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`harmaceutica Science and
`
`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 IPR2017-00905
`
`

`

`REVIEW ARTICLE
`
`Solubility Principles and Practices for Parenteral Drug Dosage
`Form Development
`
`STEPHANlE SWEETANA and MlCHAEL J. AKERS‘"
`
`Phommssmiml Sickness, Lilly Reward: Loéamwn‘es, Indiawpolés, Indiana
`
`Introduction
`
`A common problsm ospetlenood in the early develop-
`ment of drugs inteoilod for parontsrsl, especially intravo
`nous, administration is the solubllization of a slightly
`solubls or waist insolusz active ingrodisnt. Drug solubi—
`lizatlon has been tho subject of many scientific articles
`and textbooks {refsrcooso throughout this article); yet
`dospito this ottootiott and available literature, product
`development soiontists still encounter significant difficul-
`tiss in solving their solubility problems.
`Theories of solute solobilizstion are not easy to
`undsrstand. Solubilizstioo ptoosssos are: amazingly com—
`plos: and require a fair amount of sxpettise in physical
`chemistry to interpret and apply current theoretical
`models. Much of the literature deals with solubilization
`
`theory and does not offer much practical help to the
`inexperienced scientist under a lot of pressure to find a
`solution to his/her solubility problem.
`This article intends to help the scientist in early drug
`formulation design for parsnterally administerstl drug
`prod mots by reviewing pertinent literature on solubiliza-
`lion and reducing it to simpls approaches one can use to
`solve solubility problems. The classical theories of solo-
`bility, and how they relate to pharmaceutical systems of
`interest will he. roviewod and practical spplioations
`discussed. Because of the common concerns regarding
`oosolvent
`toxicity and acceptability by nteclissl and
`regulator}; oodles, we also will treat this topic in some
`detail.
`
`l. Pertinent Theory of Solublllzation of mugs
`
`Solubility theories deal with conversion of a substance
`from one state to another. sod tho equilibrium phenom-
`ena that are involved. Through pioneering work of
`Remy, Raoult and vzm’t Hoff in the lots mall’s. the
`propsrtiss of various solutions have been defined in
`theories. These early thsories form the basis by which
`most: complex systoms, such as thoss socoootored in the
`biological soiencss. are oomparsd and understood.
`No single. thsory can adequately explain solubility
`behavior of uncharged molecules in a sarist of solvent
`systems. Bash theory is suited for select combinations of
`
`Reosivsd loos 2&3, 199:3. Accepted for publication March 21. 1996.
`‘ Author to whom comspondence should be addresses: Lilly Corpo~
`rats Canter, Indianapolis, IN 413385.
`
`solutes and solvsnts when: certain iotomolsculsr forces
`
`are assumes to predominate, or conversely, be absent.
`Tho classical theorios of solubility have best: oxplained
`most simply in terms of lot-smolecular interactions.
`Ideal solution theory assumes soluts~soluts,
`solvent—
`solv‘sot and solute-solvent interactions are completely
`unifomt
`is strsrigth and nature. An sxsmpls of a.
`solution behaving ideally is a non~polsr solute in a
`nompolor solvent such as naphthalene in horizons.
`Regular solution theory ovoltrsd to account for tho imbal-
`ance of intomoleoolat interactions that often oocur
`
`ostwssn disslmllar systems of a. solute and solvent. The
`focus of this theory are systems of low polarity such as
`steroids in hydrocarbon solvents. Extendsd regular solar»
`clot: the?er incorporated additional parameters such as
`dispersion, pols: and hyétogeoboodlng interactions
`into regular solution theory. Various approaohes have
`been used to reprosent these molecular interactions,
`leading to a variety of models to predict and explain
`solubility behavior of polar solutes in polar systems, each
`with difisrsnt approximations and assumptions (1—4).
`In most pharmaceutical systems, the routine applica-
`tion of tltoso models to Media solubility and simplify
`formulation development is complsx. Most drugs of
`intsrest ars lonizabls, contain polar polyfunotional
`groups, and are capable of forming multiple hydrogen
`bonds. The majority of parontsrally asceptable oosol-
`vents-such as propylene glycol, polyethylene glycol,
`ethanol and water—are capable of self association
`through hydrogen bowl fonnatioo. Such intozactlons
`may alto: solvent structuro and, as a result, influence:
`solubility in an unpredictable mannsr (1). Examples of
`this phonomeos are. dsviatioos from log-linear solobliza—
`tics of noopolat solutes in a polar oosolvsot system {5).
`For the models to atlequstely doscribe solubility behav-
`ior, proper weighting must be assignsé to the tolativo
`importance of competing self-associations and strong
`intermolecular interactions. Currently this is being mock
`sled by various computer 'mtonsive groupacontribotion
`approaohes, some of which allow for the mutual interac-
`tions of various functional groups {1}.
`In the. biological scisnoss, many solutes of interest are
`capable of acting as acids or bases. In an ionising media
`such as water, they may dissociate into ions which are
`usually highly Watfif soluble. To what extent a molecule
`is ionized in an aqueous solution is largely dependent on
`its plis and the pH of the media. The Hendersonm
`
`330
`
`FDA Journal of Pnsmaoemlcsl Somme £42 Technology
`
`AstraZeneca Exhibit 2052 p. 2
`
`

`

`Hasselbalch equation is a. mathematical expression of
`this relationship {3). In formulation devolopmem, con—
`Sldorafion of the amount of tin—ionized drug in solution
`is helpful to avoid unoxpoctotl presipli’alion of this {om}.
