`
`
`FDA Jou all
`
`ofifiharmeaeetiltical Science and Technology"
`
`
`
`Iuuuuuuunuwuuwuuuuuwwnlwuuiu
`Plllafllliflé I115!fissmwaun
`
`
`
`Solubility Principles and Practices for Parenteral Drug
`Dosage Form Development
`Stephanie Sweetana and Michael J. Akers
`
`PDA J Pharm Sci and Tech 1996, 50 330-342
`
`Astrazeneca Ex. 2052 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01326
`
`

`

`REVIEW ARTICLE
`
`Solubility Principles and Practices for Parenteral Drug Dosage
`Form Development
`
`STEPHANIE SWEETANA and MlCl-MEL J. Al(EFlS*
`
`Pkammseutiwl Sacriwces. Lilly Research Lcabarazuries, Indfanayatis, Indiana
`
`lntrocluctiun
`
`A cammcm problem experienced in the early c§evel+:)p-
`mam; of drugs interziled for pamnteral, especially intrave-
`noas, adnzinistratien is the solubllizatiofx of a slightly
`salable or water insoluble active ingredimxt. Drug solubi—
`lization has been the subject of many scientific articles
`and tcmbnaks {referenced thmu;gheut this» article); yat
`(inspire: this attention and available litcrature, prmluct
`develepmeni scientists still amounts: significant diffi»::ul—
`tias in solving their sizklubilify problems.
`Theories of solute solubilization are not easy ta
`undsrstanci. Sclubilization processes are amazingly cam-
`plex and require 3 fair amcmnt of expenisa in ;3l1ysiLr:-al
`chemistry to interpret amzl apply current theeratécal
`mmfielsl Wlllllll of the litaratura deals with salubélization
`
`theory and does not nffer much practical help to the
`inexp-srimce.-d sciesnzist under a lat of prcssure to find 3
`solution to his/hm‘ golubiliiy prlzsblem.
`This article intends ta halp thsa scilenlist in early drug
`formulating design far paranterally administered drug
`pmd acts by reviewing pertinent literature an solxLbiliza-
`lion and rsducing it tr: simpls approaches one tzan use ta
`solvs salubility pmblems. The classical themfies of solu-
`bility, and how they relate to phannacwtical systems of
`interest will be reviewed anti practical appliésatiuns
`dlscufiaed. Bezrause of the commcm concerns regarding
`cosolvent
`toxicity and acceptability by medical and
`rcgulamry bodies, we also will area: this topic in same
`detail,
`
`I. Pertinent Theory of Solubillzatian of mugs
`
`Solubility theories deal with oonversion of :1 substance
`{mm one state :0 anotlxar, and the equilibrium phc1wm-
`arm that aim:
`invalved. Through pioneering wark {sf
`Henry, Ratault and vazft Hnff in the labs l8{l0”3:, that
`prcperziss cf various solutions have haezx defined in
`théories. These early thaories form the: basis by which
`were mmplex systems, gush as 11103: anwuntéxed in tlle
`biolegical sciences, are zzcrrnpared and understood.
`No sing]: than-ry can adsquatsly explain sclubility
`behavior Qf uhcllargeld molar.-ulas in a xrarirsty of solvent
`systems. Each them-y is suited for select wmbinations cf
`
`Rzzceiveil Jams: 29, 199:1 Amzeptad far publiszaiim lsclarch 21, 1996-.
`* Author to whom corrssponden-be should be addresguaiz Lilly C‘mp<:u~
`mm Canter, Indimmpmlis, IN 46285.
`
`salutes and solxrarzts whet: certain izztearznolscular forces
`
`are assumed to predmninairz, or cmwersely, ba alrxsant.
`The: classical thaorics of sulubility have ham: axplaincd
`most simply in terms of interrnolecular interactions.
`Ideal scdutiart
`theary assumes so]ute~solut::, mlvcm—
`solvant and solute-solvant interactrimts are completely
`unifcrm ix’: atrémgih and nature. An exaznpla of a
`solutitm behaving ideally is a noivpolar salute:
`in a
`::1c:I:~pU=lar
`sezzlvrsnt such as naplitlhalena in bsnzsne.
`Regular scfusiarz meaty szvolvcd {:1 account for the imbal~
`zmce af intarrualeatxlar inieractions that aften oscur
`
`bctween dissimilar systems (if 21, solute and solvent. The:
`focus of this cheery are systems of law polarity such as
`steroids in hydmcarlaon solvents. Extended regular gala»
`aim ihwry incorporated adciltirsnal parameters much as
`dispersion, palm and hyémgermlnundhlg interactions
`inta regular soluticxn theory, Various approaches have
`been used to represent these molcculm lnteractisznns,
`leading to a variety of medals ID predict and explain
`solubility bahavior cf polar salutsas in polar gystems, sac}:
`with diffanznt approximalimts and assuxnpli-o:1s(1—4),.
`In most phannacautlcal systems, the routine applica-
`tion of tlxes-at models to media: solubility and simplify
`farmulaticm development is complax. Most drugs of
`interest are icmizable, contain polar polyfungztional
`groups, and are capable: of forming multiple hydrogen
`bands. The majority of parentsrally acceptable casel-
`wznss-such as pmpylenn: glyml, polyathylantiz glyml,
`ethanol and water—-are capable of self association
`through hydrogen bond fccnnaticm. Such intsracfimxs
`may altar salvenl: structure and, as a result, infiuezlce
`salubilitylin an unprcdiciahlc manna: (1). Examplcs Of
`this phenomena arc», deviatians item log-linear 3_olubliza-
`tier: of noxipolar solutes in a polar eosclvcnt system £5).
`For the mcrdels. to adequately dascribe snlubility behav-
`icsz, grape: weighting must be assigned to the relative
`importance of competing self—associatien:~; and strong
`intermolecular irxleracticms. Currently this is being m<:ad~
`clad by variaus computes: intanslvc goupwontribution
`approaches, some of which allow for the mutual iE1t{3I‘3'l’.‘~
`tions afvarievus functional g1“0upS (1).
`In the biclngical sclcnces, many solutes of intents: are
`capable af acting as acids or barges. In an ionizing mcclia
`such as water, they may dissociate intn ions which are
`usually highly water Soluble. To what extent a molecule
`is iszmizecl in an aqueczxus solutlon is largely dependent cm
`its pléia and the plrl cf the media. The Henderson»
`
`333)
`
`FDA Jsrsllmal cf Phamapaufica Science 3 Technoltzgy
`
`Astrazeneca Ex. 2052 p. 2
`
`

