harmaceutica Sc;ienc:r.~?: and ‘echnolegy
`
`J a
`
`PuraniuiaéClnsxfissuciadan
`
`as.
`
`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 Ex. 2052 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01325
`
`

`
`REVIEW ARTICLE
`
`Solubility Principles and Practices for Parenteral Drug Dosage
`Form Development
`
`STEPHAME SWEETANA and MWHAEL J. AKER$*
`
`Phamméraettimi Susi-encas, Lilly Resasarcft Lcréarawries, Indianapalfs, Indiana
`
`lntrocluctiun
`
`A cammon problam experienced in the early develop-
`meat of drugs inteniled for parenteral, aspecially intrave-
`nous, administratien is the solubilization of a slightly
`solublr: or water insoluble: aclive ingredifint. Drug s0lubi—
`lization has been tha subject of many fitlénlifii: articles
`and lf:l\"ll30i3l{S {referenced tlmzaughceut ihifi. article); yet
`despita this attantirm and availabla literature, product
`develepment scientists still encounter significant difficul-
`ties in solving their strluhilily pmblems.
`Theories of solute solabilization are not easy ta
`understand. Solubilizati-an processes are amazingly cem-
`plm: and require 3 fair amount of mrpertisr:-. in phyalcal
`chemistry ta interpret and apply current thecrrratical
`moéelsl Much of the litarature deals with scrlubllization
`
`theory and does not afier much practical help to the
`inexperienced scieniist under a lot of pressure to find a
`ssalutlcm tn his,/her salubiliry prcblem.
`This article intends to help the scientist in early drug
`formulation design for parenterally administered drug
`prod uats by reviewing pertinent literature on a<)lul:riliza-
`titan and reducing it to simpla approaches one can use to
`solve salubillty problems. The classical ihearies of solu-
`bility, and how they relate to phannacrzutical systems of
`interest will he revicwsd and practical Etppliitallifinfi
`discussed. Because at‘ the common concerns regarding
`cflmlvent
`toxicity and accsptability by rrzeclical and
`regulator}; lmdies, we also will trea: this topic in semi:
`detail.
`
`I. Pertinent Theory of Solubillzatian of Elrugs
`
`Solubility ihecries deal with ccnversion cf a substance
`fmm (‘me state is anoilxer, and the equilibrium: phen~um-
`ena that are invelved. Through pioneering war}: «sf
`Henry, Rarzault and vazft Hoff in 1211::
`lair: 13[l0§S¢, the
`propertiézs 0f varimzs solutions have been defined in
`theories. These nearly theories form the basis by which
`num: mmplex systasms, such as $1103: saxxcouutered in tlm
`biological sciences, are compared and understand.
`No singlra tlzaaury can adsquataly explain solubility
`behavior of uncharged molecules in a xrariaty of solvent
`systems. Each tlzemy is suited far select ccmbinations of
`
`Reaeivgd lame 253, 19933. Accepted for puhlicatinn March 21, 1996.
`‘ Authnr ta whom carrsspsmdence should be addressed: Lilly Ca:srp<2~
`ram Canter, lmzliarlapolls, IN 413383.
`
`solutes and solvants where: certain intsnnulscular forces
`
`are assumszrl to predorninate, or conversely, be absent.
`Tbs classical theorizs af selubllity have been explained
`most simply in terms of int-arrnolecular interactions.
`Ideal salutiari
`theary assumes so]ute~s:3lute,
`SC.¢lVCT£t-
`solvent and solute—sc3lvant interactions are completely
`uniform in strength and nature. An example of a.
`Sfillilllfill behaving ideally is a non-polar salute.
`in a
`ncsmpolar solvent such as naphthalene in benzene.
`Regular solzarrlorz zfzrcrary rzvolvrzd ta account fill‘ the imbal-
`ance czf intannolesular interactions that after: oacur
`
`lZIt’:lW%:':t"tl’l clissimélar systems Cal a. solute and solvent. The
`focus mf this theory are systems of low palarity mch as
`steraids in hydrocarbon solvents. Extended regular S01L£~
`ts’-arr (keen: incorporated additional parameters ranch as
`dispersian, pcalar and hyérogtemlmndlng interactions
`into regular solutian theory, Various approaches have
`been used to represent these molecular interactians,
`leading to a variety of models to predict and explain
`solubility behavior mi“ polar solutes in polar systems, each
`with dlffrzmnt apprazcimalitms and assumptions (1-4).
`In most pharmacautical systems, the routine applica-
`tlszm of tllfisifi models nix medial solubiliiy and simplify
`formulation development is complex. Most drugs of
`interest am icmizaltrle, contain polar pelyfunctional
`groups, and are capable of forming multipls hydragen
`bands. The majority of parentarally acceptable casel-
`ventsusuch as prapylanc glyrsstrl, polyethylene glyml,
`ethanol and x>rater—-are capable of self association
`through lxyclrogcti bond fDl‘DZlatiOIl. Such intezactiims
`may altar sclvenl: structure and, as a result, influence:
`solubility in an unpredictable manmzr (1). Examples of
`this phenamena arc: deviations fmm log-linear sCalubliza-
`tier; of noxipolax solutes in a polar eosolvent system {S}.
