with high tiielectrin mnstsnts dissamlvsa
`ionic compmsncls and are water salable. *a:he"r=aas scslvants with low ciialectric:
`constants are rm: water solubie and an not dissolve imfic: compounds. Tha
`former are classified as poiar Ivénts (@.g. , water, g}yce::*in, and mathanul).
`wiaile the latter are mnp-mar img. ,
`ch1€:o1.'4:;‘»f«:31'm; benzene, and the bills}.
`801*
`vents with intermediate die-iectric mnstants (mg. , acetone and hntancrl) are
`classifiecl as semipalar. The dielectric enrsstarzts of mast gzharmaeauticafi $31-
`vents are known 11,8} and vaiuea for 22 number Uf binary and tertiary “Manda
`have been rapnrieti :63} am}, if not regzormd. can be reaziily estimaiaci £113].
`Table 2 is:
`22 liming 6f the zfiittalc.-ctric cnnatantss sf some Iiquida: user! in pharma-
`ceutical ajmtemia,
`The Bnlubiiity xmoffles of a number :22‘ pharmaceuticala EH3 ea function of
`tiialactric eanstant have been reperted by Pamta ami :z::2~wor1»:e.rs and gthers
`{11~3.’?] . By +:1etez*mining* the scalutaflity of a substance in a system at variraus
`dielectréc mnstams. ft graph Euflli as that shown in ‘Figure 2 can be ennstructeé
`to determine the dielectric constant that wiii p:'m:":l+:3e the required soiuhiiitgr.
`as can be seen from the mot, ta abtain the maximum concentration a dielec-
`tric eanstant cuf amumrl 413 is reqnireti.
`flat :11: mixtures will show a maximum;
`but such a plat illustrates the required clielectric constant to obtain the tie-
`sireri cancrantratinn. Far example, if a dielectric constant {chm} of 13121 was
`seleeied, 3 mixture mi‘ water (ride.
`'?B.5), polyethylene glyeal (PEG) «3013
`
`Talzde 1 Dielectric Congtants of Same Scalventaa ext 2596
`
`Snlvent
`
`Water-'3
`
`Glfircering‘
`
`N . N~ Eiimethylacetamit. ea
`
`Dielactric eanatant
`
`78. 5
`
`40. 1
`
`37 . E
`
`Pwpylene glyccila
`
`32.61 (30)
`
`Methzmml
`
`Ethanol?‘
`
`N—Pre;apan1
`
`Acetone
`
`Benzyl alccsholfl
`
`Pglyaathymne glycol 43?:
`
`Cottnnsead air?‘
`
`Bmzrane
`
`fjiaxsxne
`
`asolvents used in pm-enterals
`
`31 . 3
`
`2:1. 3
`
`20. 1
`
`‘L9. 1
`
`1.3. I
`
`12.5
`
`3. 11
`
`2 . 3
`
`2 . 2
`
`|nnoPharma Exhibit 1018.0013
`
`

`

`Fm-mulmiuzm of Small Volume Pfli“€‘flIf?.l"Ci§I3
`
`179
`
`A35: Snlmffiry
`
`1
`
`SGLUEELETY
`
`I0
`
`?%
`23 3%} W $3 25$}
`DEELECTRIC CGNSTQNT
`
`Figure :2 Hypothetical plea of smimbilitgr mf a suhatan-ca versus eiielentxic mn-
`stant in various mixtures of dmxane mm ware:-.
`
`(d..c. 12.5} and etharml (tic. 2&3) coulé be used. Seieciing an amount of
`aihanm necessary ta ciissmlve tha drug {E§«g'._, 18%). the percentages sf PEG
`dim and water can he rsalculatefi as fonnwsz
`
`(IE3) (24.3) + (X) (78.5) 4- (99 - X) (12.5) = (10%) (60)
`
`where: X is the giaereemzage of water required and is ealeuiaiect tea be 73.5%.
`Thcerefmse, the vehicle :42 pr-mrizie -a ciieleetrie cunatant ed‘ at} will have the fc21-
`lowing’ 0-ampnsition;
`
`Ethanol
`1.33:3 sun
`
`H28
`
`10%
`1a.5%
`
`73. 5%
`
`Since ciielectrka eonstam is :1 measure an? the polarizability and dipole mm
`mam: mf a mmpmmd, several researchers have explnreé otheer parameters am}
`pnlarity inciexes [183 which are included by molecular volume. ssnlvent anti
`salute inter-asst:-ans., and specific interactions mmh as hgzcimgen Emnciing‘.
`Hilciebranri and Scott [3] intrtzduceci soiuhiiityr garasnefers tn preéiet saith
`hflitfr at‘ regular scflutians; Since pharmaceutical systems deviate from regular
`or ideal smlutizkns, Martin anti ea-wnrkers I19} madified the Hildebranti egg»
`puma-ah to include hydmg*er1—hor1ding anti ciiprsiar interacticxns. The mrziemjlar
`surface area of the solute anti interfaciai tension between mlute and solvent
`
`were used by Amman {ED} and Yalkawsky £21} to predim solubflity. These
`51;:-Qmaches were aspecialiy applicaizele in systems in which the intermolaacuiar
`forces between servant and 301139 were different. Figure :3 shows me s®1u~
`biliijr as a function of sohrsant mnaeniration. The glam oi the line is a megs‘
`ure of the activity in me snlvent anti was fauna in be mlateci to several param-
`eters of solubility including“ interfacial tensiun and hydrogen banding: [18,22] .
`Hydrogen handing, the strangest type cf clipoiew dipeie intaracticn, is
`r:ha.r:-acterizetfi by 3 pcssitive center in the hydrogen atom {praton donm-)., 3e~
`cause sf its gram} size, we hydmgen atom can apprmach the negative rssanmr
`felectmn éomtsr} (if a neighharing ciipcsle mmre aiumely than any mher amrn.
`As a result ef this spatial manauvexmhiiity, bath intranmcalecular handing (Le. .
`
`|nnoPharma Exhibit 1018.0014
`
`