`

`Haaselbalch aquatitéu is a mathematical expressiun of
`this relationship (3). In fonnulatinn tlevsluprnent, cum
`sicleratisn cf the amcsuni of un~ionized drug in soluticm
`is lwlpful to avuid Ufliixpfitfttttl prccipizatiml Bf this font}.
`As the ?H of :1 firug solutiim is changed, the amuunt of
`free acid or has»: may increase and ewsntually exceed the
`limited salubility afthis farm. It lg passible {I} calculate
`the pH :3? precipitatien and 9f maximum solubility, if the
`pKa of the molecule and the solubility ml’ me ur;—i0r1i3e<.l
`and ionized fenns are lmovm (3, 6). Cienerally, two pH
`units abava or below the pl-{mi value: aslablishe-5 the
`desired pl-1 fer fonnulaiion. Fm drug molseules with
`multiple irmizable gmups thcse «equatiens are more
`czomplieated to apply and so exparimentally generated
`mlubilily data arc usaally mllected.
`Tlmmgh um own axpcsrictnce, we find that theary givea
`us some climciion with respect ta experimental ap-
`proaches, but we still need in mi}; on the empirical
`experimentation ms Qcraen far igastems which offer the
`most promise in solubilizing water-insoluble drugs.
`
`ll. Farmulation Design
`
`increasa the
`the first appfoaclz used ti;
`Usually,
`ss;slu§;ilityc1f an insoluble drug in water is to form mom
`water soluble Saliiz. Berga and co—workers (7) wrote what
`is new 3 mar zlassic xevicw Bf salt form stralegiiis
`acceptable far pharmaceuticals. If salt fonnation is not
`pcrssihlc, mg. we 1m$table:_, or dam; not
`r:m<ir::'
`the
`malacule sulfxciesntly water salable, a series af formula-
`ticrn approaches may be invastigateci. Table I su:nma~
`rizes these general strategies. Often a useful approach to
`incrzasc the aqua:-us solubility of an im1izal3le clmg is
`pH adjusltmcn1.The next approach most fraquently tried
`is the use of wat€§'~miS€:il)=l€i
`cosolventa Otlmr ap-
`proaches to be: discussed briazfiy include the use of
`surface active agents and complaziing agents. Davenp-
`ment of emulaified and colloidal drug cit: ivezry systems
`for intravcmms adminisiratian are incoming muréxvidely
`anti successfully applied. They may cuonfer to the en-
`trapped -:31’ associated drug sigzxificantly dif’ercnt prepar-
`
`TABLE l
`Summary of Paranleral Fesmulatéon Approaches
`
`Appmacb
`
`Exsamplafi
`
`pH adjusiment
`
`‘pH 2 {0 l2
`
`Cemlyent
`
`Pulyeihylssmz glyml
`Pmpylcna glycol
`Ethanol
`Dlmiiihylacetamidc
`
`Surface Active. Agems
`
`fislysmxtzaies
`Pnlaxamers
`Clramaphm BIS
`Lecit.hin
`Bile salts
`
`Complcxing Agrsnts
`
`(Ey-cledextrans
`Watz2r—s<)l:1bl»:: viiamins.
`
`Disglezrsed Systcms
`
`Emulsions
`Liposomcts
`Naimpafticias
`
`Vol. 50, N115 I Septemharwoclubar 1938
`
`Important Formula
`Cunsiderations
`
`Drug stability
`pH
`ions in buffer 01‘ adjust pH
`Drug precipizatiun upém infusion.
`drug crzmcentraticm
`use of hufferfbuffcr capacity
`infasion ram
`Fmmula irritation
`isgstaniesity
`infusitm rate & duration
`drug vs vehicle
`drug precipitation
`
`Syslesmés toxicity
`halal cusmlvent admizzistemd
`Drug pretipitation upen infusien
`drug cmnetentratlan
`infusion rate
`Formula irritaticsn
`isatrtcmiazity
`infusion rate & duration
`drug vs vehicle
`drug precipltatican
`
`Hypersefiaitivity in animals
`Farmula irritation
`ismtsyniaity
`infasizm rate 62 aim-azicrn
`cimg vs W.’:l‘alCl¢3
`
`Purity of erzciplents and drugs
`Furmula irritafirzm
`iseiorzicity
`irsfzzsivon rate 3: duratian
`drug V5 vehicle
`
`Szerility
`Particle size
`Phamawklnatics
`Stability
`
`Useful Tests
`
`pH rate prafile
`pH saiubility profile
`Frcseazirsg point depressim;
`In vitra precipitation model
`in viva plalebitis made!
`fa vétm cell lysis studies
`
`Mixture studies for maximum
`suluhillty
`In vitro precipilatinn modal
`In vim phlebitis medal
`{re view cell lysls studies
`
`In vim phlelaitis .model
`In vim: cell lysis atudies
`
`Phase solubility diagrams
`In vi)/¢:= phlrabitis rwadel
`1:2’ viir-9 cell lysis studies
`
`Particle size
`
`Astrazeneca Ex. 2052 p. 3
`
`