`As the 33H of a drug solution is changed, this amount of
`free acid or bass may increase and m’ontually exceed tho
`limilod solubility of this form. ll: is possible :0 calculate
`the pH of precipitation and of maximum solubility, if the
`pKa of the moleculo and the solubility of tho Jun-ionized
`and ionized forms are Room: (3, 6}. {Summally$ two pH
`units above or below tho plme waluo oatahlishe-s the
`desirod pH for fonnulation. For drug moloeules with
`muliiple ionizablo groups these equations are: mom
`complicated to apply and so experimentally generated
`solubility data arc umally collected
`Through our own axporioncm we find that thoory gives;
`us some direction with respect
`to experimental
`ap—
`proaches, but we still need to ml}: on the empirical
`experimentation lo Screen for Systems which ofier the
`most promise in solubilizing waler-insolublc drugs.
`
`ll. Formulation Design
`
`to increasa the
`the first approach usocl
`Usually,
`solubility of an insoluble drug in water is to form mom
`water soluble galls. Barge and coworkers (7) wrote: what
`l8 now 3; mar classic fallow of salt form straiegies
`acceptable for pharmaceuticalo. If salt formation is not
`possible, mg.
`too unstable, or (loo-:3 not model
`the
`molocule sufficiently watar Soluble, a series of formula-
`tion approachos may be investigated. Table I mmma~
`rizes those gsneral strategies‘ Often a useful approach to
`lncmasa the aqoeous solubility of an iomizable [frog is
`pH ad§ustmem The next approach most fioquently tried
`is the mo of matey—miscible msolvoms. Other ap-
`proaches to be: discussed brlofiy lncludo the use of
`surfaoo active: agents and comploxlng agents. Develop-
`ment of emulsified and colloidal drug do ivory systems
`for intravenous administration are bcooming more widely
`and succesgfully applied. They may confer to the en-
`trapped or associated drug significantly dif’crent propor-
`
`TABLE l
`Summary of Parenteral Fofmulatéon Approaches
`
`
`
`Approach
`
`Examples
`
`Important Formula
`Considerationa
`
`Useful Tests
`
`pH adjuslmom
`
`pH 2 m l2
`
`Cosolyom
`
`Polyelhylom: glygol
`Propylcno glycol
`Ethanol
`Dimoihylacelamidc
`
`Surfacxz Active Agents
`
`Folymmates
`Poloxamsrs
`Cromophor BL
`Lecithin
`Bile salts
`
`Drug Stability
`pH
`ions to buffer or adjust pE—l
`Drug preslpizzétion upon infusion
`drug concentration
`use of bufferlbuffsr capacity
`infusion rate
`Formula irritation
`isolonloity
`infusion rate 84 duration
`drug vs vehicle
`drug precipitation
`
`Systomio toxicity
`total oosolvont administered
`Drug protipilztion upon infusion
`drug concontralion
`infusion taro
`Formula irritation
`isotonioity
`infusion rate 8;: duration
`drug v3 vahiola
`drug precipitation
`
`Hyporsemitivity in animals
`Formula irritation
`isotoniaity
`infusion rate 6: duration
`drug vs whistle
`
`Complexing Agents
`
`qrolodextraos
`WNW—soluble vilamins.
`
`Purity of exciplents and drugs
`Formula irritation
`
`Dispersed Syslizmfi
`
`Emulsions
`Liposomoa
`Nanopafiiclas
`
`lgownicity
`infusion rate 8: duration
`drug v3 vehich
`
`Sterility
`Particle size
`l’harmacoklnatias
`Stability
`
`pH rate. profile
`pH solubility profile
`Proofing point depregaioo
`In vim) precipitation model
`fa Vim phlebilis model
`la vino cell lysis Studios
`
`Mlxtuza studios for maximum
`solubility
`In vim; precipitation moficl
`In vim} phlebitls model
`{:2 vim: cell lysis studios
`
`In vim? phlebilis model
`In vitm coll lysis Studies
`
`Phase solubility diagrams
`In vivo phlebitls model
`[:1 vim) cell lysis studies
`
`Particle size
`
`Vol 50, No. 5 ; Septemberwomobor was
`
`331
`
`AstraZeneca Exhibit 2052 p. 3
`
`

`

`ties from the free form. trimming the appurtenity E0
`pmlottg drug presence in the liltiotltttteetti ut‘ to alter
`dispt’isitien in the body. "Hermie" methedfi. regretted it“!
`the literature for variant: cancer drtigei will elect be
`reviewed although these methods: use types and amounts
`at exeipiettts that pmhebly wauld tmt commenly be
`mneideretl appmmme fer intravenmis administratitttt
`it;
`The basalt; for reliable ftitmulzttion developmettt
`acettrate determination ttf solubility Traditittnal method-
`ology is the “equilibrium method" {2%) where exeees drug
`it; adtietl m the solvent syetemt and same means {3f
`agitation is employed tinder censtant
`temperature.