`For the madels. to ailequatsly clascribe snlubility behav-
`imr, prepay weighting must; be assigned to the mlative
`importance of competing self-associatiena and strung
`intenncalecular interactions. Currently this is being mod~
`ale-:1 by various compuzer intvzznsixre group»-ccntribution
`appmazzhesl some of which allow for the mutual interac-
`tions sf varicsus functional gr0upS ll}.
`In the biological sciences, many salutes of interest are
`capable ef acting as acids or baaes. In an ionizing mcclia
`such as water, they may dissociate intc: ions which are
`usually highly vrata-1,: salable. T0 what extent a molecule
`is iatvnizecl in an aqumus mlution is largely dependent cm
`its pléia and the pH of tha media. The Henderson»
`
`3339
`
`FDA Jamaal czf Pnarmacamlczal Salaam; 8. Technsiogy
`
`Astrazeneca Ex. 2052 p. 2
`
`

`
`Hasselbalcb. equatieu is a. mathematical expressian of
`this relationship (3). In formulation devalopment, con-
`sideration of the amcsum of un—iz)nize:d drug in solution
`is lxelpful to amid unexpccttx} precipiialiuu Uf this form.
`As the 33H of a drug solution is changed, the amaunt of
`free acid 01' has»: may increase and imzntually exceed tha
`limited salubllity all this form. 1!: is passible :0 calculate
`the pH :::rf precipitation and of maximum scllubility, if the
`pKa of the molecule and the solubility Bf lh-it un-ionized
`and ionized forms are knovm (3, 6}. Generally, two pH
`units ahrrws 03' below the pH,,m value céatalglislies the
`deslrad pH fur fonnulation. For drug molaeules with
`muliiple icmizable gmups these equations are mom
`complicated to apply and 90 experimentally generated
`solubility data are usmally callected.
`Tlamixgh um awn axparicénca, we fimfl that thwry gives;
`us some direction with respect
`to experimental ap-
`proaches, but we still need to rely on the empirical
`experimentation in screen for figgstems which ofier the
`most pmmisc in solubilizing water-insoluble drugs.
`
`ll. Farmulatian Design
`
`the
`the first approach used In increase:
`Usually,
`sulubility of an insoluble drug in water is to form more.
`water soluble $211318. Barge and co—workers (7) wrote: what
`i3 new 3; mar classic :'eviaw crf salt farm straiegies
`acceptable far pharmaceuticals. If salt formation is not
`possible, mg. we unstable, or does mat nzmitézi’
`the
`mcxlacule sulfificiesntly water saluble, 3 series s:1~ff0mmla-
`ticm approachas may be inwsstigated. Table I smmma~
`rizes tlmse general strategies. Often a useful approach to
`increase the aqueaus solubility of an io:1i::al3le drug is
`pH acfiustment. The next approach most fraquently tried
`is the use of ‘fi£3t€:§’—mlS£lbl€
`oosalvents. Other ap-
`proaches to be discussed brinzfiy includa the use of
`surfact: active: agents and camplexlng agents. Davenp-
`ment of emulaified and acnlloidal drug de ivary systems
`for intravenmzs administration are becoming more widely
`and succesgfully applied. They may cstmfer to the an-
`trapped 01’ associated drug sigzlificanily difbrcnt proper-
`
`TABLE l
`Summary of Parenteral Fesmulatéon Approaches
`
`Approach
`
`Examples
`
`pH adjuslmaant
`
`pH 2 m 12
`
`Cosnlycznt
`
`Polyelhylczm: glygol
`Propylene gly-cal
`Ethanol
`Dimaihylacelamidc
`
`Surfacfi Active Agents.
`
`Fcslymrljates
`Pnloxamsrg
`Cramophcxr EL
`Lecithin
`Bile salts
`
`Important Formula
`Consideraticma
`
`Drug stability
`pH
`ions to buffer or adjust pH
`Drug, presipizatitm upém infusion
`drug crzmcerztraticm
`use sf bufferlbuflszr capacity
`infasian rate
`Fmmula irritation
`ismunisiqr
`infusion rate & duration
`drug vs vehicle
`drug precipitation
`
`Systemic tcxicity
`tatal cusmlvent admixzistercd
`Drug pretipiiation ups-I: infusicln
`drug concentration
`infusinn rate
`Formula irritatitm
`lfifllflfiifilty
`infusion rate :9: duration
`drug VS vehiele
`drug prccipltaticn
`
`Hypézrserasitivity in animals
`Fnrmula irritation
`iszittlniaity
`infasinn rare :9: ziurazican
`drug vs vehicle
`
`Complexing Agents
`
`Qrcludextrans
`Watz3r—s<>l:1bl::: vilamins.