`

`fmm the free fomt. pmviclirtg the Gpilmfillnfty E0
`pmltzmg tlmg pl’l35E3l"lC£’t in the l”:i8.lO(;l$il‘C&itll at to alts;-3'
`dispnsiticm in the
`‘*Her:3ic" melhcdsl. reported in
`tltc:
`iitcraturc fer variclus canmr drugs, will aim has
`reviewed altltcmgh these mtttlmcls; use types anti ammtnts
`ef axtgipicnts that pmhalaly would nnt mmmcinly be
`cnnsidereci appmvahle far intravenous; adminisiratlnn.
`is;
`The basin for reliable fttrmulation devealopment
`atzstttale stlelerminatltm tlf aaluhility. Traciitianal method-
`ology‘ is the “equilibrium method" (Ell where mtceas drug
`is adtlecl
`tea the st:-lvent system. and same means cf
`agitation is amplnysd amder canstant
`temperature.
`Samples are withdrawn, filtered. anti analyzed fur drug
`cnncantration over a pcrind sf time: and equilibration is
`demnnstzated by unifnmniy cf the data (ms: the llilflé
`interval. Fm sparingly soluble drugs where cquilibria are
`Slow. aczctttate delelminations Elf sctlubility 11133’ be clil°fi—
`cult. Useful tcchniqutzs in these instances include using
`highly speslfil: analytical melltods to detect pnrent c0m—
`pnunds, minimizing the amcranl nf excesa solid added,
`and assuring sufilcienl equilibratiattn time {l}. Settlid slate
`factors and ba{Cll—ti}-battlh variatinn (clitferent pally-
`mcrphs, hytzltatinn slate, crystallinity. cryatal h«:>mt:>gen::-
`ily, and impurities) may afiect reprocltmibilify (if érug
`solubility determinations.
`
`A. pf! xldjusznterzz
`
`Current FDA apprnved market:-zl parenteral prod-
`ucts range in pH from 2 to l l. A cmmprehensive listing of
`these products may be found in Table ll. Fm l:!lQ€flmpai~
`ability reasons, formulation csf injectahles. within the pH
`ranges of 4 to 8 is mas: mmmmt. However, me achieve
`sufficient drug s::s1t.:bility. 3 pH trutsicle this range may be
`neccssatjy.
`“Ilia pH at whlrzh a product is formulated is usually
`dctcnnincd from ihf: pH scalability and pH rats: profiles.
`of 12113 drug (9). A mean! example of their application to
`aid parenteral fmmulatitm élaveittpment
`is Ci-988‘ 3
`cholecystokinin-B recepmr aniagtmist (10).
`Additicmal formulation variables 20 be C«0l'lSiCl€1‘t?£l are
`the mwtsssily M 2:1 buffitr, buffer capacity. and drug
`concentration. These can influance supersaturated drug
`concentratinns in the blncsdstrcam, at C(3l1{IlitiiC&l’lll'EE‘2l may
`lead £43 in viva drug precipitatimn. The blond is very
`slficisnt at 91-1 ncutralizazicm ant} normally maintains a
`narmw pH range of 17.33 to 7.42. Fm’ cxarnplc, a law
`incirience Di phlshitis was observed in {he rabbit‘. 62: vein
`milclel when ‘solutions OWE! the pH range at 3 to 11, with
`buffer ctmcentrations Gf apprcximately 0.3 M. were
`adminisierlsd in a single: small volume: [1 ml.) bolus chase
`{ll}. Simple screening tests consisting {if a computa-
`tional model where drug solubility is platted as a
`function cf dilution, and in vttro diluti-an experiments
`were Shawn to be effective tmls in evaluating the ability
`:3? ma pH-solnbillzed drug to remain in solutimt dilution
`£12, 33). Davie at al. { 14) Shawna} that in nine precipita-
`tion of the pH-scrzlubilizetl drug ditekiren was clependent
`upon drug ctmocntratlon and infusion ram. Lew comma»
`tratlnn drug solutimzs. which are rapidly diluttzcl belnw
`
`332
`
`saturation solubility, and rapid infuslcms were preferred
`tn minlmits precipitation.
`The most cnmmnnly used buffer components in patien-
`taral products and their pKa‘s are: citric: acid £3.13. 4.76.
`54(9), acetic acid {£1.76} and pltasphoric acid (2.15, ?.?.(l.
`.l2.33). when bullets are employed. the stability cf the
`mt;l«::::u1r: must alst) ht: Ctfirlfildtffid, sings it may be:
`infiue need by the ions in Solutinn (*9). Examplag of buffer
`catalyzed stztluticm degradation include fantoticline. 3
`histamine H2 receptor inhibimr {l5} and lotacatbef. 3
`zwittationic ezepltalctsparin (16).
`
`3. Use of C0301:/tznts
`
`In recent yaearzs, surveys uf FDA-apprcwed parenteral
`products {ll-19} show live water-miscible: cnsolvents-~
`glycerin, ethancal, prepylene glycnl. pelyathylane glycol.
`and N,N,~dim::thylacetamide—~—-as Compenents of sterile
`fomtulations (Table III and IV). Casnlvcnts are cm-
`pioyecl in approximately l{}% of FDA. appraised. paren-
`teral products. Thfiy are useful bscausva they may Gften
`provide axpnnential increases in solubilifir {Z3} and also
`allow exclusinn cf water for compounds susceptible in
`hydrnlysis.
`lnvestigatitm 01$ the snlubilizing potential of various
`cosolvenis may be apprnached empiricallgr by deterrninv
`éng the iaompitunds Solubility in cnsnlvetit campositions
`similar to marksted pmducts {21—-.3), or by one in“
`several systtzmatic approaches, Such as leg-linear st::lubil~
`ity relationships at statistical experlmetntal design.
`In thse study of log-linear Solubility relatinlnships.
`Yalltowsky and Roscmzn (20) investigated a range of
`atzsltstes in binary casolmznl mixtures {Ff ethanol, pmpylw
`ans glycol, and glycsrin in water ané discussed the
`clnseness of fit of apparent scnlttbllity tn 3 log-linear
`snlubilitg: equatian. Briefly, this technique involves experi~
`mentally detetrninirtg the selubility of a cotnpmmd in
`increasing percentages of a cxosalszcm and germrating 3
`semi—l0gat'ithmil: plot of the apparent solubility of the
`drug as 3 function of the volume-fraction of the i1CiSCll-
`vant. Using the slcrpc and tltfi Solubility Gf tha c:m‘r1;3i:>uI1ti
`in pure water, an equatien may be written to cletcrihe
`fits;-: sulubility in a binary system.
`Assuming that the laglinear increases in seluhility of
`‘individual cosolvnnts are additiva. mquatitsns. may alw be
`written far ternary and quaternary mixed cosnlvent
`systems (24). Mathematically, these relatinnships are
`described by the following equatinns:
`
`Binmy zrosaftterzz ztystem
`
`leg (1; = log Cw -- :1,3;
`
`Temmy cosoimant system
`
`log C, = log Cw -« ecj, ~t wfil
`
`Quatttmany cosgivent system
`
`1031?} = 103% * uni + all; + aflfb
`
`wlmte Cw is the drug snluhility in watér; ifs are the
`slopes of thfi semi
`lcagafthmic plots: C3.
`is tha drug
`solulpiliwzf is the volume ‘reaction cf the cosolvcnt; and
`the subscripts a, £9. 2: denote the cnrsetlvents/4, B, and X
`
`FDA Jnumal at Pharmaceutics Science & Tesnttnoéngy
`
`Astrazeneca Ex. 2052 p. 4
`
`