`Samples are withfirawn. filtered. and analyzed fur (lng
`caneentration over a pcried of time and equilibration is
`demunstrated by unifmmity of the data are}: the time
`intewali Fm immineg soluble drugs where cquilibria are
`SlOW‘ accurate deterttiittatitms Elf wlubility may be diffi-
`cult. Useful techniques in these instances include using
`highly spesific analytical methods to detect parent cont
`pCIURdS? minimizing the ameunt 0f excess solici added,
`and assuring sufiiciettt equilibration time {l}. Solid state
`factors and batchbtewatch uariatitm tdifierent poly-
`mflrphs, hydration state, crystallinity, cryatal hemagene-
`ity, and impurities) may affect repmdttcibility {if drug
`wlubility determinatiens.
`
`A. :25 Adjustment
`
`Current FDA appmved marketecl parenteral prodw
`eats range in pH from 2 t0 1 l. A eempreheneive listing at
`these products may be found in Table II. For biommpatw
`ability reasons, formulatien of injeetahlee within the pH
`ranges of 4 to '8 is mast Ctlmtt‘mrh However,m to achieve
`sufficient drug selnbility. a pH eutsiele this range may be
`necessary
`“lite pH at whieh a product is; formulated is usually
`tietemtittecl from the pH seluhiiity and pH rate profiles
`of the drug (9}. A recent example of their applieetiott t0
`aid parenteral fmmulatitm {levelttpment is {fl-988‘ a
`eholeeyetokinin-B teceptm‘ antagmnist (ill).
`Additicanal formulatimt variables 10 be coneidered are
`
`the necessity at)? a buffer, buffer capaeity. and drug
`eencentratien, These can influence supersaturated drug
`concentratiens in the blmdstream, a eonditicm that: may
`lead £43 in viva drug precipitatian. The blaw is very
`efficient at pH neutralization and manually maintains a
`narrth pH range of 7’38 to 7.4.7.. Far example a law
`incizlence of phlebitis was observed in the rabbit ear vein
`model when solutions over the pH range at 3 if) 11, with
`buffer cancentratiuns 0f approximately 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 asiubility is platted as a,
`function 0f dilutimt, and in vim) dilution experimenie
`were shesth to be effective tools in evaluating the attility
`of the prBQlflbillzfifid drug to remain in solutien dilutien
`{12, 33). Davie et al. {14) shewed that it"? vii/e pteeipita-
`time of the pH-selubilizetl drug, ditekiren was dependent
`upmi drug cattcentratien and infusion rate. Low eoneem
`ttation drug mlutiatts, which are rapidly diluted below
`
`332
`
`gammtimt suitability and tepid infusions; were preferred
`m minimize preeipitatiee.
`The most eemmtmly used buffet components in paten-
`terel precincts and their pKa‘s are: citric: acid {3.13. 436,
`6.40), acetic acid {4.76} and phosphoric acid (2.15, 120.
`$233)» When buffers are employed. the stability {if the
`molecule must aim he Ctfififildemdt eittce it may be
`influenced by the ions in eolutiett (9)» Examples of buffet
`catalyzed salutien degradation include famotitlitte. a
`histamine H2 receptor inhibitor {15) anti loracat‘bef, a
`zwitterienie eephalosgarin (let
`
`3.
`
`like Of Comments
`
`lit recent years, surveys ttf FDA-apprcwed parenteral
`products {17—19) show five water-miscible cesolttentea—
`glycerin, ethancl, propylene glyml, pelyeihylene glycol,
`and N,N,-dimethylacetamidew—as compenents 0f Sterile
`formulations (Table III and IV). Casaltrents are emv
`pioyed in approximately 10% of FDA appraised parenw
`teral products. They are useful because they may often
`prmitle expsnential increases in selubility (23) and also
`allow exclusiein 3f water for compounds susceptible t0
`hydmlysis.
`Investigatian 131' the salubilizing patential of various
`cosolvenis may be approached empirically by determin»
`ing the mmpflttnds solubility in emolvem campositions
`similar to marketed preducts {EL-23L cut by one of
`several systematic appmaehes, such as l0g~lineat selubib
`ity relatienships 0r statistical experimental design.
`In the study of leg~linear solubility relatienships,
`Yalltowsky and Rosemen (20) inveetigatetl a rattge at
`salutes in binary casement mixtures of ethatictl, propylm
`ene glyeel, and glycerin in water and discussed the
`cleseness of fit of apparent selubility m a log-linear
`eelebility equatien. “Briefly. this technique involves experi
`mentally determitting the selttbility of a competmd in
`immersing percentages of a eosolvem and generating a
`semi~logatithmie plat of the apparent solubility of the
`drug as a function 0f the volume-fraction Of the meal-
`vent. Using the slept: and the mlubility ef the catapulted
`it: pure water, an equation may be written it} deseribe
`the solubility in a binary system.
`Assuming that: the legulinear increases in eelubility 0f
`individual cosolvems are additive? equaticna may alas be.
`written fer ternary and quaternary mixed, casewth
`systems {24} Mathematically, these relaticiiships. are
`described by the following equatimts:
`
`Bitter}? mmivetzz gusts???