`
`Purity uf epzciplents and drugs
`Fcminula irritaticm
`
`Dispersed Sysuzmzé
`
`Emulsions
`Liposomaa
`Nazmpzmicles
`
`isewraicity
`infusiajn rate 3: duraticln
`drug vs vehicle:
`
`Sterility
`Particle size
`Fhannacaklnatics
`Stability
`
`Useful Tests
`
`pH rate prafile
`pH solubility profile
`Freezing paint depreasiuzx
`In visra precipitation model
`I21 Vim phlebitis mcclel
`it: vim: cell lysis istualics
`
`Mixture studies for maximum
`sulubility
`I22 uizro precipilatinn model
`In vim phlebitis medal
`32:: vim: cell lysis studics
`
`in viva? phlebitis medal
`In vitm call lysis ?’§ll.llZllES
`
`Phase salubility diagrams
`In vEv::- phlebitis maacial
`[:1 l«’ll’P‘{3‘ cell Iyzris studies
`
`Particle size
`
`Vol. 50, N115 I Septemberwoctobar 1996
`
`331
`
`Astrazeneca Ex. 2052 p. 3
`
`

`
`ties front the free form. timvitiirig the otiiztxrtttnitgg to
`prtilottg drug pl”t3SE3llCt‘:
`in the liltiotlstteaztti Gt‘ to alts;-3'
`Clisptisitltm in the ’:m<lj;;. “Her»:3i€" melhfldfi. reptmecl in
`the literature far various cancer tlrtigre. will alec:
`lie
`reviewed altlicmgh these methtidza ties: types and antmtnts
`Of exelpicnts that pmhtihly waultl
`tmt commclnly be
`cesnsidereti appmviahle for intrzaventttis adminietratitin.
`is
`The basis for reliable ftirmuiation development
`acsttrate tletettninsititm tif solubility. Traditianal method-
`ology is the “equilibrium metlmd" (S) where excess drug
`iii adcletl
`tea the solvent system. and some means {if
`agitation is employed tmcler constant
`temperature.
`Samples are withdrawn. filtered. and analyzed Fm‘ drug
`mncentration over a pcritid Of time and equilibration is
`demtmstialed by Lliilfflfmlly‘ cal‘ the data enter the time
`interval. Fair eparingly soluble drugs where cquilibria are
`slow. accurate detetmittatitjns til sctluiiility may be cliffi-
`cult. Useful techniques in these instances include using
`highly speaslfic analytical metltods to detect parent (:0m—
`p{3ul}{LlS, minimizing the amount {if excess solid added,
`and assuring Sttilicieiit equilibration time {i}. Solid state
`factors and batch-ltibatch uariatien tdifierent poly-
`merphs, hydration state, crystallinity, crystal hemc:>gen::-
`ity, and impurities) may affect r<:pr(‘.:dt.1cibilit};
`ttxf drug
`solubility determinations.
`
`A. Mi’ xldjusintimi
`
`Current FDA approved marl-tetecl parenteral prod»
`ucts range in pll from 2 to 1 l. A ettmprehensitre listing of
`these products may he found in Table II. For l3lCIC1J§I‘tpal~
`ability reasons, formulatien of injectahles. within the pH
`ranges of 4 to '8 is most C{)mm{)n& However, to achieve
`sufficient drug sulubiliiy. 3 pH ttutsitle this range may be
`necessary
`The pH at which a product is formulated is usually
`iietemiinecl from the pH saluhility and pH rate profiles
`of the drug (9). A recent example elf their applicgticm in
`aid parenteral
`fmmulativzm éievelttpment is CI-988. 3
`eholeeyetokinin-B receptm“ antagonist (ill).
`Additienal formulatitm variables to be coneidered are
`
`the necessity vi a buffer, buffer capacity. and drug
`concentration. These atan influence supersaturated drug
`concentratitzns in the blmdstream, a conditicin that may
`lead £0 in i=z'w:: drug precipitatiun. The blow is very
`cifieicnt at pH neutralization and Il0I'm3ll3' maintains a
`narrcsw pH range of 17.38 to 7.412. Far example, El law
`incifience of phlebitis was observed in the rabbit ear vein
`model when solutions over the pH range sf 3 to 1l,witlt
`buffer ccncentraiicns Gf apprtiximetely 0.3 M, were
`administered in a single small vezxlume (1 mL) bolus close
`{11}. Simple screening tests consisting {Sf a computa-
`tional nicidel where drug solubility is platted as a
`function of dilution, and in mm dilution experiments
`were shrgswn to be effective tools in evaluating the ability
`of the pllwaelubilized drug to remain in solutien dilutian
`£12, 33). Davie et al. { 14) shtiwed that if? tsive ;:=1’ti=:.“.lpita-
`tion of the pH-selubilized drug, clltekiren was dependent
`upaii drug caiicentration and infusion rate. Lew ettiicem
`tration drug solutions. which are rapidly diluted below
`
`332
`
`saturation solubility. and rapid infusitms; were preferred
`in iiiinimiee precipitation.
`The most eemmozmly used buffet components in paren-
`teral precincts and their pKa‘s. are: citric: acid (3.13. 4.?t3_
`fix-iii), acetic acid {4.76} and phtispltorie acid (2.15, ’?.Ell.
`l2.33). when buffers are employed. the stability ill the
`mtileetile must also he t:tttts~;ldeted_ since it may be
`irtliueneed by the ions in soluiien (9). Examples of buffet
`catalyzed stztltititin degradation include faniotitlitte.
`at
`histamine H2 receptor inhibitor (15) anti loracatbef, 3
`zwitterienie cepltalosgorin (16)
`
`3. Use of Cosoivents
`
`in recent years. surveys uf FDA-apprcwed parenteral
`pl‘0ClEICt$ (17-19) show five water-miscible CQSOWCQIE-—
`glycerin, ethane-l, propylene giyctil, pvzilyethjglene. glycol.