`

`TABLE 33
`Examgzies 93 Marketed Pareenterai Preducts wfsb Saiuticm pH Outside Range GT 410 B (18. W)
`
`pH
`pH
`Generic
`Market-ad
`
`(cnnsiituted)
`Adjustment
`Name
`Trade Name
`Farm
`Routes
`
`13}! w: 4
`3.3-4
`3.25-3.65
`
`Lactic: acid, Nam-I
`Benzenesuifcnis acici
`
`Amrintme Lactate
`Atracuréum Besyiate
`
`3
`3-4
`3.3-3.9
`3-4
`2.5-$1.3
`35?-4.1
`
`1.3-3/V3
`
`3-3.8
`2.’?-3.5
`
`3.2-3.3
`
`2-3
`3-3.6
`3-4
`
`3-4.2
`2.’?-3.5
`
`3
`3.2-4
`2-2,8
`3.5
`3-4
`3.3-4
`2.5-4.5
`3-4
`‘2-3.8
`3-4
`
`pH > 8
`9.2
`105-1 1 xix
`
`8.5-9
`
`9.I3~i€L4
`9.6
`
`8-10
`
`8.5
`
`9.2-1%
`11.6
`9-1&5
`
`Lactic ac.-ici, HC1
`Citric: acifl
`NaO}-L PIC?
`{Time acid, Na citrate
`
`Lactic acid
`Lactic acici, ethyl
`lactate
`Lactic acid
`
`NaOH,fHC}
`Lactic acid
`
`Na0H, citric. acid
`Tariarfic acid
`
`MADE, H631
`
`Na citratsz, citric acid
`BC]
`Citric acid, Na citrate
`Acetic acid
`NaOH
`
`Tartaric acici, Na
`citrate
`
`EiCI[Na0H
`
`N:tQH
`
`Nag}-EFO4, NaOH
`
`NaOH
`N-a0?
`
`Chiardiazzepwxide HCI
`Bcazquinamidc HC1
`Cipmfioxacin
`Dacarbazims
`Depamine HC1
`Dihiazam HCI
`
`Doxycyciine Hyciate
`
`Drsssgzericiol
`Ergemmine Maicate
`
`Fentanyfi Citrate and
`Dmgzcridoi
`Giycopyrmlate
`Hainpéiritiei Lactate:
`Labetalul RC1
`
`Mcthyidiupate H9211
`Mgthyfiergonovina
`Maicate
`Midazaiam RC1
`Miirimme Lactate
`Mizmcyciine HCE
`Nalhuphmc: HCI
`Nalaxcme HG}
`Ondansetmn HG}
`Oxymcixz
`Papavcrinc HCE
`Pyricioxim: Eiiii
`Tdiazoiine HC1
`
`Acelaxolamidc Na
`Acyclovir Na
`
`Aminaphyilinc
`
`An1€:b:a1b§:a3 Na
`Azaihioprine Na’:
`
`Ampiciilin Na
`
`Beiamcihasane Na
`R1.
`Chlmothiazide Na
`Diazaxidc
`Diethyrxiiltrestrul
`Diphusphau:
`Fiuestcauracii
`F<:«Eic acid
`§..é15i1£
`
`Gancicluvir Na
`Lezscmzorin. Ca
`
`Imam! (Samtsfi W'1na:hr::>p‘)
`Tram‘-ium {Bumrughs
`Wcilceme}
`Librium {Roche}
`Em»:-re-Con {Rox:rig)
`Cliprca 1.191 {M3135}
`DTIC-Dams (Mfias)
`Inmzpin (I3nPm1t)
`Cardizem {Mama Martel}
`Ilixjwj
`Vibramycin EV {R,4::e:r§g,
`3ILcins~Sinn)
`Inapsine Qanssen)
`Ergotrate Maleate (Liiiy)
`
`Immvar 1;Janssen)
`
`Robina! (Robins)
`Haida] (McNeil)
`Normodyne {Schering}
`Trandate (Siam)
`Aidomet Ester HC1 {Merck}
`Methergéne [Sand0z}
`
`Verscd (Roche)
`Primamr {Sancufi Winthrop)
`Min-acin fibedcrle}
`Nubain (DnP‘x:mt)
`Narcan (DuP~:;~m}
`Zofran (Cemncx)
`Pimcin (Parkcwfl avis)
`Papavtzrirze HCE {Lilly}
`Pyridaaxinc HG? (fiterisf;
`Priscolém: RC] (Ciba)
`
`Diamm: (mantle)
`Zcwiraa {Eunvnghs
`Welicolm}
`Aminapiljgliiae {AbbL9t3:,
`Elkins-Sim, American
`Regent}
`AmyéalNa{Lil1y)
`fmmaxx (Bufloughs
`Wclicume)
`Puiycillin-N Qsipnillecun}
`Tuiao:i1lin~N (fieecham)
`Qmnipen-N iwyszth)
`Ceizastcmr: Phusphate
`fschering)
`Sodium Diuril (Merck)
`Hypcrstat (Sciacring)
`S11‘tphoszrol {M388}
`
`Selurian
`Sntution
`
`Powder
`Powéez
`Concentrate
`Powde:
`Soiution
`Sohxtian
`
`IE, IF
`EB, IF
`
`{B
`IM, IF
`IF
`IF}, I?
`IF
`IF, IB
`
`Pawdet
`
`ii?
`
`Solutien
`Solutie-n
`
`Sczlutimt
`
`Suluiicm
`Sc: mien
`S0 utim
`
`So mien
`S0 uticm
`
`Sam ntim
`So mien
`Pccwdct
`Solutien
`Sclutien
`So mien
`S0 uticm
`5:) mien
`Saluticm
`Sr,» mien
`
`IM, EF, IE
`IM, EB
`
`IM, TB, IF
`
`IM, IB
`{M
`IE, IF
`
`IF
`IM, IF
`
`EM, £1?
`if‘
`{F
`IM, EB
`IM, 133, IF
`IF
`[F
`[£3,127
`IM, IB
`IB, IM
`
`Puwdez
`Pmvdcr
`
`IM, IE, IF
`EF
`
`Selutian
`
`II}, {F
`
`Puwdei
`Pawdttx
`
`Puwder:
`
`Sialutian
`
`Powder
`Suiuticm
`Scfluiiezm
`
`Soiatim:
`Somzicn
`Soiuiimz
`
`Powder
`Pnwder
`
`Pawcier
`
`IM, IF
`KB, IF
`
`IM, IE, IF
`
`113, IM
`
`IB, IF
`EB
`[F
`
`[33, IF
`IE
`EM, 333, IF
`
`EE?
`EM, E3, E1‘?
`
`‘EB, I}?
`
`333
`
`Astrazeneca Ex. 2052 p. 5
`
`NaOH
`Mai)
`N30}
`
`E2
`_ 11
`8-9.3
`
`Z?
`8.;
`
`Fluomuratrii (Roche)
`Foivite fbedafic)
`Fumsemide
`(finachst-Roussel)
`Cymvenrz {Syntax}
`Waiimmrin fimmunex,
`Bummghs; Wellmme)
`Brevizal Na (Liiiyj;
`Methohexizat Na
`Na caxbnmxtc
`9.5-105
`{M = intramuscular, IF -- intravenous infusiam. IE -~ intravczmus dime: iajacticrn.
`
`Voi. 50, No. 5 / September-Geisha: 1996
`
`

