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`harmaceutica
`Science and Technology
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`Solubility Principles and Practices for Parenteral Drug
`Dosage Form Development
`
`Stephanie Sweetana and Michael J. Akers
`
`FDA J Pharm Sci and Tech 1996, 50 330—342
`
`AstraZeneca Exhibit 2052 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01910
`
`

`

`REVIEW ARTICLE
`
`Solubility Principles and Practices for Parenteral Drug Dosage
`Form Development
`
`STEPHANlE SWEETANA and MlCHAEL J. AKERS‘"
`
`Phummoomiml Soiwces. Mil)? Research Lawful-odes, Indiawpulét, Indiana
`
`Introduction
`
`A common problem experienced in the early develop-
`ment of drugs intontlod for parenteral, especially intravo
`nous, administration is the solubilization of a slightly
`soluble or water insoluble active ingredient. Drug solubi—
`lization has been the subject of many mentifir: articles
`and textbooks {reforouood throughout thia article); yet
`dospito this attention and available literature, product
`development soiontists still encounter significant difficul-
`ties. in solving their solubility problems.
`Theoriee of solute solubilization are not easy to
`understand. Solubilization processes are amazingly coro—
`plot: and require a fair amount of expertise in physical
`chemietry to interpret and apply current theoretical
`models. Much of the literature deals with solubllization
`
`theory,s and does not offer much practical help to the
`inexperienced scientist under a lot of pressure to find a
`solution to bin/her solubility problem.
`This article intends to help the scientist in early drug
`formulation design for parenterally administered drug
`prod were by reviewing pertinent literature on eolubiliza-
`titan and reducing it to simple approaches one can use to
`solve Solubility problems. The classical theories of solu-
`bility, and how they relate to pharmaceutical systems of
`intereet will be reviewed and practical npplieations
`dlecussecl. Because of the common concerns regarding
`coeolvent
`toxicity and acceptability by nteclicnl and
`regulator}; oodles, we also will treat this topic in some
`detail.
`
`I. Pertinent Theory of Solubillzatlon of mugs
`
`Solubility theories deal with conversion of a substance
`from one state to another, and the equilibrium phenom-
`ena that are involved. Through pioneering work of
`Henry, Raoult and van’t Hoff in tho late mall’s. the
`properties of various solutions have been defined in
`theories. These early theories form the basis by which
`utoro complex systems, such as thorn: encountered in. the
`biological soienoos, are oompared and understood.
`No single theory can adequately explain solubility
`behavior of uncharged molecules in a variety of solvent
`systems. Bash theory is suited for select combinations of
`
`Received June 2?, 199:3“ Accepted for publication March 21. 1996.
`‘ Author to whom correspondence should be adamant-rt: Lilly Comm
`rate. Center, lndinnapolin, IN 4:3385.
`
`solutee and solvents where: certain iotomolooular forces
`
`are assumerl to predominate, or conversely, be absent.
`The classical theorize of solubility have been oxplainod
`most simply in terms of lntonuolecular interactions.
`Ideal solution theory assumes solute~soluto,
`solvent—
`solv‘ent and solute-solvent interactions are completely
`uniform it; strength and nature. An example of a.
`Solution behaving ideally is a non~polar solute in a
`uumpolar solvent such as naphthalene in benzene.
`Regular solution theory evolved to account for tho imbal-
`ance of intermoleoular interactions that often oocur
`
`between disaimllat‘ systems of a solute and solvent. The
`focus at" this theory are systems of low polarity such as
`steroids in hydrocarbon solvents. Extended regular 5011.4»
`{inn (neon: incorporated additional parameters ouch as
`dispersion, polar and hyétogenbondlng interactions
`into regular solution theory, Various approaehes hare
`been used to represent these molecular interactions,
`lending to a variety of models to predict and explain
`solubility behavior of polar solutes in polar systems, eaoh
`with different approximations and aesumptions (1—4).
`In most pharmaceutical systems, the routine applica-
`tion of these models to Media solubility and simplify
`formulation development is complex. Most drugs of
`interest are innizable, contain polar pelyfunntional
`groups, and are capable of forming multiple hydrogen
`bonds. The majority of parenterally anceptable casel-
`ventsueuch 21$ propylene glycol, polyethylene glycol,
`ethanol and water—are capable of self association
`through hydrogen bowl fonoation. Such intoraotions
`may alter solvent structure and, as a result, influence
`solubility in an unpredictable manner (1). Examples of
`this phenomena are. deviations from log-linear solubliza—
`tion of nortpolar solutes in a polar oosolvoot system {5).
`For the models. to auequutely dascribe solubility believ-
`lor, proper weighting muet be assigned to the relative
`importance of competing self-associations; and strong
`intermolecular interactions. Currently this 113 being modv
`616d by various computer intensive groupacontribution
`approaohee, some of which allow for the mutual interac-
`tiorre of various Emotional groups {1}.
`In the biological scienoos, many solutes of interest are
`capable of acting as acids or bares. In an ionizing media
`such as water, they may dissociate into ions which are
`usually highly water soluble. To what extent a molecule
`is ionized in an aqueous eolution is largely dependent on
`its plin and the pH of the media. The Henderson“
`
`330
`
`FDA Journal of Pnennaceutlcnl Somme it Technology
`
`AstraZeneca Exhibit 2052 p. 2
`
`