`and l\l,N,-dimethyiacetamidewes Cc-mptments of sterile
`formulations (Table Ill and IV). Cesalvents are emv
`ployed in approximately 10% of FDA appraised paren-
`teral products. They are useful because they may often
`prtwitle exponential increases in selubility (20) and also
`allow exclusiun af water for compounds susceptible to»
`liydrtilysis.
`lnvestigaticm of the salubilizing pctential of various
`cosolveitis may be approached empirically; by detcrmin»
`ing the Cnmpflunds solubility in cusolvetti campositions
`similar to marketed pmtiucts (2143), cut by one of
`several systematic approaches. such as lQg~lln€'SEll‘
`ss:rlub§1~
`ity relationships or statistical experimental design.
`In the study of log-«linear solubility relationships,
`Yalltowsky and Rosemen (20) investigated a range at
`salutes in binary cosolvenl mixtures of ethanol, ptopyl~
`ene glycol, and glycerin in water and discussed the
`clctseness of fit of apparent selubility in a log-linear
`solubility equatitm. “Briefly. this technique involves ex1:se;t'i~
`mentally determining the selttbility of a compeund in
`increasing percentages of a eosolvent and generating a
`semi—~l0gatithmiu: plat of the apparent seltihility of the
`drug as 3 function cf the volume-fraction at’ the casel-
`vent. Using the slope and tlie solubility til the Cflmpflufifi
`in pure water, an equation may be written tti cletcribe
`the solubility in a binary system.
`Assuming that the Iogdinear increases in eelubility cf
`individual cosolvents are additive, eqttaticna may aim be
`written for ternary and quaternary mixed CGS€3lVt’:‘J1‘i
`systems (24). Mathematically, these relaticzttships are
`described by the following eqttatitzms:
`
`Binary msaiverzz system
`
`log Cx = leg (1,. + tax};
`
`Temztry trosoivent system
`
`lag C3. = leg Cu. + agfi. + 11,3;
`
`Quzsfemairy rrosoiverzt system
`
`tog Ci = mg £2. + '15} + ax. + out
`
`where Cw is the drug stilubility in water; ifs are the
`slopes of the semi
`logarithmic plots; C} is the drug
`solubility; f is the velume fraction 0f the msolvent; and
`the subscripts :2, £9, 2: denote the ceeolvents/l, B, and X
`
`FDA Jcmmal nf Pharmaceutical Science ‘St Teettnoéeggr
`
`Astrazeneca Ex. 2052 p. 4
`
`

`
`pH
`{cuufititnteci}
`
`pH 4: <3
`3.2-4
`3.25-3.65
`
`3
`3-4
`33-33?
`3-4
`2,541.5
`3.’?-4.1
`
`I.3—3~3
`
`3-3.8
`2.’?-3.5
`
`Lactic acié, HC1
`Citric: acid
`N301-L HC?
`Cizrirs acid, Na citrate
`
`Lactie: acid
`Lactic acid, earthy!
`laciate
`
`3.2-3.3
`
`Lactic acid
`
`2-3
`3-3.6
`3-4
`
`3-4.2
`2.’?-3.5
`
`3
`3.3-4
`2-2.8
`3.5
`3-4
`3.3-4
`2.5-4.5
`3-4
`2-3.8
`3-3%
`
`pH > 8
`9.2
`{(1.5-11.6
`
`8.6-9
`
`9.13-I414
`9.6
`
`8-13
`
`8.5
`
`’}.2-ii}
`11.6
`9-1&5
`
`NaOH;‘H{l‘I
`Lactic acid
`
`Na{)H, citric acid
`Tartaric ac:-id
`
`Na0H, I-{Ci
`
`Na citram, citric acid
`PIC]
`Citric acid, Na citrate
`Acetic acid
`NaOH
`
`Tartaric acid, Na
`citrate
`
`HCI;’NaOH
`
`N£tOH
`
`NMHFO4, NaOH
`
`NaOH
`Naflfi
`
`Chiordiazepcxide HC1
`Banzquinamide HC1
`Ciprsftoxacin
`Dacarhazine
`Dapamine HC}
`Diitiazsam PIC]
`
`Boxycyciine Hyciate
`
`Draperifiul
`Ergmnmzine Mafrzate
`
`Fentanyi Citrate and
`Dmperid-31
`Giympyrrnlaie
`Hamgaericiai Lactate
`Labetalal HG!
`
`Methjgidapate EC!
`Mcthflargonovina
`Maicaie
`
`Mfidazalam RC1
`Miirirmne Lactate
`Minacyciinc HG}
`Nalbuphinc HC]
`Nalomne. H5221
`Ondanseimn HG}
`Oxymcin
`Papavcrinc HC§
`Pyridexina Eiifii
`Tcdazeiine HC1
`
`Acezazwlamidc Na
`Aczysiovér Na
`
`Aminaphyilinc
`
`A.x“m::b:5;rbi:a! Na
`Azaihicrprine Na
`
`Ampiciflin Na
`
`B&%ams:{ha:~;0I:€: Na
`?C:L.