`

`TABLE 1!!
`Cnsslvent fianzermatiena in Scams: Currently Mari-zeiecé Parenterals W3. 19)
`
`Cnsslvent in
`Marketed Vehicle
`
`Etharml IE}£]“§-
`
`Generic
`Name
`
`C‘2:mms1im.'
`
`Trade Name
`
`Marketed
`Form
`
`BiC‘NU {Brisinl-Myers: Drug
`Onarniogyi
`+ Dziucnt
`
`Rotates
`
`Administratinn
`
`Appx.
`Vehieie
`per Base
`
`IF
`
`Dilute: 2:10
`
`3 mi
`
`fiupylcne: giyml 4il‘,}f>
`Ethyi aI::u§m1 1Q‘?*E*
`
`Diazepam
`
`Vzxlium {R(3c'i1:‘)
`
`Seiuiivzm
`
`IM. IB
`
`Direct injectinm
`
`0.5-4 mi
`
`Pmpjdene Giyvtoi 4%‘?
`Mmhml £€1‘3{<
`
`Digmin
`
`Benzyl alcsahm 5%
`Prupyicna gljxmk 5(}"7£~
`
`Pmpgmtm: gly-cc)! 25%
`Ethamzal 2&9’?!
`
`Pm-pylcsnc glycol
`1£}.3Ea%
`
`Ethcazml §{]‘i%
`
`Dimenhydrinatc
`
`L21r::»ci:1{Burrc3ugTm;
`Wclimmc)
`
`Btimenhydfinate
`(1-2I£ri:<}
`
`Snlmion
`
`EB
`
`Direeci injeciinn
`
`1»-3 ml
`
`Selutizm
`
`IM. IF
`
`Dilute 1:10
`
`1 m}
`
`Esmmaal NC!
`
`Brevibitzc {DuP:mt}
`
`Cnncemrate
`
`SF
`
`Diluie 1:25
`
`1~i{? ml
`
`Hydralzizinc I-{Ci
`
`Aprcsniint: HCI (Ciha) Sulutian
`
`EM. [B
`
`Direct Enjectivzm
`
`0.5-I ml
`
`Ketiaroiat:
`Trumcmzamine
`
`L01‘a“ze;Jam
`
`Tczriadtai (Sgmiexj
`
`Siélutian
`
`EM cmly
`
`Direct injection {M 1 ml
`
`Seiutian
`
`EM, {B
`
`E m}
`
`?EG 4051 8.18’ mifiml
`Benzyi almhal 297%
`Frnpyicne glytml
`Peavidoncz 20 mg
`Diiucnt (10 ml)
`Progyyiczne glywk (2 mi
`Ethanol {LS2 ml.
`
`Ethane! 30%
`Frapyiene giymt 3&6?
`
`Prnpyicne. glymi =i(3%
`A}cs::s‘;ml 1£}‘§%
`
`i(?"<?f-:
`A1£:::>§1 mi
`Pmpjslezni: g1ymi€:«'?.8%
`
`Fmwpyie me giycoi eiflfiiév
`Alcohal 10%?
`
`Atixran {kvyezha
`Aycréet}
`
`IP91 Direct injection
`Difute 1:1 W
`
`Melphaian H-(IE
`
`Aikeran {Burrougixs
`Wxzlkromcfi
`
`Drug
`+ Diiuam.
`
`IF
`
`Dilute constitute
`‘:2 1:10
`
`10 ml
`
`Nitroglycexin
`
`Tridii (DuPont)
`
`Concentrate ZF
`
`Dilute 1:180
`
`25-U3 ml
`
`Pcnmbarbitzfl Ma
`
`Nembutal {Abbvrm}
`
`Solutioim
`
`EM. IE
`
`Siaw direct injcctian 2 ml
`
`Phcnebarbiial Na
`
`Lumina1Na§Sam:-fi
`Wimhmp)
`
`Snlueian
`
`12%. 113
`
`Direct injcctiea
`
`1 ml
`
`Phcnymin Na
`
`Dilemtin (Parke Davis)
`
`Sotuticn
`
`IM; IB
`
`Direct injaciicxn
`
`3-<3 mE
`
`F‘-:11)/t:Lhykm<: ghemE 50%
`
`Pmpylcm: gtymi 4[)€?».
`Emanni It
`
`Scmbarbitai 1%
`
`Sccabarbitai Na
`[‘5v’yeth»A3;£:rs;3'}
`Trimethnprim-S113~ Septra {Bmmugbs
`famcihmzaznh:
`Wcilcnmez)
`Hamrim (Roche?
`
`Solutian
`
`IM. EB. IF Direct ifijfiflfiflfi
`
`I-5
`
`Cimcentrate
`
`IF
`
`Dflute E25
`
`5-10 mm
`
`N.N—DimethyEacet~
`amide £{l(}‘;F£-
`
`Drug
`Amsidine C:3neen—
`+ Diluczm‘.
`trace {Parka-Davia)“
`EM = izstsanausclfiar. IF m intravenous infusinn, I3 = ir:u';wen<ms. dizect injectiim,
`" Drug axsazi{ab{e outside me Uniivsd Stairs
`
`Amsacrim:
`
`IF
`
`Dilnte 1:560
`
`1.5 ml
`
`respactivalgg. In 213 simplest form. determining the drug
`solubility in water and pure msalvents wank? émow
`estimatian of the ammmt and type (of ctuswzent raquired
`ti: attain a desired sulubiiify.
`11‘: must cases imwever.
`éeviaticms from iog-linear increases of ;§uI'ubi1ity Been: in
`aqueaus cc,-solvent mixtunes as iniiicateci by curvature in
`the solubility plms. The deviations are atiributcd m
`s{)¥vent—:-mlvent irsieractions (S. 25).
`ihifi
`For first appzriz-xinlaticsns 01" swlubfiity howmzzzf.
`appraaéh has been shown in bx‘; uscfui {2E>—27}. Chien
`(28) used this ta£h:1iqus.: and pniarity indexes of C0301-
`wznts ta calculate the pralarity 43f
`22 mlution that pro-
`duced the. greenest sniubiliiy of ihe drug nmtmnidazole.
`
`Aqueous/rsosoivent rating cf corresponding palarity csuld
`than be: calcumted for other G050 want systems :0 pravidc
`quaiitative idantificaticm of solubility maximums (29,
`30}. Polarity indexes Elf Gammon water missible cost)!-
`vents have been tabulated and dkcussesd by Rubimt and
`Yalkawsky. Thsge i§"td€X?.S refiect the mhesive proper»
`iit":S of the SCJWEHI {$(3h.sbi1iEy paramaicr and inierfaciai
`tension). hydmgen banding abi it}? {pretwtcm donor and
`accepiw" darifiityjx. and polarity (s:ii~*.=;}e'.<2:t1"€v;: conatmzi).
`Another imlubility detcrmina £01: approach particu-
`Iafly heipful fm" complex mixtures i5 a statistical expcriv
`rnéntai design {3}}. Idcntifying he optimum combina-
`ticm of coscrivcntzs for soiubifiizafon may reduc: the 11:1
`
`334
`
`FDA. .lmama£ of Pharsnamaazttcat Science & Technmlogy
`
`Astrazeneca Ex. 2052 p. 6
`
`