`
`log CK = lug CW + tax};
`
`Ternary awoken: system
`
`leg Cl. = leg Cu. + egfi + mag
`
`Quatemmy megahertz getem
`
`tog Ct --« tog Ci + 09-5} + at}; + mt
`
`wheee Cw is the drug selubility in water; en’s are the
`slopes of the semi
`logarithmic plots; C} is the drug
`solubility; f is the valume Erection 0f the msolvent; and
`the subscripts a, b, 2: denote the easements/4, B, and X
`
`FDA Jaumal at Pharmaceutical Science 3: Teefinetegy
`
`AstraZeneca Exhibit 2052 p. 4
`
`

`

`TABLE 3!
`Examgzias of Marketed Parentara‘ Precincts wi‘ah Schaan pH Dutside Range :3? 4 is 8 (18, 1Q)
`
`pH
`5%
`Geueric
`Marketed
`
`{Cflnfifitfltfli}
`Afiustmmt
`Name
`Trade Name
`Farm
`Routes
`
`Lame acid, Nam-I
`Benzenesgifonis 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
`
`Lactigt acid
`Lactic acid, ethyl
`133mm
`
`591mm
`Smutioa
`
`Powder
`Powdw
`Conwmraie
`Powdar
`SC.le i011
`Sam ism
`
`Pawdet
`
`80111 km
`Sc} 11 ion
`
`St) La. im
`
`
`
`
`
`So 11 im
`So 11 ion
`30 n im
`
`So u ism
`80 11 Sen
`
`Si) :1 ion
`So n im
`Pawth
`80111 icm
`$0111 ien
`So :1 ion
`So 13 ion
`So 3 ion
`39111 3200
`St? 11 iml
`
`13, IF
`18, IF
`
`I3
`1M, [F
`IF
`IE, I?
`IF
`1F, EB
`
`{F
`
`1M, £13“, EB
`1M, EB
`
`1M, 18, IF
`
`IM, 18
`1M
`113, IF
`
`IF
`1M, IF
`
`EM, 2F
`if?
`IF
`1M, 113
`IM, IE, IF
`IF
`IF
`IB, IF
`IM, IE
`1133, EM
`
`vadar
`Powder
`
`IM, 13, IF
`3F
`
`Salution
`
`IE, I?
`
`Powder
`Pawder
`
`Paw-def
`
`1M, IF
`3TB, IF
`
`IM, IE? IF
`
`Sfliutiun
`
`13, EM
`
`vadm
`Soiutiun
`Soiuiiwn
`
`EB, IF
`EB
`IF
`
`Sniatiun
`Scimian
`Scimitar:
`
`13’ IF
`[R
`EM, EB, 2F
`
`Ingmar (Sanafi Winthmp)
`Tracrium {Burroughs
`Weilceme}
`Librium (Roche)
`Emma-Con {Romig}
`Cipro 131 (Miles)
`DTICiDoms (Mfias)
`Immpin (DuPont)
`Cardimm (Marian Marta“
`139w)
`Vibramygin IV (Rmrig,
`EikinsySinn)
`Inapsine {Janssen)
`Ergmratc Maleate (Liiiy)
`
`Innwar {131155511}
`
`Robina? {Robins}
`Haida] (McNeil)
`Nermodyne {Scheringj
`Trandaie (613%)
`Aidomet Ester HQ} (Merck)
`Methargéne [8311602)
`
`Varscd (Racks)
`Primacm {Sanofi Winthrop}
`Mix-1min {mama}
`Nubain (Dnan)
`Naman muffin!)
`Zofran (Germans)
`Pimcin {Parkmflavis}
`Papavcrine HCZ {Lilly}
`Pyriéflxinc HG? (Stan's)
`Priscaléna HQ {(13133)
`
`Diazmx (IA:de
`Yfl‘iiffifi {Eunuughs
`Weflcome}
`Aminopilyfliaa {Afibmfia
`Skins—3km, Amwican
`chem}
`Amyéal Na (Lilly)
`Inwran (Burmugfis
`Wcliwme}
`PuiycillimN {Apoihacm}
`TuiacillimN (8369mm)
`Qimipen—N Wyeth)
`Ceiastme Phnsghata
`(Schariflg)
`Sodium Diuril (Merck)
`Hypcrstai (Schcriag)
`Slitghusmfi {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%}
`11,6
`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
`
`HCUNaOH
`
`N30}!
`
`NagHFO4, N303
`
`NaOI—i
`NaDH
`
`9.2
`84 l
`33.3
`
`NaOH
`N308
`NaQH
`
`Fiuvmuracfi (Kathe)
`Fnivitt (Lederie)
`Fumsemide
`(Hmchst-Roussgi)
`IE3
`Fawder
`fiytmane {Syntax}
`flanciclmir Na
`I?
`8.1
`Leammrin Ca
`Waiimvmin {Immunex,
`Pawder
`EM, 13$ IE3
`Burmughs Wellmmc)
`
`9.5405
`Na carbanatc
`Methohexim? Na
`Bravita] Na (Lifiy)
`Powder
`EB, IF
`1M = intramuscular, IF = intravmtma infusiam IB ~—~ intravamus dércct injactim‘
`
`V9158, N0. 5 I Septemhes-Gambe: £996
`
`333
`
`AstraZeneca Exhibit 2052 p. 5
`
`

`

`TABLE ll!