`Chlumthiazidc Na
`Diazaxielc
`Diethyisiilbeaérul
`Diphusphatz:
`Fiuerouracii
`Foiic acid
`Lam:
`
`Ganciclavér Na
`Lezzcamrin Ca
`
`Na('JH
`N308
`N308
`
`9.2
`8-1 3.
`8-9.3
`
`13
`8.1
`
`Fiuomuracii ['R0r:he.}
`Fnivite flxzderiej
`Fumsagmide
`(finachst-Romasai)
`(Z153/trrvenaa {Syntax}
`Waziimvorin {lmmunezg
`Burroughs Wellmmc)
`Bravital Na (Liiiyfi
`Methahexitzfi Na
`Na carbanatc
`9.5-10.5
`IM -- intramuscular, IF -- intravemtms infusian, IB -~ intravanmis dércct injacticm.
`
`V4158, No. 5 I Septemtze:-Gatabe: S996
`
`TIXBLE 3!
`Examizies of Marketed Parentarai Prcéucts wifih Szzéution pH Dutside Range :2? 4 is 8 (18. 19)
`
`yfl
`Aefiustment
`
`Geueric
`Name
`
`Trade Name
`
`Marketed
`Farm
`
`Routes
`
`Lame acid, Nafii-I
`Benzenesuffonis acid
`
`Amxinvzme Lactate
`Atrztcuréum Bssyiate
`
`Inumr (Sanefi Wimzhrop)
`Tracrium {Burroughs
`Wcilcoma}
`Librium {Roche}
`Ema-re-Con {Roxarigja
`Cipro 138?. (Miles)
`DTIC-Dome (Miias)
`Imrcpin (i}nP::>nt)
`Cardimm (Mariam Merral}
`Dew)
`Vibramycin IV (Rmrig,
`E.EL;ins~3inn)
`Inapsine fjanssen)
`Ergatrate Maleate (Liiiy)
`
`Solutiem
`Smutioa
`
`Powder
`Powde:
`Con-centraie
`?0wd&r
`Solu ion
`Sow ism
`
`IB, IF
`18, IF
`
`153
`IM, [F
`IF
`IE, I?‘
`IF
`EF, EB
`
`Pcrwdet
`
`{F
`
`Sch: icm
`Sc} 11 ion
`
`1M, £F, £3
`IM, EB
`
`Innovar {Jan3sen)
`
`So 1; ion
`
`IM, 18, IF
`
`Robina? {Robins}
`Haida! {McNeil}
`Normodgme gjfichezringj
`Trandaie (Giam)
`Aidomet Ester HC1 {Merck}
`Methergéne (Sande-2:)
`
`Varscd (Racks)
`Primacor {Sanofi Winthrop}
`Mincscin fibczdcfle}
`Nuhain (DLIPQM)
`Narcan (DuP~::~m}
`Zofran {Cemn»:;x)
`Pitocin {P2u'kc~Davis)
`Papavcrine HCE {Lilly}
`Pyridxbxinc HC1 (Sleds)
`Priscaaléns HG ifliba)
`
`S0 11 icm
`So 3.: ion
`So 21 ion
`
`So :1 ion
`So 11 ion
`
`Sn :1 ion
`So u ion
`Pawdct
`S0111 ian
`S0111 ion
`So :1 ion
`S0 13 mm
`3:) 1: ion
`Sam icm
`3:3 11 ian
`
`IM, IR
`{M
`IE, IF
`
`IF
`IM, IF
`
`2354,21?
`PF
`H‘
`IM, IE
`IM, IB, IF
`IF
`IF
`IB, IF
`IM, 1}}
`IB, EM
`
`Diamox (Lcdm“I<:}
`’2’m'iraz-: {Eummghs
`Welicolnei
`Aminopilyfiizars {Abbota
`Eikins-Sim. Alzrmrican
`R:=:g<-ml}
`AInyEaINa(Li113:)
`IrIu:1":a:1 (Bui’I"C:ugf1s
`Wclicumei
`P<3iys:.il1in~N iapoiilecun)
`T0isu;:i1}in~N (Baecham)
`Omnipen-N {"Wy::1h)
`Creiezstuné: Phnsghate
`(Scmering)
`Sodium Diuril (Merck)
`Hypurstai (Schcriag)
`Slifphustroi {F/H383}
`
`Powder
`Powder
`
`1'M,IB, IF
`EF
`
`3B]uEi0n
`
`IB, {F
`
`Powder
`Pewder
`
`Powder
`
`I'M, IF
`KB, IF
`
`IM, I33, IF
`
`Sifiutiun
`
`IB, FM
`
`Powder
`Soiutiun
`Soiutirsm
`
`Sniaticm
`Soimian
`Soiuiion
`
`Powder
`Pawder
`
`Powder
`
`IE, I}?
`EB
`IF
`
`IB, IF
`IR
`EM, IE, EF
`
`IE3
`EM, IE, IF
`
`EB, IF
`
`333
`
`Astrazeneca Ex. 2052 p. 5
`
`

`
`TABLE ill
`COS{.‘:lVi3ni Eoncentraticarzs in Some Currently Marketed Parents:-rals $118. 19)
`
`Cnsalvent in
`Marketed Vehicle
`
`Generié
`Name
`
`Trade Name
`
`Marketed
`Farm
`
`Routes
`
`Administmtim
`
`Appx.