`

`TABLE N
`Surfactant Cmcenirations in Same Currently Marketed Parenterats (16,. 19}
`
`Suiuhilixer in
`Marketcd Velnitie
`
`NN~dimz:2hy|acetamide fifi
`mgfmi
`Cremuphur EL 509
`mg? ml
`Dehydrated alcohiral
`rfL2.7‘%£>
`
`Rcsiyséarbate Si? 213 mglml
`?ropy!enr:: giywl 23.7
`mg} mi
`
`Cremopher EL 5227
`mgjml
`Ethzmel =3-9..7%
`
`Propjrlcnc g1ymi3{)%
`Polyszarbate Sf} 1.6%
`Polysnrbatc EB 0.028%
`
`Palyssrbate SB 4%
`?r0pylc~:;“:e giywi 20%
`
`Cmmuphor EL 650
`mgfml
`Alcohol 32.9%
`
`Pofyethylene: giycel 300
`13513 mgimi
`Ethyi almho} 30.5% V31!
`Pmysarzerbzxte St) 8%
`
`iienerizt Name
`
`Trade Name
`
`Rueutes
`
`Administration
`
`Appx»
`Vehizfle
`per Dust
`
`Teniprzsirie
`
`‘Vumnn (firisamfi-Myers
`Squihh)
`
`IF
`
`Bilute 1:10 at 1:200
`
`37-? mi
`
`Phytonadittzne
`
`Rona].-Lion (Kathe)
`
`IM «crnly
`
`Birect Eujestion IM
`
`1-v2.5 mi
`
`Paxzlitaxel
`
`Taxes} fBris.l;s::-I-Myars
`Squibb}
`
`Multivitamins
`
`M.V.I.~12(A:-;tra)
`
`IF
`
`IF
`
`Dilute 1:5 01' 1:20
`
`29 ml
`
`Diiutr; 1:‘£‘{!U at 1:500
`
`5 ml
`
`Chiordiazzzpmzidtz HCI
`
`Librium (Ruchc)
`
`EM Billy
`
`Direct injecting {M
`
`,2 ml
`
`Cyciosporim:
`
`Saxxdimmune {Sami:.32:)
`
`IF
`
`Diluizs 1:2€!—l:1Di}
`
`5 ml
`
`Etopnsiée
`
`VeP<:sid (Bristol-Myers
`Ctncalegy)
`
`[F
`
`Dilute 1:139
`
`5 mi
`
`Phggtcmadione
`
`IM, iB
`
`Bi:-eat inject FM,
`pmfcrmd
`
`L25 mi
`
`Pcxiyezyethytated fatty
`acizi 713%
`
`PEG:-ii} casts: mil 9.] 15
`mlfmi
`
`Aq.uaME.FH“x‘T(}N
`(Merck)
`
`Miszmnazole
`
`Mcmistat i.v. (1 anssen}
`
`IF‘
`
`Dilute 1:13
`
`20 mi
`
`Direct infiectim §M
`
`I-2 mi
`
`Direct infzssicm
`
`20-1130 ml
`
`Fofysarbaxe SC: 12%
`
`Vitamin A
`
`Poiysorbatc; 86 ().{){}8%
`
`Altcplass
`
`Aquasol A Parenteral
`{Astra}
`
`Activase (Gcncntcch)
`
`Na dcsoxyaholatc 0.41%
`
`Amphmszricin B
`
`Fungizane (Apmthcc-3:2)
`
`IM
`
`IF
`
`IF
`
`Fmijgsmrbsxit 2C9 3.49%
`Pmysazrltsates 86 0.04%
`
`Caiciiriul
`Cafazoiisx Na
`
`?0¥ysi3rbaI.t: Si} U.0f}4%
`
`Fikgrastim
`
`Calatijcx :fAbb~::m)
`Ref."-mi {Lil}-X}
`Ancef (Smithiilinc
`Beechamj
`
`Neupngtira (Amgcn)
`
`Sodium -tiodecyi wifak:
`3.13 mglmi
`Polysorbate SB 13%
`
`Pmieukin (Cetus
`Once-Iagz}
`Corsiiarone X 11/ (Sanofi
`Winthrop?
`{M = Entmmnscukar. IF -- intravmwus infusivn, IE w intravenous direct injection.
`" Drag amilnhéa imtxme fin‘: Unii:e.r:l States.
`
`Aidesieukin
`
`Amiudarone HC1
`
`Diluts: 1.:5€J
`
`Direet §1:_§<:&:1icm
`EB
`IM, EF, 13 Direct infivzction
`
`3~2§} ml
`
`9.54 mi
`
`IE
`
`IF
`
`IF
`
`Direct injctetiars
`
`{}.25~—3 mi
`
`Dilute 1:4?
`
`Dilute 1:50
`
`1.2 ml
`
`3-7 ml
`
`in the fmmula (26). They aim
`amount if eoscévent
`facifitata ths study cxf systems characterized by um»
`Iimzar mcraasrsss in mlubiliiy. Optimization techniques in
`pzharrnaceuticai
`formulation have racentiy ham re-
`viewed (32). A41 exampls of their use is a simpléx sxsamh
`for 5:3!»-fin: bhends producing maximum drug solubility
`(2)-
`Ascasptabie levels 01’ cosolwznt in parsmtcral formula-
`tions are Hat easiiy defined. A rasriaw of CL1§‘Tu‘3I‘1fl}’
`
`markated parenteral products shetyws 323$ percentages
`range fmm {E} to 106% {Table Hi and IV}, Appmpriate
`product ammmts are: after! 3 mama of rxmsidzzring :1
`divrerae set of factors such as: 1) administration candi-
`tions, 2) 53131 dasa, 3) target yycxpuiation and 4) duraticn
`Gf
`therapy.
`’I‘0xicity and adverse clinical affects 9?
`common cosolvsznts are summarizcszi (33-34). Racent
`safety assfisfiment reviews af propylena glycol (35)po1y-
`cthylcnc glyml {:36} and glyccrof (3?) have laser: pub-
`
`ms. 5%, N0. 5 2‘ S»e;:>tember~{3ctohE:r199$
`
`335
`
`Astrazeneca Ex. 2052 p. 7
`
`