`Casalven: fiancemratiens in Some Currently Marketefi Paranterals {18. 19)
`
`Cnsslvenl in
`Marketed Vehicle
`
`Appx.
`Vehicle
`Marketed
`Generig
`Name
`Trade Name
`Farm
`Rallies
`Administmtim
`per Base
`
`
`Elhannl mm
`
`C‘zamnminc
`
`BEND {Brisml—Mycrfi Drug
`Onmlmgy)
`+ Dilucm
`
`1F
`
`Dilute i110
`
`34ml
`
`F'rupylcm: glyml 4(qu Diacham
`Ethyl alurl‘ml 1053*?
`
`Valium {Rucltgl
`
`501mm
`
`1M. IE
`
`Dime: injacilun
`
`0.34 ml
`
`Pmpylme Glycol 4W?»
`Almth ll]???
`
`Digmin
`
`Larmxln {Bmmuglm
`Wcllmmc")
`
`Sulmian
`
`IE
`
`Direct injectlan
`
`1-3 m]
`
`Benzyl alcmhal 5%
`Pmpylcna glyml 50%
`
`Pmpylcnc glycol 25"}?
`Ethane-l 25%?
`
`Pragylena glywl
`10.35%
`
`[imam]! it]???
`
`Dimenhydrinatc
`
`Dlmanhysflrinate
`(5:13:33)
`
`Eelmim
`
`1M. IF
`
`Dilute 1:10
`
`1 ml
`
`Esmolal I‘lC‘l
`
`Brevibliyc {Dquz}
`
`Cnncentralc ll:
`
`Dilulfi 1:25
`
`l~lll ml
`
`Hydralazins HC‘l
`
`Aprssolinc H‘C‘l (Ciba) Selutlzm
`
`IMk [8
`
`Direct injectitm
`
`05-1 ml
`
`Kemrolac
`Trumcthamina
`
`hu‘azepam
`
`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
`Benzyl 31mm)! 2%
`Propylene glyml
`
`Pmidonc: Ell mg
`Dllncm {10 ml)
`PrOpylcne glywl 6 ml
`Ethanal €152 mL
`
`Emanul 33%
`Frapylcnc glyml if???
`
`Atiwn (Wyeih-
`Agent}
`
`Melphalan MC!
`
`Alkrcran gBurmughs
`Wellwmc}
`
`Drug
`+ Dilucm
`
`IF
`
`Dilute wastltute
`:> 1:10
`
`13 ml
`
`Nitroglycerin
`
`Tridil (DnPQm)
`
`Cmcemrate IF
`
`Dilute 1:100
`
`2.5-“) ml
`
`Pmpylma glym! 40% Pent-zlbamiml N3
`Alca’nml 1G9?
`
`Nembutzil (Abbefi)
`
`Solutitm
`
`1M. 18
`
`Slaw direct injecticm 2 ml
`
`Almlml 10%
`Propylcnc glyml 618%
`
`Phcmharbiml Na
`
`LuminalNa éSanmfi
`Winthmp)
`
`Solulkm
`
`1M. 18
`
`Direct injection
`
`1 ml
`
`f‘rmpylme glycol 40% Phenytoin Na
`Almhal 106i,
`
`Fulyethylme glywl 50% Sectmarbitai Na
`
`Dilamln (Parlor: Dav'vs)
`
`Solutiim
`
`11% 18
`
`Direct injeciitm
`
`3-»:3 ml
`
`Sfimbarbital Na
`(Wyelhfiymml
`
`Solmitm
`
`1M. 18.1? Direct injemim
`
`1-5 m‘:
`
`Pmpylcm glyml 40% Trimammprim-Sul» Septra {Burroughs
`Emma! 19%
`famcthmamla
`Wcllmme}
`Bamrim QRQCth
`
`fancentratfi
`
`lF
`
`Dilute 1:25
`
`Swill mi
`
`N.N~Dimethylacet«
`amide 190%
`
`Amsacrinc
`
`1.5 ml
`Dilute 1:568
`IF
`Drug
`Amfidine Ccmcen—
`
`male 1: Parka-Davia)" + Diluam
`
`EM 2 immmuswlar. l? x intravenous inlusinn. l3 L- intravannus dizect injection
`" Elmg available CUBE-Cliff me Unitrsd Slam;
`
`respectively In iis ximpiest form datermining the. drug
`solubility in water and pure caselxzents wuuld allcw
`estimatiun 0f the ammunt and type 0f cmsolvem Yaquired
`ta attain a desired sulubility.
`11‘: must C3335; him/ever.
`éel’iatiflns from logvlinfiar incrsases 0f Sulubiliw Draw; in
`EIQLEEOUS mgalveni mixtums as indicated by curvaturs: in
`the Solubility plans. The deviatiomi an": al‘iributcd m
`solvent-salvcm imeractiens (5. 25).
`For firm apprmimatians 0f solubility hwwemn this
`approach has been 3110mm m be usaful {26—27}. Chien
`(28) met? this taclmiqw: and pularity indexes 0f €050}—
`vents m Calgulam {has pmlarity of a :snlmixm that pro-
`duced the gmatfsst sglubilily 0f {he drug mmmnidazole.