`

`Hasselbalch equatieu is a. mathematical expressian (if
`this relationship {3). In formulation devslopmem, can—
`Siderafion of the ameum of un-ienized drug in solution
`is helpful {0 amid unaxpectéd precipii’atiun Uf this fem}.
`As the 33H of a drug solution is changed, this amaunt of
`free acid or bass may increase and m’cnmally exceed tha
`limitad salulnility 13f this form. 1!: is passible :0 calculate
`the pH {If precipitation and 0f maximum salubility, if the
`pKa of the moleculr: and the solubility 0f [hit un-icmizeld
`and ionized forms are known (3, 6). (linenmall};$ twt) pH
`units ahave or balcw fly: pHmx 3:31:16: fiatahllshe-s the
`deslrgd pI—l far formulation. For drug molaeules with
`muliiple imnizable gruups these equatiens are: mom
`complicated to apply and m experimentally generated
`solubility data arc umally callecmdl
`Thrungh um awn axparimcm we firtd that thwry gives;
`us some direction with respect
`te experimental
`ap—
`proaches, but we still need 112) ml}: on the empirical
`experimentation :0 Screen fer gystems which ofier the
`most pmmisc: in solubilizing water-insolublc drugs.
`
`ll. Farmulatian Design
`
`:0 increasa the
`the first approach 13513:}
`Usually,
`salubility of an insoluble drug in water is m farm mars
`water soluble $21123. Barge and w~w0rkers (7) wrote: what
`l8 new 3; mar classic: reviaw 0f salt farm straiegies
`acceptable fur pharmaceuticals If salt fomation is not
`pmsible, mg. mo unstable, or dots-:3 21m milder the
`malacule sufficiently wane-r gamble, a series flf formula-
`ticm approachas may be investigated. Table E mmma~
`rizes these gsneral strategies‘ Often a useful approach to
`immerse the aqtmaus solubility of an iomizable fimg is
`pH ad§ustmem The next approach most fraquently tried
`is the use of walla—miscible: msalvmts. Other ap-
`proaches tcs be: discussed tarball};
`includfi
`tha use: of
`surfacf: active: agents and complexlng agents. Develep-
`meant 43f emulsified and calloidal drug d3 Wary systems
`for intravenous administration are bcmming mam widely
`and succesgfully applied. They may cvnfer to the en-
`trapped 0r associated drug significantly dif’crerat proper-
`
`
`
`TABLE l
`
`Summary of Parenteral Fefmulatéon Approaches
`
`Important Formula
`
`Appmacb
`Examples
`Consideratiuna
`Useful Tests
`
`pH adjuslmfim
`
`pH 2 m l2
`
`Comb/cam
`
`Folyelhylczm: glyfiol
`Pmpylcnr: glycnl
`Ethanol
`Dimfiihylacetamidc
`
`Surfacr: Active Agents
`
`Felymmates
`Paloxamers
`Crammphm BL
`Lecithin
`Bile salts
`
`Drug Stability
`pH
`ions tea buffer or adjust pH
`Drug presipizzétiun upém infusion
`drug canceutration
`use of bufferlbuffer capacity
`infasian rate
`Farmula irritation
`ismanizity
`infusism rate & duration
`drug vs vehicle
`drug precipitation
`
`Systems laxicity
`mml casmlvent administered
`Drug pretipitatian 11pm: infusicm
`drug concentration
`infusim ram
`Formula irritatitm
`{sataniatity
`infusion rate 8;: duration
`drug v3 vahiela
`drug precipitaticn
`
`Byparserzsitlvity in animals
`Farmula irritation
`ismcmiaity
`infasinn rate 6: duratiun
`drug vs whistle
`
`Complexing Agents
`
`Qrflludextrans
`Watar—solublz: vilamins
`
`Purity Of excipients and drugs
`Farmula irritatim
`
`Dispersed 3375me
`
`Emulsions
`Liposomea
`Namparticlas
`
`igewraicity
`infusisn rate & duratian
`drug v3 vehicle
`
`Sterility
`Particle size
`l’harmamklnatias
`Stability
`
`pH rats: pmfile
`pH salubilizy profile
`Fraazing point depresaiun
`In vim) precipitation model
`fa Vim phlebitis medfil
`fa vitm cell lysis 3&1th
`
`Mlxmza studies for maximum
`solubility
`I22 vim; precipitation meficl
`In vim} phlebitis model
`{:2 vim: cell lysis awaits
`
`In vim phlebitis medal
`In vitm mall lysis Studias
`
`Phase svlubility diagrams
`In viw phlebitis Infidel
`[:1 vim; cell lysis studies
`
`Particle size
`
`Val 50, N115 ; Septemberwomobar was
`
`331
`
`AstraZeneca Exhibit 2052 p. 3
`
`