`

`TABLE 5.‘
`Same Currently Marketed Parenteraia Utilizing Ccsmplexing
`Agents, Mixed Miaellesr or Lipid Systems
`
`Solnbilizer
`System
`
`Generic
`Name
`
`Trade Name
`
`Compiexing Agents
`Hgrdmlyzcd
`gelatin Il;l.'.-"(E-»
`Ethfglenediaminc Antinuphyllim:
`
`Curticotmpin
`
`Athcar (Ethane-
`Pcvulenc Rorer}
`Arnirtmpliyllizie
`(Abbott. Ell«:in:s:-
`3§1’lii,.$k?l“l(3f!‘lC‘i’.ll’I
`Rfigfllllj
`Amphmcricin B Alelmt {The Lips}-
`mm: Cu. 14”
`
`Amphmericin B
`
`Amphmcil {Liga-
`same Tack“
`Ytillflgy}
`
`Valium MM
`{R0Cl1e}“
`Kunakirms‘ E20
`{Rsmzhzz-)=‘
`
`DMPG and
`DMPC lipid
`mmpiex
`Na <:h<}l::s"-lazy}
`sulfale, ml»
`ltoidal dispep
`sion
`Mixed Micellcs
`Gl§rc0c’h0lic acid Diazcpam
`lecithin
`Glycoclwlic acid Vitamin K
`lecithin
`Emulsions at Liposomas
`Lipid emulsian
`Ditlzapam
`
`Lipid tsmulsifln
`Lipid cmuisicm
`
`Pmpufol
`Pcrflimrndccalin
`
`Liptiswme
`
`Di:»:21c {G}: medal
`Diaizcmuls.
`{Burns 5;)“
`Diptivim Qzanccal
`Flur.:xml—DA (Alpha
`Thcrupciiticsj
`Amphmericin B AmBisumc
`{Vcstary
`IM “ intramuscular. EF * intravenmvt infufiiana 18 ~, intravermus
`direct injection‘.
`*’ Drug available omsittc the Unitesi Siam;
`
`toxicity of 5:3‘-n~:i'al msulvent vehicles in
`llshcd. Lcscal
`animals is: summarized in Table V].
`
`C. Use oftiiirjface xlctii-2* Agents
`
`Surface active agents are usually incerpermed into
`pamntutala to prtivéttc one of several tlesirahle proper-
`ties; l} increase drug solubility thrmtglt micrzllizatien. 2)
`to pttmtrlt drug, pttcipilatiun uptm dilttliuti (38). 3)
`impmvc. thfi inability of 3 drug in solution by inmrpurav
`{ion (at tlic rlrug mm a micizllat Structure (3%. and 4} in
`protein l‘.7m‘t1‘lEll€lll{3T1Sl. prevent zigg.-"cgaticm due to liquidz’
`air or liquidfsoliil intarfatial interactiutis.
`‘Table IV prcwides cxamplfis of FDA-approvezd paren-
`teral produsts mntaining surface actiw: agents. While
`many ditferfinz types cf surfactants exist £;‘3€i”_L cmly an
`extreme few have precedence for use in giarenieral
`groducts. Fm example, far Btariilizatian uf proteins
`against *_;3ml’,ilem5 0f aggrcgatitin. cmly [;}0ly0!{j/£:fh}fl€S‘;€
`sorbitan monooleate {pvlysorbatc S0‘)
`is an Fl)A—
`appraweél surfactant (18), Other surfactants which have
`Eugen US£€l
`in parenteral products are pvolttaxamer
`l83
`{puiyoxyctliyi::n<":~p0lym<ypropyl€r;tr ct>pcclym:3rl. ;:mlys::>r—
`bate 20 and 40 {polyoxycih}'l::ne~p:3ly0xj;propj;len2 {ptfilyv
`myazhylenc scgztlaitan mnnnfaity acid esters). Crcmcapliar
`EL“ and Emulphor EL ?l95l"’ {poly-ethmtylattzé fatty acid
`‘i‘,Sl_€:1“.-3 and oils}. Which surfactant it must ttflttctiuec:
`ii
`soluhilizer at stabilizer is often a matter of empirical
`
`333
`
`(4l‘;~. Dctailtd revicws of miccllr; struc-
`imzcstigaticm.
`tures, characteri.zatla::n techniques, and piiarmacentical
`applicatiens have l‘li3€D published {42, 43).
`The tmticity of surfactants reported in the literature
`prior to H783 are summarizeci by Attwcmtl and Flaerence
`(43). Reviews on the pharnzamlagy of polystzsrbate >80
`(44) and the incidence of clinical side effects at Creme-
`phcrr EL3 {42} have tseen published. Children and
`newborns may be particularly sensitivx: to these agents
`and administraticm to this population is discnased (46).
`
`D. £23? of Carrrpiaiéng Agents