`Vehicle
`per Base
`
`Ethanol l€l£l“—§
`
`C‘2:mms1im*
`
`BMSNU {Brism}-‘.V1j.=cr:§ Drug
`Oncology)
`«S» Dzlucnt
`
`IF
`
`Dilute? 5110
`
`Elm!
`
`F'rupyln’:ne;: glyml 4fl‘}?>
`Ethyl alccrllxpl 1{)"T*§#
`
`Dl2i;£L‘jL3I;!II‘.l
`
`Valium {Rc1»<:‘n:")
`
`Sctlullzim
`
`IM. IE
`
`Dirisci injezctiun
`
`0.34 ml
`
`Pmpfglene Glycol 48%
`Alcahol l€l‘:?§'
`
`Digmin
`
`L21r1nxi:1{Burr:2ugE1s;
`Wcllmmc")
`
`Smltuicm
`
`IE
`
`Dire-ct injection
`
`1»-3 ml
`
`Berzztyl alcmheal 5%
`Prupylcntt glyxml 50%
`
`Dimenhydrinatc
`
`Ifiimrznhyaiirinate
`(S‘:;:ri:{)
`
`Ecslmiém
`
`IM. IF
`
`Dilute 1:10
`
`1 ml
`
`Pmpgxlcmz gl3'cc:)l 25% Esmolul NC’!
`Ethazm-J 25¢’?
`
`3I‘€\*’ibl£}C :{DuPv:':m}
`
`Cnncerztratc
`
`ll:
`
`Dilute. 1:25
`
`1«-Ill ml
`
`Pru-pylene. glycol
`lf}.3E;‘§‘%~
`
`Ethamul 1114?’?
`
`Hydralazins HC‘l
`
`Aprssolinc Hi‘! (Ciba) Stzlutizin
`
`EM. IB
`
`Direct injecticm
`
`0.5-1 ml
`
`Kemroiar:
`Tmmctlls.-amine
`
`Lmazepam
`
`Tczra-ilol (Syntax)
`
`Scalutian
`
`EM cmly
`
`Direct injesiztiezm {M 1 ml
`
`Atiwan (“é/ye:l1—
`Agent}
`
`Solution
`
`EM, 13
`
`IM Direct injection
`Dilute 1:1 W
`
`1 ml
`
`PEG 400 0.18 ml} ml
`Betzzyl alcolml 2%
`Propylene glycml
`
`Pcwidonc: 26 mg
`Dilncnt (10 ml)
`Propylene glywl 6 mi
`Ethanol 352 ml.
`
`Etharwl 3(l‘3?E:
`Propylene glyml 30%
`
`Propylene. glym! $095:
`Alcafnul 1(lԤ2-
`
`A1m§ml i(l"rPEv
`Propfglcnc glyml (i«’?.8‘f/1»
`
`Wcxpylexze glycol «'3U‘.5{:=
`Alccclml 10‘/FE
`
`Melphalan HCE
`
`Nkrcran §}3urrr:>ughs
`W€llC{§mC:é
`
`Drug
`+ Dfiuam
`
`IF
`
`Dilute wsistitute
`:> 1:10
`
`1'3 ml
`
`Nitmglycerin
`
`Tridii (DnP<mtf)
`
`Cczencentrate
`
`IF
`
`Dilute 1:100
`
`2.5-10 ml
`
`Penmbarbiml N3
`
`Nembutzil (Abbefi)
`
`Soluticm
`
`EM. IB
`
`Slow direct injvzctitm 2 ml
`
`Phcnoharbiial Na
`
`Luminalbla §S:;m-mfi
`Winthmp)
`
`Soluairm
`
`1M. IB
`
`Direct injection
`
`1 ml
`
`Phcnytoin Na
`
`Dilemtin (Parlor: Davbs)
`
`Soluticm
`
`IM. 13
`
`Dims: injecticm
`
`3-«:3 ml
`
`Fnflycthylemz glyml 50% Seczmharbitai Na
`
`Sccabarbital Na
`(‘§'r’j;eth~Ayer$:}
`
`Prczpylxz-1:4: glyml ai()<“Z«~.
`Exzhannl 19%
`
`Trimmhnprim-S111» Septra {Burroughs
`fame-tho.:c:a;r.ma
`Wcilmme}
`Bacftrim (Rachel
`
`Solusien
`
`IM. 18,1‘? Direct injeminn
`
`1-5 m‘:
`
`fancentrats
`
`IF
`
`Dilute 1:25
`
`Swill mi
`
`N.N~Dimeth5=la<:et~
`amide I{l()€¥§.-
`
`Amsacrim:
`
`Amsidine Cc'mcen—
`mate 1: Parka-Dmria)"
`
`Drug
`+ Diluczmt
`
`IF
`
`Dilute: 1:568
`
`1.5 ml
`
`W! = iréttamuscular. IF -~ inlrzwenoufi inlusicm. YB '- intravanous dizect injection‘
`" Elirvg available Qutsi-63 me Unified Stains
`
`rsspectively. In his fiimpiest form. determining the drug
`solubility in water and pure cosolvents wuulcl allaw
`estimatiun 0f the amount and type 01‘ rsrzsiylvent required
`ta attain a desired solubility.