`
`Aquemislwsolvent rating 0f canegpmding pelarity csuld
`than be. calculated for {filler casclvam systems m provide
`qualitative idantificatlun of solubility maximums {293
`3(3):. Polarity indexes 0f cammun water miscible casual“
`wants have been tabulated aad discussed by Ruhim and
`Yalkuwsky. Thefie indexes reflect the Cfihesive properw
`this of the when: (sulubilily paramcier and interfacial
`tension)‘ hydrogen banding ability {prawn danor and
`30251316!" daily}, and yolaréty (dielectric constgm}.
`Another alllubilibf determinatien approach particu-
`larly helpful for complex mixtures i5 a siatistiizal experlv
`mental dssign {31'}, Identifying the Optimum cambina-
`lion of cesalvants 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}
`
`Sminbilixer in
`Marketed Vehitie
`
`NN~dimethyla§etamide :60 Tenipnside
`mgs’mi
`Cremaphm EL 50?)
`mg} ml
`Dehydrated alcohu]
`stifle?»
`
`Generk Name
`
`Trade Name
`
`Rnutes
`
`Administration
`
`Vumon (Brigid-Myers
`Squibb)
`
`IF
`
`Dilute 1:10 or 1:300
`
`9Giysmbate Si} 293 mg! ml
`9ropyiene 95160123.?
`mg} mi
`
`Cramophor EL 527
`mg! ml
`Ethanel 493%
`
`Pmpylcns glym130%
`Pelysarbam 848 1.6%
`Polysarbatc 2G 0.028%
`
`Polysmbats SB 4%
`Propylme glymi 20%
`
`Cmmuphur EL 650
`mgfmi
`.Aicehm 32.9%
`
`Potyethylene: giyml 301:!
`650 mg! m
`Ethyi 31mm} 30.5% v.1?
`Pmysmbma Sf; 8%
`
`E’Qiyoxyethytamd fatty
`acid 7Afl%
`
`Aim»
`Vehicie
`per Base
`
`5—9 m!
`
`14.5 m}
`
`‘20 ml
`
`5 m1
`
`2 m]
`
`5 In]
`
`5 m1
`
`
`
`Phyionadigne
`
`Konakion (Emilia)
`
`11% (ml)!
`
`Skeet iajestian 1M
`
`Paslitaxel
`
`T21on (Brfismleyars
`Squibb}
`
`Multivitamins
`
`M.VEI.~12 (Ram)
`
`1?
`
`IF
`
`Di uta 1:5 var 1:20
`
`Di uh: 1:300 m‘ 1:530
`
`Chiordiaztpaxide HCI
`
`Librium (Ruche)
`
`1M 439]}-
`
`Bi {set injwtifln 1M
`
`Cydosporim
`
`Sandimmune {321mm}
`
`IF
`
`DE 131:: 3:3}12190
`
`Empaside
`
`VePesid (Brégtol-Myars
`Onwlagy)
`
`IF
`
`Di ma 1:300
`
`Phymnadione
`
`AquaMEFHYTQN
`{Merck}
`
`{MS IE:
`
`“mix-{set inject 1M,
`preferred
`
`L25 mi
`
`PEG:in $3533: 0519.] 15
`mHmi
`
`Mimnamlé
`
`Manistat ix. (Jansscn)
`
`IF
`
`Dilute 112i}
`
`213ml
`
`Poiysmbate 38 12%
`
`"Vitamin A
`
`Aquasol A Parenteral
`(Astra)
`
`Poiymrbatc 86 0.088%
`
`Mtcplase
`
`Actixrage (Genentcgh)
`
`Na dcsnxyfihniatrz fl.41%
`
`Amphamricin B
`
`Fungimne (Apetbemm)
`
`PQEywmaw 2113 0.40%
`
`Caiciirim
`
`Pmyssrbate 813 0.04%
`
`Cafazoiin Na
`
`Calgijex iAbbmt)
`
`Rafael (Lilly)
`Ans-3f (SmithKlinc
`Beacham)
`
`IM
`
`IF
`
`IF
`
`IE
`
`Diffifit injectian EM
`
`1—2 m1
`
`£32er infission
`
`20—108 mi
`
`Dilutc 1:58
`
`Dircet Mention
`
`3&3 m1
`
`0.54 mi
`
`I’M, EFT IE Direct injection
`
`Pulysmbam 8B 0.034%
`
`Filgrastim
`
`Neupflgen (Amgen)
`
`Sodium dodccyl 5111122113
`{3.18 mg! m!
`
`Ndesleukin
`
`Prnleukin {Cetus
`Gaming?)
`
`18
`
`IF
`
`Direct injectinn
`
`{125—3 mi
`
`Dilute 1:42
`
`1.2 ml
`
`3—? m1
`Dilute 1:50
`IF
`Cortiarone X IV (Sanofi
`Amiadamne HCI
`Polysorbate SE? 10%
`
`Winthrop?
`EM 2 intramusculai} IF = intravcm‘ms infusiém. IS = intravenaus direct injection.