`

`ties from the free form. ermidlhg the appurtenity E0
`pmhmg drug presence in the ltltrodetreettr at to alter
`disphsitlen in the body. “Hermie" methedfi. reperted ’m
`the literature for variant: cancer druge. will alert: be
`reviewed although these methods: use types and amounts
`at exelpients that pmhehly wauld tmt commenly be
`mnelderetl approvehle fer intreventms administratitm.
`is
`The basalt; for reliable fttrmuletion developmettt
`acehrate determination {if solubility. Tradittanal method-
`ology is. the “equilibrium method" {3) where exeees drug
`it; adrletl
`tr; the solvent syetem. and same means elf
`agitation is employed antler censtant
`temperature.
`Samples are wilhrfirawn. filtered. and analyzed fur drug
`canmmration over a pcriud of time and equilibratinn is
`demunstrated by unifmmity of the data are}: the time
`interval. Fer 5paringl3; soluble drugs where cqullibria are
`Slow. accurate determinatitms a? salub'tlity may be diffi-
`cult. Useful techniques in these instances include using
`highly speslfic analytical methods to detect parent cont
`parallels. minimizing the ameurtt 0f excess sollcl added,
`and assuring sutficiert’t equilibration time {l}. Solid state
`factors and batchbtehatch uariatitm ldifierent poly-
`merphs, hydration state, crystallinity, cryatal hemagene-
`iry, and impurities) may affect repmducibility {Bf drug,
`wlubility determinatiens.
`
`A. :25 Adjuszmen!
`
`Current FDA appeared marl-retract parenteral prodw
`eels range in pH from 2 t0 1 l. A eempreheneive listing at
`these products may he found in Table II. For hiermmpatw
`ability reasons, formulatien ef injeetahlee within the pH
`ranges of 4 to “El is mast mmmtm. However. to achieve
`sufficient drug selnbility. a pH hutsiele this; range may be
`necessary.
`The pH at whieh a product i3 formulated is usually
`tletermirtecl from the pH soluhility and pH rate profiles
`of the drug (9}. A recent example of their applieetion t0
`aid parenteral {firmulatlan {levelttpment is (71-988. 3
`eholeeyetokinin-B receptm‘ antagmnist (1G).
`Additicxnal formulatitm variables 10 be coneldered are
`
`the necessity at)? a buffer, buffer capaeity. and drug
`concentratien. These can influence supersaturated drug
`concentratlens in the blmdstream. a eonditicm that may
`lead tr.) in viva drug preclpitatian. The b10136 is very
`efficient at pH neutralization and manually maintains a
`narmw pH range of 7’38 to 7.4.7.. Far example. a law
`incidence of phlebitis was observed in the rabbt't ear vein
`mndel when solutions over the pH range at 3 ti.) 11, with
`buffer cancentralluns 0f appreximetely 0.3 M. were
`administered in a single small valume {1 ml.) bolus close
`{11}. Simple screening tests consisting {3f :1 computa—
`tional medal where drug testability is platted as a,
`function 0f dilutian, and in elm) dilution experimeme
`were shewn to be effective tools in evaluating the ahility
`of the prtzeluhillzed drug to remain in solutien dilutien
`{12, 33). Davie et al. {14) {thawed that lie hive precipita-
`tion of the pH-selubilized drug ditekiren was dependent
`upon drug cattcentratien and infusion rate. Low eoncem
`tratlon drug mlutiens, which are rapidly diluted below
`
`332
`
`gammlion seluhilltyl and tepid infusions; were preferred
`in minimize preeipitatiee.
`The most eemmenly used butler components in paren-
`teral precincts and their pKa‘s are: citric: acid {3.13. 4.?6.
`6.40), acetic acid {4.76} and phosphoric acid (2.15, ”2.20.
`$2.33)» When buffers are employed. the stability at” the
`molecule must alert he ettmidered. Siflflé it may be
`influenced by the ions in eolutien (9)» Examples of buffer
`catalyzed salutien degradation include famotirlitle. a
`histamine H2 receptor inhibitor {15) anti loracarbef. a
`zwitterienie eephalosgarin (16).
`
`3. USE 9f Comments
`
`In recent years. surveys ttf FDA-apprcwed parenteral
`products {17—19) show five water-miscible cesoltreatea—
`glycerin, ethancl, propylene glyml, pelyethylene glycol,
`and N.N,-dimethylacetamidew—as compehents 0f Sierile
`formulations (Table III and IV). Casalrrents are emv
`ployed in approximately 10% of FDA apprcwed parenw
`teral products. They are useful because they may after}
`prmiile expsnential increases in salubility (23) and also
`allow exclusien 3f water for compounds susceptible t0
`hydmlysis.
`Investigatian 131' the salubllizing patential of various
`cosolvenis may be approached empirically by determin»
`ing the mmpflunds solubility in emolvem campositions
`similar to marketed preducts {2143). cut by one of
`several systematic appmaehes, such as leg~linear selub§l~
`ity relatienships 0r statistical experimental design.
`In the study of leg~linear solubility relatienships,
`Yalltowsky and Rosemen (20) lmreetigated a range at
`salutes in binary casement mixtures of ethereal, propylm
`ene glyehl. and glycerin in water and discussed the
`cleseness of fit of apparent selubillty m a log-linear
`eelehility equatien. ”Briefly. this technique involves experi«
`mentally determittirtg the selttbility of a compmmd in
`immersing percentages of a eosolvem and generating a
`semi~logarithmie plat of the apparent solubility of the
`drug as a function 0f the volume-fraction 0f the easel-
`vent. Using the slept: and the mluhility at the enmmuntl
`it: pure water, an equation may be written It} describe
`the solubility in a binary system.
`Assuming that: the legulinear increases in eeluhility 0f
`individual cosolvems are additive? equaticna may aim be.
`written fer ternary and quaternary mixed, coselvem
`systems {24}. Mathematically, these relatlertships. are
`described by the following equatims:
`
`Binary mmiverzz garish“:
`
`log CK = lug CW + tax};
`
`Temary cayoivenr system
`
`leg Cl. = leg Cu. + egfi + ea};
`
`Quatemmy wealvem getem
`
`log C. --« tog cl + 015} + (1.2:. + ell;
`
`where Cw is the drug selubility in water; en’s are the
`slopes of the semi
`logarithmic plots; C3.
`is the drug
`solubility; f is the velume Erection 0f the easement; and
`the subscripts a, b, 2: denote the easements/4, B, and X
`
`FDA Jaumal at Pharmaceutical Science 3: Teehneéegy
`
`AstraZeneca Exhibit 2052 p. 4
`
`