`

`DeLuct;z and Baylan
`
`159
`
`1:30
`
`
`
`SC‘.iLLl8}LlTY,mcrfesll
`
`10$
`
`203
`
`9
`
`an
`so
`can
`22:
`PRQPYLENE GLYCOL. %
`
`we
`
`Figure 3 Lag-nnea: miuhility rezatiunship far a series of alkyl p*amin0benw~
`ates~g}ycs1~water. {Fmm Yafltuwskgz. S. B. , Flynn. G. L. . and Amman, G.
`14., J. Pharm. Sci. . $31333 (1§’?2).j
`
`3“
`Cans-{in-H-~~Q\
`
`R
`
`‘"3
`C-1
`
`e
`
`Q...
`
`intermolecuiar I-I bending
`
`imrarnalecular H band mg
`
`|nnoPharma Exhibit 1018.0015
`
`

`

`Formnlmican cf Small Vevltune Purentemle
`
`181
`
`between gtroupe within e sinegle meleeule) and the intermaleculer type (Le. ,
`emexng meieeulee} can eeeer. The letter is responsible for essacietien in most
`eehrente em} eiesehgtiee ef meet druge.
`h§'4?31’flX‘§'1.. amine 01' am‘-hie
`Generally, the proton is donated by e carbaxsrl.
`gmug. The hjflimgen frem S~H er E:-«Iri can else farm hydregen beetle, but
`gene:-ellgr the bones ere weak.
`‘I”he ereten attached to e halogen is generally
`quite eetive. HF ferme strong hyéregen bends. Tyzsieal eleetrzm eentri.'bu~
`trees are exygen, zzcitx-:2-gen and helegen atzxms fsunri in eieeheli, eihere, elciew
`hyclee, ketenee, amide anti nhheteeeegreiie cempeunds.
`some ezcempiee of h;s;~
`cleegen bending with water feline:
`
`alcotmi
`
`ketczvne
`
`amine
`
`R
`H
`1
`1
`‘E!
`:.*i‘r~~~H-~D-— «H-13* ->~H-E§.!~—~
`3
`H
`
`H
`H
`;
`;
`R-{'_:aG~ - ~H--C3-«H~ * -exam
`
`Hf
`
`RaN~WH--33' “NR3
`
`Aiemheie ciieeuhre in water by hydrugexx bonciirzg, up in en aikyl chaizv.
`length of five eerben etcume. Fhenols disselve in water and eieelhcsl enxi, as
`the number of ’h;3rc1rexy1 groups increase, the water suiubility is enhanced
`heeauee ref the ixiereeeerl ap§:t{3;’:‘tLIi“:i?.§f fer hyfimgen bending. Mast erematie
`eerboxylie eeside. etereicieg and eerdiee glggrecoeidee are net water seluble but
`cifieeeive in elcohoi, glycerin, er glyeale by hycimgen harming. Since the
`mrereli eenfermatien of pmteine is most infmemzeari by hyclmgen bending,
`weterwthe eohrent of eheiee for meat preteine-—«-eemributee to the hyr:i23egen
`bending and, thereiere, can have 3 etrerzg influence on protein confermetien.
`1}ipe1e~ien'interee1iene are reepeneihle fer the dieselution ef ionic +:::tr3?eta}~
`line substances in paler exmrente {ii.e. . water or exeehel}.
`{one in equecme
`eemtien are generally hydeetecl (eurreuneeci by wetee molecules) by as many
`water molecules as can epefially fit ereumtl the ion. The attributes @f 5. ge-ed
`eelvent for eleeirelytee inclutie:
`(1) e higrrciipole mement; (2) a email melee-
`ular eiee; and {3} a high clieleedez-ie constant to reeuee the force ef ettreetien
`between the eppeeiteiy ehaegeci ions in the crystal. Water peeeeesee ell of
`these eherecterieiiee em: is, therefere, a gated eelvent fer eleetrnijrtee. The
`cation ef the electrelyte is ettreetet} tee the negative» oxygen atom, while the
`anion Mt:-ante the hydrogen atoms: in the riipeler water molecules.
`Generally, when eieetmlytee dissolve in water, Thee‘: is generated because
`the ien-eipeie imereetion energy exeeecie the sum ef the ier:-ion interaction
`energy of the eelme end the :i:EpeIe~dipe1e interaction energy of the eeivent.
`Examples ef 51 negative heat ef eelutiorz are enhydmue magnesium sulfeie and
`eediem hydrexide. Where the iexaweipole energy is ieee than the eum of the
`energies helciring: the sehzte and solvent meleeulee mgether, heat is ebeorhezi
`fmm the eurreunfiing‘ area to make up fee the energy ciefieite Eleetzmlytee
`ehewing; e peeitive heat emf enlutinn meluxie petaeeium inriide and endiaim b:::~e~
`
`|nnoPharma Exhibit 1018.0016
`
`