`11‘: must C3323 h{JW€V<3:F..
`éeviaticms fmm log~linear increases cf s{*.»lubi1ity orrscuz in
`aqxzeous ac,-semen: mixtums as indicated by curvature in
`the solubility plmzs. The xslewiations arr-: aliributcd m
`solvent-smlvcnt imteractisns (5. 25).
`this
`For first appmxixilaticms of solubility l‘1C)W€\«’I2i’,
`approach has been shown in be uslzful {2Ea——27}. (‘men
`(28) useé this llffllillqllfi and pwalarity indexes of C0301-
`vents ta calatulate the pmlarity of a is-uluiixm that pro-
`duced téael graatfsst solubility ef 213:: drug metronidazole.
`
`Aqueous/casolvent ratios c-f curresponding paiarzlty csuld.
`than be calculated for aiher casement systems ta prcvidc
`qualitative identification of smlubility maximums (29,
`3(3) Polarity indexes uf cammcnn water miscible cosasla
`wants have been iabulated and discussed by Ru}:-5:10 and
`Yallwwsky. Thsge indexes reflect the Caz:-hesive proper~
`{E63 of the Swlveni (zsulubility parameter and inierfacial
`tension}. hydrogen bonding ability {pmton dcmcxr and
`accepicu" d<z:£15ity§, and gaolarity (dielectric constam}.
`Another zmiubiliql detcrminatien appmach particu-
`larly helpful for complex mixturw i5 :5: sizzetistisxal experi-
`mental drssign {3}}. Identifying the optimum combina-
`ticrn of cosalvents fer salubilizatinn may reduce: the net
`
`334
`
`FDA Journal at Pharmaceutical Science & Technmlogg;
`
`Astrazeneca Ex. 2052 p. 6
`
`

`
`Surfactant Concentrations in Same Currently Marketed Parenterals (18, 19}
`
`TABLE IV
`
`Suinbilixer in
`Marketed Vehhtle
`
`;\lN~dimethylacetamide: :60
`mgiml
`Cremxjphm EL 50?)
`mg! ml
`Dehydrated alcolml
`-'l2.7*':f~E»
`
`lkalysmlzate Si} 293 mgiml
`?ropylene glycol 28.7
`mg} ml
`
`Cramophor EL 52’?
`mgjml
`Ethzzrml 49.?‘?'§>
`
`Propylcnc glyml 30%
`Polys<)r1:a2ue SE 1.6%
`Polysorlzxatrz 2G 0.028%
`
`Polysmbate SB 4%
`?r<:>pyl<:::1e glyml 2{3‘}’£:
`
`Cxcmuplwr EL 6139
`mgfml
`Alcohnl 32.9%
`
`Ewtyethylene: glyml 3042!
`650 mgiml
`Ethyl alcohol 30.5% V3‘?
`Pnlysrzzerbzxie Sf; 3%
`
`Falyoxyethylated fatty
`acid 7.52%
`
`Generm Name
`
`Trade Name
`
`Rnutes
`
`Adlninistration
`
`Appx»
`Vehicle
`per Dose
`
`Teraipnsirie
`
`Vumrm (Brisml-Myers
`Squibb)
`
`IF
`
`Dllaxte 1:10 or 1:l{}ffl
`
`5-9 ml
`
`Phjstonacliczne
`
`Knnakion (liachaj
`
`IM cinly
`
`Etirect injestian IM
`
`l~2.:S ml
`
`Paxzlitaxel
`
`Taxol (I3rists;~l~lv1yc:rs
`Squibb}
`
`Multivitamins
`
`M.V,I.~l2. (mltra)
`
`IF
`
`IF
`
`Ell ute 1:5 var 1:20
`
`28 ml
`
`Di utter. 1:300 m‘ ‘1:5{“,l{3
`
`5 ml
`
`Chiordlaztpaxide HCI
`
`Librium (Rachel
`
`[M maly
`
`Di cct injczzrtiam IM
`
`2 ml
`
`Cyclosporim:
`
`Sarlclimmunt: {fianalsazj
`
`IF
`
`Di um: l;2€l«l:l£3£3
`
`5 ml
`
`Ezopaside
`
`VePesid (firéstol-Myers
`Oncology)
`
`IF
`
`Di at: 12300
`
`5 ml
`
`Phggtmnadione
`
`AquaMEFl—T‘t'TC£N
`{Merck}
`
`TM, IE:
`
`Elircsct inject IM,
`pmfcrmd
`
`I-2,5 ml
`
`Zll ml
`
`PEG:1U aasmr 0510.] 15
`mlfmi
`
`Mimnazolr:
`
`Mcmistat ix. (llanssezn)
`
`IF
`
`Dilute 112:3
`
`Polysflrbate 88 12%
`
`"Vitamin A
`
`Aquasol A Parenteral
`(Astra)
`
`Polysorbatc SC: 0.088%
`
`Altcplase
`
`Activase (Gencntmh)
`
`Na dcsnxycholatrz £l.41‘}"o
`
`Amphmrszricin B
`
`Fungizonu: (Apathecm)
`
`Polysmrbaic 213 0.49%
`
`Calcilrim
`
`Polysarbates 813 0.04%
`
`Cafazolin Na
`
`Calatijex {Abbott}
`
`Kafzal {Lilly}
`Am:-zf (fimithlillnc
`Beacham)
`
`Pixlysorbate SB 0.094%
`
`Filgrastim
`
`Neupngéra (Amgen)
`
`Sodium clodecyl wlfaie
`(3.18 mgjml
`
`Aid-asleulcin
`
`Prnleuldn (Cetus
`Oncologr}
`
`Polysorbaie SE 10%
`
`Corclarone X IV (Szmofi
`Winthrop?