`

`YABLE 3!
`Examgzias of Marketed Parentara‘ Precincts wi‘ah 80%}:an pH Outside Range :3? 4 is 8 (18, 1Q)
`
`pH
`5%
`Geueric
`Marketed
`
`{Cflnfifitfltfli}
`Afiustmmt
`Name
`Trade Name
`Farm
`Routes
`
`Lame acid, Nam-I
`Benzenesuifenis acié
`
`Maximize Lactate
`Attacuréum Besyfiate-
`
`13H 4: 4
`3.3-4
`3.25—3.65
`
`3
`34
`33-33?
`3+4
`2,541.5
`3141‘ 1
`
`13—33
`
`3—3.8
`2.16.5
`
`Lactic acié, HQ
`Citric: acid
`NaOH: HG?
`Civic acid} Na citrate
`
`Lactiit acid
`Lactic acid, ethyl
`133mm
`
`591mm
`Smutioa
`
`Powder
`Powdw
`Conwmraie
`Powdar
`$0le i011
`Sam ism
`
`Pawdet
`
`80111 km
`Sc} 11 ion
`
`Sm u im
`
`
`
`
`
`So 11 im
`So 11 ion
`30 n im
`
`So u inn
`80 11 Sen
`
`Si) :1 ion
`So n im
`Pawdct
`8011: icm
`$0111 ien
`So :1 ion
`So 13 ion
`So u '10:}
`39111 3200
`St? 11 iml
`
`IE, IF
`18, IF
`
`I3
`13%, [F
`IF
`IE, I?
`IF
`1F, EB
`
`ii:
`
`1M, £13“, EB
`I'M, EB
`
`1M, 18, IF
`
`IM, 18
`1M
`IE, IF
`
`IF
`1M, IF
`
`EM, 2F
`if:
`IF
`$1,113
`1M, IE, IF
`IF
`IF
`IE, IF
`IM, IE
`IE, EM
`
`vadar
`Powder
`
`IM, 13, IF
`3F
`
`Saluticm
`
`IE, I?
`
`Powder
`Pawder
`
`Paw-def
`
`11%, IF
`IE, IF
`
`IM, IE? IF
`
`Sfliutiun
`
`IE, EM
`
`vadm
`Soiutiun
`Soiuiiwn
`
`IE, IF
`EB
`IF
`
`Sniatiun
`Soimim
`Scimitar:
`
`IE, IF
`[1%
`EM, EB, 2F
`
`Ingmar (Sanafi Winthmp)
`Tracrium {Burroughs
`Weilcema}
`Librium (Roche)
`Emma-Con {Romig}
`Cipro 131 {Miles}
`DTICiDoms (Mfias)
`Immpin (Damn!)
`Cardimm (Marian Marta“
`139w)
`Vibramygin IV (Rmrig,
`EikinSySinn)
`Inapsine {Janssen)
`Ergmratc Maleate (Liiiy)
`
`Innwar {131155511}
`
`Robina? {Robins}
`Haida] (McNeil)
`Normodyne {Scheringj
`Trandaie (Siam)
`Aidomet Ester HQ} (Merck)
`Methargéne [8311602)
`
`Varscd (flame)
`Primacm {Sanofi Winthrop}
`Mix-1min {Lcdcfle}
`Nubain (Dqu1)
`Naman muPam)
`Zofran {Ceremx}
`Pimcin {Parkmflavis}
`Papavcrine HCZ {Lilly}
`Pyriéflxinc HG? (Stan's)
`Priscaléna HQ {(13133)
`
`Diazmx (13(1ch
`’Zavirax {Eunuughs
`Welicome}
`Aminophyfiiaa {Afibmfia
`Skins—Sim}, Amwican
`chem}
`Amyéal Na (Lilly)
`Inwran (Burmugfis
`Wclicume)
`PuiycillimN {Apoihrscm}
`TuiacillinaN (8369mm)
`Ginnipen—N Wyeth)
`Ceiastgme Phnsghata
`(Schariflg)
`Sodium Diuril (Merck)
`Hypcrstai (333161135)
`Slifphnstm? {Miles}
`
`Chiardiazepfixide HQ}
`Banzquinamide HCI
`Cipmfioxacin
`Dacarhazine
`Dapamine HC}
`Diltiazam HG]
`
`fioxycycfine Hyciate
`
`Draperifiul
`Ergmnmine Mabzate
`
`Fenianyi Citrate and
`[Imperidai
`Giympmnlaie
`Hamperiaia} mama
`Labetalal HG!
`
`Mcthyidapate EC!
`McthyEergmovina
`Maicaie
`
`Mfidamlam RC1
`Miin‘uona Lactgte
`Mfimczgrciina HC}
`NalbuphEnc HC]
`Nalomne HG}
`Omiansmmn HG}
`Oxymcin
`Papavcrinc Hm
`Pyridexina EC}
`Tuaniim: HG
`
`Acezamlamidc Na
`Acysimér Na
`
`Mifiaphyilinc
`
`Amabarbiiai Na
`Azaihiwprine Na
`
`Ampécifiin Na
`
`Beiamuihasona Na
`I’CL.
`Chluwthiazidc Na
`Diazaxidc
`Diethyigiilbeséml
`Diphusphatz:
`Fiwmuraci}
`Pom: acid
`Lam:
`
`3.2—3.3
`
`Lactic: acid
`
`2-3
`3-3.6
`34
`
`3-4.2
`Eff—35
`
`3
`3.3—4
`2-2.8
`3.5
`3—4
`3.34
`2.5-4.5
`3—4
`2—3‘8
`34%
`
`pH > 8
`9.2
`{05—1133
`
`8.6—9
`
`91340.4
`9.6
`
`8-10
`
`8.5
`
`9.24%}
`1? ,6
`9495
`
`NaOHg‘HC}
`Lactic acid
`
`NaOH, citric mid
`Tariaric 2min?
`
`NaOH, HCi
`
`Na citram, citric: acid
`HC]
`Citric acid, Na citrate
`Acetic acid
`NaQH
`
`Tartan-it acif}, Na
`citrate
`
`HCIg’NaOH
`
`N30}!
`
`NagHFO4, N303
`
`NaOI—i
`Nani
`
`9.2
`84 l
`343.3
`
`NaOH
`N308
`NaQH
`
`Fiuvmuracfi (Kathe)
`Fnivitt (Lederie)
`Fumsemide;
`(Hmchst-Roagsgi)
`IE3
`Fawder
`flytmene (Syntax);
`flanciclmir Na
`I?
`8.1
`Leacnmrin Ca
`Waiimvnrin {Immunem
`Pawder
`EM, 111 IE3
`Burmughs Wellmmc)
`
`9.5405
`Na carbanatc
`Methohexim? Na
`Bravita] Na (Lifiy)
`Powder
`XE, IF
`1M = intramuscular, IF = intravmtma infusiam IB ~—~ intravamus dércct injactim‘
`
`Vat 58, N0. 5 I Septemhes-Gambe: £996
`
`333
`
`AstraZeneca Exhibit 2052 p. 5
`
`