`1‘ {3mg availabéa immide it“: Unitas! Stamx
`
`amount 0f msnivam in the: formula (:26), They aim
`facifitate the study 0f systems. characterized by now
`"mar immams in mlubfiitya Optimization techniques in
`pharmaceutical flammath have tamame been rev
`viewed (32). Pm axample uf their 113% is a fiimplex 3:331:11
`for salami: biands pradsscmg maximum drug solubility
`
`(2 .Lazeptabie lavas; 0f COSQIWSHIT in parentaml formula-
`
`tions. are flat casiiy dcfinsd. A rsyiev: of cuzrfintly
`
`marks:th parenteral pmductg shaws. thaz percentages
`range fmm {O to 108% {Table Hi and H7). Appropriaie
`product amaunts am often a mafia}: of nunsidaring a
`diverge set of factors such as; I) administration conéi~
`tions, 2) mm! £11086, 3) target pupuiation and 4) duration
`(if
`therapy.
`’I‘Uxicity and adversse clinical affects at”
`cammon cawlvams are summaz‘ized (33—34). Racem
`safety assessment reviews of propylene glycol (35) poly-
`ethylena glyml (36) and glyceroi {3?} have been 13113:»
`
`V0!“ 5:}, N0. 5 ! Septembermflcmbar 19533
`
`335
`
`AstraZeneca Exhibit 2052 p. 7
`
`

`

`Aihcar (Rhone
`Paulenc Rem)
`Amimphyllim:
`{Abbmt‘ Elking-
`Sim, American
`Regent}
`Alfilcm {The Lipa-
`same 60.)”
`
`Valium MM
`{Rmhel‘l'
`Kunakirm! l20
`{Rmth
`
`Amphiiimicin B
`
`DMPG and
`DMPC lipid
`mmplex
`Na ahelizslcryl
`sulfaie, ml»
`lmidal dispe i-
`Sim
`Mixad Micelles
`Glymcholic avid- Diazcgmm
`lecithin
`Gly‘mchtblic acid— Vitamin K
`lacithin
`Emalsiuus 61‘ Lipasnmes
`Lipid emulsii‘m
`Diazfipam
`
`TABLE V
`Same Currently Marketed Parenteraia Utilizing Camplexing
`Agents, Mixed Miaellea, or Lipid Systems
`
`Solubillzer
`Generic
`
`System
`Name
`Trade Name
`
`Camplexing Agents
`Hydmlyzed
`gslaiin ll???
`Elhylenfldiamim Aminophyllma
`
`Curtimimpiri
`
`Amphetcricln B Amphucil {Lipa-
`same T5361?“
`analogy)
`
`Lipid flmulsiim
`Lipid emulsicm
`
`Pmpofol
`Perf’lmimdccalin
`
`Di}:sz {Ghmeda}
`Diazcmulz’;
`{Dumex’y‘
`Dlpiivzm (lemma)
`Flumal—DA (Alpha
`Therapcuiics)
`AmBisume
`Amphulcricin l3
`Lipowme
`
`{thar}“
`1M w intramuscular. IF - immvenmm: fining-1m; lB ' iniravcmmis
`direct injection
`‘3 Drug available muslin: me Unitesl Sigma
`
`toxicity of” several msulvani vehicles in
`IiShs‘id. Lacal
`animals is: mmmarlzed in Table V].
`
`C.
`
`{£56 0}" Smface Afffl’é’ Agents
`
`Smlace active agents are usually incmpcraied mm
`pammumla li) priiviilc (in: of several desirable proper-
`lies; 1») increase drug solubilisy thrmigh micallimtian. 2)
`l0 pfifillfiil‘ll 6mg pritclpllallun iian dilmiun (38) 3)
`impmvc» the inability of a (ing is“; sululim by manpow-
`timi of H13 drug mm a mimllar structure (39}. and «ill in
`prmein lbrmlllélliflnfil prevent Zlggregaliaa (luff Ii) liquidi‘
`air 01" liquidi‘soliil inlarfacial intemctlong.
`Table IV puwides examplfis 0f FDA—appmwd paren-
`teral products Gawainng surface active ageing. While
`many difiemnt types 0f surfactants Exist {491 only an
`extreme few have macadamia l‘m use in parenteral
`graducts. Fm cxamplc, fur atalwilizalim {if proteins
`against problems, of aggrcgaliim. (ml); polyaxyethylefie
`sorbilan moneoleale {ptilysmbalc 80’)
`is an FDA—
`agpmiied surfaclam (l8), Omar surfamams whiz}: have
`Eugen usail
`in parenieml products are pulmxamer 188
`{polyoxymhylenwpolyuxypmpyleriis copcilymerl‘ pelysww
`bate 20 and 40 {polymyezhylene-palynxypmpylene (pi;va
`myazhylane sorbitan maml‘aity acid estars), CFCWQthT
`EL-‘g‘ and Emulphaor EL 'fwll {ptalyezhmylawd fatty acid
`islets; and oils). Which surfactant is magi talkative: as; a
`glilubilizer or Stabilizer is; alien a matter of empirical
`
`336
`
`investigatian (all? Detailad mviaws of micsllf: struc-
`tures“ characterization techniques, and pharmaceutical
`applicatians have been publisheé {42s 43}.