`

`182
`
`£;ieLuct2 and Bflfyifin
`
`mide. Hycirated salts generally show a pasifive heat of smutian. Citric acid,
`am-bihal, am} mammttoi have positive heats cf aviation an that during ciiasaln-
`titan the scfluticm hemrnea -C."I}{}§. when rexmnsaziitzzting dry prndmziis cmntaining
`§.az.*g'e amounts of these autmstancea, which ia quite mmmon in freezewdteied
`prszciuats, it is mace-Mary ta be aware cf’ thiss phenomenan and warm the solu-
`ticon prior to injecatien.
`Man?’ cnmplexea result because cf an iun~imiuea<i dipole intex“-actiem. Fm-
`example. imiine is scluhiiized in a salution of pntassium iudifie in the folmwing
`manner:
`
`+~
`I£+i{I
`
`+-~
`4- K13
`
`Although the iazzciine moiecule is electrically neutral, :51 temporary pomrity may
`remit from aleiztrnnic mmremants within the molecule. Such rzzmrements inciuce
`
`zriipnies in noaighbaring molecules anti are respmasibie for maintaining benzene
`and aarbmn tetrachloride in the licguizzi state.
`’I‘h.a‘ imiicisa camping forms be-
`cause the mmng electrical fielti of ihe aiectrnlyte in sac;-iutinn induces a ziipoécsz
`in the pczslarizsahle imiine molaculez. Benzene is; :4 neutral mulecule that is 1-*ea»:1~—
`fly polarizable ami aoluhle in 3100110},
`Symmetrical molecules. such as henztene and carbazm tetrachloritia, paasess
`a zem dipole moment and are nnngolar. Solubility of Each molecules or their
`eiatisteanca in a Iicgzrici state is cine in van der Waals forces.
`‘In the maxmer c1aa—
`s«s:::c~i1::e<1 eamier, an inducticzn affect mmura in these elactricaliy neutral mnZ1e~
`cules, and the: mczleculezs orient themselves with surrounding malecules an that
`negative am} pcrsitixre pokes are mgether. Sash orientation is rafarreti tcs as
`resulting from indumefi ciipmle-inducxzxfi dipoia interam‘.i~;m$. These very weak
`attractians are some/cimea called Landau farms, because they were first cie~
`smribati by Lonfimn in 1933. The}; are reagiransibie far dissolution nikf hydmphtzw
`his substances in mnpnmar solvents E-mg’. , wax in carmn tetrachlmricle anti
`paraffin Sm petmleum banzin}.
`if the salute and solvent in mmgmlar systems
`are aimilar in size aria structure. rhay can be mixer-3 witham‘. any appreaiahle
`heat csf solution.
`if the heat of sekminn is zero, the sniutirm is referred to
`as an iciaal snlufion.
`
`Ancsther type of van der Waals farce is that 1*sasu1t:'mg~ fmm induced dipc;1e-
`fiipuie inmractimns , aim called Qeiiye interactians.
`In this case, a wzitipxziiar
`mszrlecule is capabie cf inntuaing an eiectrical dipole in 9. nnnpmlar mnlecule.
`A mnlmzuie that resmnates, such as ‘tsensena, can be pnlarized by £3. fiipu