`

`TABLE ll!
`Casalven: fiancemratiens in Some Currently Marketers Paranteralg {18. 19)
`
`Cnsslvenl in
`Marketed Vehicle
`
`Afipx.
`Vehicle
`Marketed
`Generig
`Name
`Trade Name
`Farm
`Rallies
`Administmtim
`per Base
`
`
`Ethaml mm
`
`C‘zamnminc
`
`BEND {Brisml—Mycm Drug
`Onmlmgy)
`+ Dilucm
`
`1F
`
`Dilute $110
`
`3m:
`
`F'rupylmg: glyml 4U???» Diachanl
`Ethyl alufi‘ml 1053*?
`
`Valium {Ruck}
`
`Selullm
`
`1M. IE
`
`Dime: injacilun
`
`0.34 ml
`
`Pmpylene Glycol 4W3»
`Almhol ll]???
`
`Digmin
`
`Larmxln {Bmmuglm
`Wcllmmc")
`
`Sulmian
`
`IE
`
`Direct injectlan
`
`l-3 ml
`
`Benzyl alcmhal 5%
`Pmpylcna glyml 50%
`
`Pmpylcnc glycol 25"}?
`Ethane-l 25%?
`
`Pmpylene glywl
`lflfiffin
`
`[imam]! it]???
`
`Dimenhydrinalc
`
`Dlmanhydrlnate
`(5:13:33)
`
`Eelmim
`
`1M. IF
`
`Dilute 1:10
`
`1 m2
`
`Esmolal I‘lC‘l
`
`Breviblm‘: {Bul‘uml
`
`Ctmcentralc ll:
`
`Dilulfi 1:25
`
`l~l€l ml
`
`Hydralazins HC‘l
`
`Aprssolinc H‘C‘l (Ciba) Selutlzm
`
`IMk [8
`
`Direct injectitm
`
`054 ml
`
`Kemrolac
`Trumcthamina
`
`harazepam
`
`Toraclol (Syntax)
`
`Selutian
`
`1M cmly
`
`Direct injecting 1M 1 ml
`
`Solutifin
`
`EM, 13
`
`IM Direct injection
`Dilute 1:1 W
`
`1 ml
`
`PIECE 400‘ 8.18 ml} ml
`Bemzyl 31mm)! 2%
`Propylene glyml
`
`Pmldonc 2G mg
`Dllncm {10 ml)
`PrOpylcne glywl 6 ml
`Ethanal €152 mL
`
`Etharwl 33%
`Frapylcnc glyml if???
`
`Alixgan (Wyeih-
`Agent}
`
`Melphalan l‘lCl
`
`Alkrcran gBurmughs
`Wellwmc}
`
`Drug
`+ Dilucm
`
`IF
`
`Dilute wastltute
`:> 1:10
`
`13 ml
`
`Nitroglycerin
`
`Tridil (DnPQm)
`
`Cmcemrate IF
`
`Dilute 1:100
`
`2.5-“) ml
`
`Pmpylmc. glym! 40% Pent-zlbamiml N3
`Alca’nml 1G9?
`
`Nembutzil (Abbefi)
`
`Solutitm
`
`1M. 18
`
`Slaw direct injecticm 2 ml
`
`Almlml 10%
`Propylmc glyml 618%
`
`Phcmharbiial Na
`
`LuminalNa éSanmfi
`Winthmp)
`
`Solulkm
`
`1M. 18
`
`Direct injection
`
`1 ml
`
`l‘rz‘xpylme glycol 40% Phenytoin Na
`Almhal 106i,
`
`Dilamln (Parlor: Dav'vs)
`
`Solutiim
`
`11% 18
`
`Direct injeciitm
`
`3-5 ml
`
`Fulycthylme glywl 50% Sectlbarbitai Na
`
`Sfimbarbltal Na
`(Wyethfiymml
`
`Prcgpylcm glyml 40% Trimammprim-Sul Septra {Burroughs
`Ethanm 19%
`famcthmamla
`Wcllmme}
`Bamrim QRQCth
`
`Solmitm
`
`1M. 18.1? Direct injemim
`
`1-5 m‘:
`
`fancentratfi
`
`lF
`
`Dilute 1:25
`
`Swill mi
`
`N.N~Dimethylacet«
`amide 190%
`
`1.5 ml
`Dilute l:5C=G
`IF
`Drug
`Amfidine Ccmcen—
`+ Diluam
`male 1: Parka-Davis}?
`EM 2 immmuswlar. l? x intravenous inlusinn. l3 : intravannus dizect injection
`" Drug available CUBE-Cliff me Unitrscl Slam;
`
`Amsacrinc
`
`respectivsly‘ In iis ximpiest form dalermining the drug
`solubility in water and pure casulvents wuuld allcw
`estimatiun 0f the ammunt and type 0f cmsolvem Yaquired
`ta attain a desired sulubility.
`11‘: musl C3335; him/ever.
`éeviaticms from logvlinfiar incrsases 0f sulubility 0cm; in
`aqueous mgalveni mixtums as indicated by curvature. in
`the Solubility plans. The deviatiomi are aliributcd m
`solvent-salvcm imeractiens (5. 25).
`this
`For firm apprmimalians 0f solubility hwwemt’.
`approach has been 3110mm m be usaful {26—27}. Chien
`(28) usecl this taclmiqw: and pularity indexes 0f €050}—
`vents m Caligulam {has pmlarity of a :sulmixm that pro-
`duced the gmatfsst sglubility 0f {he drug mmmnldazole.
`
`Aquemislwsolvent rating 0f canegpmding pelarity csulcl
`than be. calculated for either casclvam systems m provide
`qualitative idsntificatlun of solubility maximums {293
`438}. Polarity indexes 0f cammun water miscible cowl“
`wants have been tabulated aad discussed by Ruhim and
`Yalkuwsky. Thefie indexes reflect the Cfihesive pmperw
`this of the when: (sulubilily paramcier and inicrfacial
`iensim‘)‘ hydrogen banding ability {prawn dame-r and
`30251316!" daily}, and yolaréty (dielectric constwi}.
`Another mlubilibf determinatien approach particu-
`larly helpful for complex mixtures i5 a siatistiizal experlv
`mental dssign {31'}, Identifying the Optimum Cambina-
`lion of cesalvents fm' salubilizatian may reduce: the, wt
`
`334
`
`FDA Jaumal at Pharmaceafical Science & Techmlogy
`
`AstraZeneca Exhibit 2052 p. 6
`
`