`The mxicity of surfactants reporteii in the litez'anire
`prim m 983 are: summarizecl by Atmmid and Florence
`{43}, Reviews on lhi‘: pharmacong of polysmbate 8f)
`{'44} 211163 the incidence of clinical side effects (if Crema-
`
`phm‘ EU? {42} have:
`{36511 published. Childrcn and
`newborns may be particularly SEflSitiVE in these agents
`and administratim‘l to this; populatian is diSCllfiSéd {46}.
`
`L! 536" of Campimng Agents
`
`Cemplexation Elf water insoluble drugs usually in-
`volves Elia incorpmatian 0f Ihfi drug wiihin tha inner
`core {if the complexing agent so that 1th outlar hydra
`philic gmups 0f the: camplexlng agent interacts with
`water rendering the sample}: soluble.
`An example: Bf successfiil appliizatlm 0f this lei:th
`agy is Amphizcil‘gg a lipid cemplax formsd between
`amphotericln B and sodium Chclasterjl sulfatfi, a nam-
`rally «curring cholesteml metahalite (4?). In solutiom
`the: cumplex is pestulated to: be a stable disolike
`structure that remains intact in the systemic circulating}.
`Comparative Sllidifis in animals with micellr: solubilizad
`ampmwi‘icin B (Fungimnelfi) have Shown a Significant
`reductian in systemii: {axially as a result 0f altered
`systemic distributiun and elimination characteristies (48}.
`Naturally ancurring Cycladextrins, partitularly B—cyala—
`dextrin, are able to temple): water insaliible drugs. and
`fitndffil‘ them Sfllfiblfi in water. However. B-cyclodextrin
`have bean associated with ranal {axially upnn parenteral
`adminlgtratianl The mxicity [121$ been attributed the low
`aqumus solubility of B~cycladaxirin and precipitation in
`the: kidney. Newer cyclodaxtrins are chemically modified
`in improve: water gulliblle and inarease lheir usefulness
`{49}. Brewster at al. {50} have described the preparation
`and successful use of chémically modified (chlndexlrins
`such 33 2.hydroxypmpybfiwcyclcdextrin in mlnbilizing
`and even stabilizing various praising and paptidiss.
`An example where the drug was 2101 incorpiimzecl
`within same kind m” matrix. but cambined with an
`adéitivc to obtain basically a solublfi salt mmplex
`involved asmrbic acid (51). Similarly, trométhamine has
`been repurtrzd to sulubilize zameplrac, an anienic drug,
`by micelle {asssciatian colloid) foimation {523g The
`aqumus solubility of metronidamlfi was rapurled to be
`enhanmd by the watar gullible vitamins nicotinamide,
`ascarblc acid or pyridoxine EC] {32}. A cages-like. struc-
`ture farmed by the vitamins: amuml muleculea {if merm-
`rzidazole was pmlulated‘
`
`E. Emulsian Systems
`
`If a molecule has sufficient lipid solubility? Emulsions
`may be: employed. Typical emulsions contain triglyceride—
`rich vegetable rails and lecithin and may aim cantain
`maimic surfaca actlva agents as smulslfying agents,
`lnmluble drugs may be inmrparated into commercial
`fat emulsians at
`through emulsificatien 0f iha ail—
`solu‘ailized drug. The farmer is uaually not succeasful
`
`FDA Jaumal of Phamaceutlcai Science 3: Technology
`
`AstraZeneca Exhibit 2052 p. 8
`
`

`

`because drugs influence the stability ef these trimmer-e
`Ciel emulsions (53+).
`
`Limuleiett fmmules have shown edeanteges ever high
`eoeolvent levels by reducing local veneus irritatiert {55%).
`While emulsions hold peteniial as; cerriers fer lipeehilic
`drugs, great ehellenges exist in; i} etheient incorpora-
`tion at“ the drag into the dispersed phase? Z} validation 0f
`censieteney in preparation anti eterilizetien, anti 3)
`dependable biolegieel eealuetierr ef the safety and
`ellieeey ef drags delivered frtrm emulsions. These topics
`are addreseeti in Some detail in several review articles
`
`{SS-58}
`Mere recent examples include a garenterei water-in-
`eil emulsion at an LH~RH analog (5%) and solubilizetien
`of an aeti~HlV thiecarhemate drug try extemporaneeus
`emuleifleatien (60). The patent literature contains a
`large number of references claiming safe end stehie
`emulsiee eyetems fer parenteral injection. The trimmer“
`Ciel application for drug delivery has. yet ta be pre—
`eeuneed in the United States. Marketed precincts are
`meetljr fennel
`in the Eureeeari and Japanese market
`{Table V).
`Miereemuleian systems are thermedynemicelly stable
`traesparent eolleidel diaperriens. The advaeteges they
`have over maeroemttlsiens are their stability and ease of
`manufacture. Dreplet sizes are typically ill times smaller
`than maereemuleiene anti are an the ertiet 0f ltlwlllll
`
`am. To achieve such a small Size, ritually high amounts
`ef surfaetant are required {43), Miereemulsien syetems
`have. found utility in enhancing penetratien by the
`tepieel and recently etel teute (til, 62). Requirements
`fer each high lereie ef serfeezente hare imeeeetl Iimite
`time he thei