`
`Cempleztation elf water insoluble drugs. usually in-
`volves the irtcnrgzmratimi
`till the drug within the inner
`care {Til the eamplexing agent 80 that the cuter hydro-
`phiiic groups of the: cemplexing agent interacts with
`water rendering the ctxmplex soluble.
`An example 1317” succaesfirl applicatiran cf this Kashmir!-
`egg;
`is Amphecilfig a lipid complex format} between
`amphotericin B and sodium Chfllfistéfyl sulfate, :3 mam
`rally cicéurrirrg chalesterczl metabalite (43). In solution,
`Ilia ccemplex is pastulated to be a stable 4;lisc—like
`structure that remains intact in the systemic circuiatiim.
`Comparative sutdies in animals with micellr: solubillzecl
`amplmteriszin B [Fimgiz<me®) have shown a significant
`reductimz in systemic toxicity as a result of altsred
`systemic: distribution and elimination characteristics (48).
`Naturally mscurririg cycloduezétrins. partitularly E-—cys::lt:n—
`dextrin, are able to complex water insatiable: drugs and
`ntndtsr tlmm soltsblt: in watar. Howevar. $3-cycledextrin
`have bean asscsciated with rcnal tcxicity upon patenmral
`c’1Cli1’!i1‘1l$t1‘EitiG}‘LTl1C taxjcity has been attributcd the law
`aqumus solubility of [3~a:ycladextr§n and precipitati-an in
`Illa kidney. Newer cyclodttxttins are chemically modified
`in improve water smluhility and increase their usefulness
`(49 }. Brewster at al. Q50} have described the preparation
`and successful use Of chrémlcally modified cfrcltnclextriris
`such as 2.hydroxyprolpgl-33-eycledextrin in mlubilizing
`and west stabilizing vatiaiius priattzinrg and paptidfis.
`An axample where the thug was not
`inmrporated
`within same kind {inf matrixt but combincri with an
`adiiitiisc:
`to cl-htain basically a soluble salt camplax
`involved ascclrbic acid (51). Similarly, tmmethamine has
`bccrz repartfid D3 sillubilize zamepirac, an articlnic drug,
`by rrricelle {asmciaticm colloid) formation {S2}. The
`aqueous solubility cf metrenidazealst was rapurted to be
`enhanted by the wstzsr scrsluble vitamins nicctinamixfle,
`ascarbic acid or pyrédoxine BC] (32). A caga-like struc-
`ture famed by the viiamim: amxmd molecules nf metro-
`rzidazola was posstulatedt
`
`E. Enmlsirirz Sysranzs
`
`If a molecule has sufficient lipid Sfllllbllltyt émulsii:-as
`may be cimplayrzezl. Typical cmulsianscontain triglgm-:riz:lc:—
`rich vegetable ails anti Eacithin and may aim contain
`nmiianic surface active against as emulsifying agfims.
`Inmlublc drugs may he lTlE€ll’pUE'3lE(l
`inm commercial
`fat cmulsitztts 0:
`thruugh amulsificaticsn of this nil-
`solubilized drug. The farmer is uaually rim successful
`
`FDA Jaumal at Fhannacemicas Science & Technology
`
`Astrazeneca Ex. 2052 p. 8
`
`

`

`became drugs influence the stability of these ccmnieza
`cial emulsions (53).
`Emuleicm femmles have sliovm advantages aver high
`casolvcnt levels by reducing lccal venous itritaticm (54%).
`While emulsions hold pcstcntial as carriers fer lipcpltilic
`drugs, great challenges exist in; i) eificient incarcera-
`tion of the drag inter the éispersed phase, 2.} validation cf
`consistency in preparatitm and tterilizetitm, and 3)
`dependable hiolcgieal evaluaticm cf the safety and
`efficecy cf drugs delivered frcni emulsions. These topics
`are ad