`

`TABLE IV
`Surfactant Cmcenirations in Same Currently Marketed Paranterals {18, 19}
`
`
`(imam Name
`Trade Name
`Rnutes
`Administration
`
`Aim»
`Vehicle
`per Dose
`
`Tenipnside
`
`Vumon (Brigid-Myers
`Squibb)
`
`IF
`
`Dilute 1:10 or 1:?00
`
`‘3—9 ml
`
`Phyionadigne
`
`Konakion (Emilia)
`
`1M (ml)!
`
`Skeet iajestifim 1M
`
`14.5 ml
`
`Eli uta 1:5 var 1:20
`
`20 ml
`
`
`
`Di uh: 1:300 m‘ 1:500
`
`Bi {set injwtifln 1M
`
`Di ms: l;2€lfil:lfll}
`
`Di ma 1:300
`
`53 ml
`
`2 ml
`
`f m]
`
`5- m1
`
`1-25 ml
`
`Ell ml
`
`Salnbilixer in
`Marketed Vehitle
`
`NM~dimmhylamtamide :60
`mgiml
`Cremaphm EL 50?)
`mg} ml
`Dehydrated alcolml
`stifle?»
`
`9Glysmbate Si} 2% mgiml
`13mpylene 95160123.?
`mgzlml
`
`Cramophor EL 527
`mgg’ml
`Ethanel 493%
`
`Prnpylcns glyml 30%
`Pclysarbam 848 1.6%
`Polysarbatc 2G 0.028%
`
`Polysmbats SB 4%
`Propylme glyml 20%
`
`Cmmuphur EL 650
`mg] ml
`Alcahnl 32.9%
`
`Polyethylene: glyml 3012
`{350 mg! ml
`Ethyl alcohol 30.5% v.1?
`Pmysmbma Sf; 8%
`
`E’Qlyoxyethylamd fatty
`acid 153%
`
`Paslitaxel
`
`Tam} (Brfismleyars
`Squibb}
`
`Multivitamins
`
`M.VEI.~12 (Ram)
`
`1?
`
`IF
`
`Chlordlazepaxide HCI
`
`Librium (Ruche)
`
`IN 439]}-
`
`Cyclosporifla
`
`Sarlclimmunt: {Santlvzj
`
`IF
`
`Empaside
`
`VePesid (Brégtol-Mytzrs
`Onwlagy)
`
`IF
`
`Phymmdione
`
`AquaMEFl—l‘t‘TQN
`{Merck}
`
`{MS IE:
`
`Elk-act inject 1M,
`pmfcrmd
`
`P3040 £35m: oil 0.] 15
`film:
`
`Mimnamlé
`
`Manistat ix. (Jansscn)
`
`IF
`
`Dilute: 112i}
`
`Polysmbate 80 12%
`
`"Vitamin A
`
`Aquasol A Parenteral
`(Astra)
`
`Polymrbatc 86 0.088%
`
`Mtcplase
`
`Activase (Genentcgh)
`
`Na demxychmlatr; fi.4l%
`
`Amphamricin B
`
`Fungimne (Apetbemm)
`
`Palysmbaw 2Q 0.40%
`
`Calcium
`
`Polyssrbate 813 0.04%
`
`Cafazolin Na
`
`Calgijex iAbbmt)
`
`Rafael (Lilly)
`Ans-3f (SmithKllnc
`Beacham)
`
`IM
`
`IF
`
`IF
`
`IE
`
`Diffifit injectian EM
`
`1—2 ml
`
`{Meet infigsion
`
`20—103 ml
`
`Dilutc 1:58
`
`Dircet lujeclion
`
`3—23 ml
`
`(3.54 ml
`
`I‘M, EF, IE Direct injeclian
`
`Paylysmbam 8B 0.034%
`
`Filgrastim
`
`Neupngea (Amgen)
`
`Sodium dodccyl 511112313
`{3.18 mg! ml
`
`Ndesleukin
`
`Pmleuldn {Cetus
`Oncglogy)
`
`18
`
`IF
`
`Direct injaefim
`
`{125—3 ml
`
`Dilute 1:42
`
`1.2 ml
`
`3—? ml
`Dilute 1:50
`IF
`Cortlarone X IV (Sanofi
`Amiadamne HCI
`Polysorbate SE? 10%
`
`Winthrop?
`Mi 2 intramusculai} IF = intravcm‘ms infusiém. IS = intravenaus direct injection.
`1‘ {3mg availabéa immide it“: Unitas! Stamx.
`
`amount 0f msnlvam in the: formula (26), They alas)
`facilitate the study 0f systems. characterized by now
`”mar immams in mlubfiitya Optimization techniques in
`pharmaceutical {amulatiml have racently been rev
`viewed (32). Pm axample uf their 1133 is a fiimplex 3:331:11
`for selvant blands pradsscmg maximum drug solubility
`
`(2 .Lazeptable lavas; 0f Gogolvent in parentaml formula-
`
`tions. are flat casily dcfinsd. A rsyiew of cuzrfintly
`
`markated parenteral pmductg shaws. Ella: percentages
`range fmm ll) to 108% {Table Hi and lV). Appropriaie
`product amaunts are: often a mama}: of nunsidaring a
`diverge set of factors such as; l) administratian conéi~
`tions, Z) {(3131 £11086, 3) target pupulation and 4) duration
`(if
`therapy.
`’I‘Uxicity and adversse clinical affects at”
`cammon casalvams are summaz‘ized (33-34}, Racem
`safety assessment reviews of propylene glycol (35) poly-
`ethylena glyml (36) and glycerol {3?} have ham 13113:»
`
`Vol“ 5:}, N0. 5 ! September-0ciabar1993
`
`335
`
`AstraZeneca Exhibit 2052 p. 7
`
`

`

`TABLE V
`Same Currently Marketed Parenteraia Utilizing Camplexlng
`Agents, Mixed Mtgellea, or Lipid Systems
`
`Solubillzer
`Generic
`
`System
`Name
`Trade Name
`
`Camplexlng Agents
`Hydmlyzed
`gclatin 9.???
`Ethylenétliammt: Aminophyllma
`
`Cmttmtmpt‘tt
`
`Athcar (Rhone
`Paulette Remit)
`Amimaphylliné:
`{Alztmttl Elklng-
`Sim, American
`Regent}
`Amphtltmcin B Alclcm {The Lipa-
`mm: 60.)”
`
`Amphetcrlcln B Amphttcil {Lipa-
`:9.me Tszchw
`analogy)
`
`DMPG and
`DMPC lipid
`mmplex
`Na aheltzstcryl
`sttlfateg ml»
`Initial dispe t-
`sltm
`Mixed Micelles
`Glymcholic avid- Diazcgmm
`lecithin
`Gly‘mchttlit: acid— Vitamin K
`lacithin
`Emalsiuus 61‘ Lipasnmes
`Lipid emulsit‘m
`Diazfipam
`
`Valium MM
`(Rmhel‘l'
`Ktmakitm! l20
`{Rasher
`
`Lipid ttmulsitm
`Lipid emulsitm
`
`Pmpofol
`Perf’lmtrttdccalin
`
`Dlzac {Ghmeda}
`Diz‘lzcmulz’;
`{Bums x)“
`Dlptivzm (lemma)
`Flumttl—DA (Alpha
`Therapmtlicsl
`AmBisttme
`Amphutcricitt l3
`Lipowme
`
`(tharl"
`1M w intramuscular. IF - lntmvemmt infuttltm; lB ' intravcmmts
`direct injettéonl
`‘3 Drug available mttsitlc the Unitesl Statasl
`
`toxicity of” several cttsulvant vehicles in
`lighad. Lacal
`animals ls: tummarized in Table V].
`
`C.
`
`{£56 0f3£1lfiii€€ Active Agents
`
`Surface active agents are usually incerpcrated mm
`pamntumla it) prttvitlc 0m: of several desirable proper-
`ties; 1») increase drug solubility thmttgh micallimtivn. 2)
`to ptwsnt 6mg prttcipltatiun uptm dilution (Bill 3)
`impmvc ths‘: atability of a drug it“; Sttlutltm by manpow-
`timt 0f “‘11? drug mm a micellar structure (39}. and ill in
`pmtein thrmttlatitmst prevent aggregating) tint: Ii) liquidz‘
`air or liquidl‘soltil interlacial intemciiong.
`Table IV prtwides examplfis 0f FDA—appmwd paten-
`teral products cantainlng surface active ageing. While
`many different types at" gutfactants Exist {491 only an
`axtteme few have precedanct’:
`t‘m use in parenteral
`graducts. Fm cxamplc, fur ata'twilizatim 0f proteins
`against problems, of ttggrcgatitm. (ml); polyaxyethyletée
`sorbitatt moneoleate {pttlysmbalc 80’)
`is an FDA—
`agpmved surfattlam (l8), Othttt sutfmztants whitth have
`I32m usail
`in parenietal products are pttlttxamer 188
`{polyoxyethylenawpolyuxypropylmt: copttlymwl‘ pelysww
`bate 20 and 40 {polymyezhylene-ptylyttxypmpylEtna (pal?
`myazhylane SOThllal‘t mnnm‘atty acid esters), Cmmttphm
`ELF?“ and Emulphaor EL 33% {ptalyethmylatttd fatty acid
`islets; and oils). Which surfactant is mam talkative: as; a
`$t>lttbilizer or Stabilizer it; mitten a matter of empirical
`
`336
`
`investigatian (4E5. Detailad FfiVlfiWS of micsllt: struc-
`turesl characterization techniques, and pharmaceutical
`applicatians have been publisheé {42s 43}.
`The tmticity of surfactants tepm‘teti in the litez'atttre
`prim to 983 are: summarizecl by Atlwmfld and Florence
`{43}, Reviews on th: pharmacolagy of polysttrbate 8f)
`{'44} anti the incidence of clinical glde effects Bi Crema-
`
`phm‘ 3U? {42} have:
`{36511 published. Childrcn and
`newborns may be particularly sensitivt: to these agents
`and administratitm to this; populatian is discutged {:46}.
`
`L! 536" of Campiaxt‘ng Agent‘s
`
`Cemplexation Elf water insoluble drugs usually in-
`volves the? incorpmatimt 0f Ihfi drug within tha inner
`core 0f the complexing agent so that tha Guitar hydra
`philic gmups 0f thc: camplexlng agent interacts with
`water rendering the sample}: soluble.
`An example: Bf successfitl applilzatitm at this techmb
`agy is Amphecll‘gg a lipid cemplax formal between
`amphotericin B and sodium Chclastml sulfatfi, a nam-
`rally {recurring cholesteml metahalite (4?). In solutiom
`the: cumplex is pestulated to: be a stable di5€»like
`structure that remains intact in the systemic circulatt’mt.
`Comparative stitches in animals with micellr: solubillzad
`amphetaticin B (Fungimttelfi) have shown a significant
`reductian in systemit:
`toxicity :33 a result 0f altered
`systemic distributitm and elimination chat‘acteristies (48}.
`Naturally ancurring Cycladextrins, partitiularly S—Cyalca—
`dextrin, are able to temple): water insaltable drugs and
`fitndffil‘ them Sulfiblfi in water. However. B-cyclodexttin
`have bean associated with ranal taxicily upnn parenteral
`adminigtratiant The taxlcity has, been attributed the low
`aqumus solubility of B~cycladaxttin and precipitation in
`the: kidney. Newer cyclodttxttlns are chemically modified
`m improve: water solubility and lnttrease their usefulness
`{49}. Brewster at al. {50} have described the preparatien
`and successful use of chémically modified (:yclndaxlrirts
`such 33 2-hydrogpmpybfiwcyclcdextrin in smlubilizing
`and even stabilizing various praising and paptidtss.
`An example where the drug was mt incorpflmtecl
`within same kind at” matrix. but cambined with an
`adéitivc to abtain basically a solublfi salt mmplex
`involved ascmbic acid (‘5 1). Similarly, tromvathamine has
`been tepvttrzd to sulubilize zameplrac, an attienic drug,
`by micelle {aswciatian colloid) fotmation {523. The
`aqumus Solubility of metronidamlfi was rapurted to be
`enhanmd by the watar saluble vitamins nicotinamide,
`ascarbic acid or pytidoxine EC] {32}. A saga-like. struc-
`ture farmed by the vitamins: amuttd muleculea ttf mam)-
`tzidazole was pmtulated‘
`
`E. Emm‘sian Systems
`
`If a molecule has sufficient lipid solubility? Emulsions
`may be: employed. Typical emulsions contain tréglyccride—
`rich vegetable rails and lecithin and may aim cantain
`maimic sutfaca actlva agents as smulslfying agents,
`lnmluble drugs may be inmrparated into commercial
`fat emulsiatts at
`through emulsificatien 0f tha ail—
`solu‘aillzed drug. The farmer is uaually not sucnewful
`
`FDA Jaumal at Phamaceutlcafi. Science 3: Technology
`
`AstraZeneca Exhibit 2052 p. 8
`
`

`

`because drugs influence the stability ef these eemmer-e
`Ciel emulsions (53+).
`
`Limuleiett femules have shown edvanteges ever high
`eoeolvent levels by reducing local veneue itritatiett {55%).
`While emulsions hold peteniial as; carriers fer lipaehilic
`drugs, great ehellenges exist in; i} eifieient incorpora-
`tion 01’ the drag into the dispersed phase? Z} validation ef
`censieteney in preparation anti sterilizetien, anti 3)
`dependable biolegieel evaluatien ef the safety eed
`ellieeey ef drags delivered frtxm emulsions. These topics
`are addreseetl in Some detail in several review articles
`
`{SS-58).
`Mere recent examples include a parenteral water-in-
`eil emulsion at an LH~RH analog (5%) and solubilizetien
`of an anti~HlV thiecarhamate drug ‘tty extemporaneeus
`emuleifleatien (60). The patent literature contains a
`large number of references claiming safe end Steele
`emulsiee eystems fer parenteral injection. The eemmer“
`Ciel application for drug delivery has yet ta be pre—
`neuneed in the United States. Marketed precincts are
`ghastly fennel
`in the Eureeean and Japanese market
`{Table V).
`Miereemuleien systems are thetmedynemically stable
`ttaespareht eolleidel diapertiens. The advaeteges they
`have ever maeroemttlsiens are their stability and ease of
`manufacture. Dteplet sizes are typically ill times smaller
`than maememuleiens and are an the ettiet 0f lflwlllll
`
`am. To achieve such a small Size, ueuellgg high amounts
`ef surfaetant are required {43), Micmemulsien syetems
`have found utility in enhancing p