`EM = intramuscular? IF = intravcncsus infusiwm. I8 = intrzwezxczus direct injection,
`" Drug availabia imltxlfie ills: Unitraci Slams
`
`Amiadamne HCI
`
`IM
`
`IF
`
`IF
`
`IB
`
`Direct injectizm EM
`
`l-2 ml
`
`Qircct infusion
`
`20-10% ml
`
`Dilutt; 1:59
`
`Direct ixsjection
`
`$23 ml
`
`9.54 ml
`
`IM, EF, IE Direct mjrzction
`
`IE
`
`IF
`
`IF
`
`Direct injeetlnn
`
`ll.Z§—3 ml
`
`Dilute 1:42
`
`Dilute 1:50
`
`1.2 ml
`
`3-? ml
`
`amount (Bf msolvent in the formula (2215). They aim
`facilitate the study ef systems characterized by nor»
`linear increases in snlubilityl Optimization techniques in
`phannaceutical
`formulation have racently been rev
`viewed (32). Pm example uf their use is a aitnplex araarclx
`for swalvsnt blends producing maximum drug solubility
`(2)-
`Ameptabie levuelg cf cosolvent in parenteral formula-
`tions. are not casily dcfinasd. A review of cuzrentrly
`
`marlzated parenteral pmdu-2:5 shezswa thaz percantagas
`range frtsm {O to I089: {Table Hi and IV). Appropriate
`product szmmzmts are often a mama: of uxmsidaring a
`diverge set of factors such as; 1) administration condi~
`tlons, Z) {Mal dose, 3) target pcxpulation and 4) duration
`cf therapy.
`’I‘e:}xicit3,r and adversse clinical affects saf
`common cawlvents are summarized (33-34). Recent
`safety assessment reviews of propylene glycol (35) poly-
`ethylanc glyml (36) and glycerol (3?) have been pub-
`
`Vol. 5%, No. 5 I Septemberwflciohar 19533
`
`335
`
`Astrazeneca Ex. 2052 p. 7
`
`

`
`TABLE V
`some Currently Marketed Paremeraia Utilizing Ccsmplexéng
`Agents, Mixed Miaelles, or Lipid Systems
`
`Saluhilizer
`
`System
`
`Generic-
`
`Name
`
`Complexing Agents
`Hydralyzed
`gclatin !Zl.?<?é-
`Ethylenediamtnt:
`
`Certicotmpin
`
`An’zll1()pl1}‘lllt‘lE:
`
`Amphmcticln B
`
`Amphotcrlcin B
`
`DMPG and
`DMPC lipid
`mmplex
`Na tthctltzstcryl
`sulfate, 1;-ml»
`luidal clispe t'-
`slam
`Mixed Micelles
`Glymcholic arid- Diazcpam
`lecithin
`Cilymchctlics ax:is:l— Vitamin K
`lecithin
`Emalsiuns tn‘ Liposomeé;
`Lipid trmulsinn
`Diaztspam
`
`Trade Name
`
`Athcar (Rl1tm<:~
`Pczulenc Rater)
`.-"’tl¥1tl':(13pll}’llif‘lt£
`{r\l::t)c:z-it. Ell<'.fm3-
`Sim, American
`Regettt}
`Alsslctcl {The Lipa-
`same Cult’
`
`Amphctcil {Lipo-
`some Tszcrhw
`notogyl
`
`Valium MM
`{R0<:he}*‘
`Kunakimns‘ l2O
`{Rrm:hc)*‘
`
`Lipid tzmulsiim
`Lipid cmulssicm
`
`Pmpofol
`Pssrfiutamdccalin
`
`Lipc>so:3me
`
`Amphctttiricitt B
`
`Diézat‘ lfihmedal
`Diazcmuls
`{Dume>;)**‘
`Diptivzm {Zr:nr.:«:a)
`Flucmml-DA (Alma
`Therapmziicsl
`AmBisumc
`{\»'i:s~:tar}"
`llvi ~ intramuscular. IF - iniravennut: infutai-zml 1B - intravcntxuis
`direct it1js:::t§onl
`" Drug available mnsittc the Unitesi Statasl
`
`L;‘t‘;vSUl‘se't§:§1l vehicles in
`toxicity of several
`lislzed. Lacal
`animals is: xummz-triyed in Table V].
`
`C. {J56 of Stzrface /lctit-2:’ Agertts
`
`Surface active agents are usually inczyrp-stated inta
`patantutetls to prtwitle on: of stwtzral desirable proper-
`ties; 1) increase drug solubility thtmtgh micellizzttian. 2.)
`to ptcvsnt drug pteclpllatlun uptm dilltlitm £38)‘ 3)
`impmzwc» the aatability of 3 drug it“; Sfllullflfl by incorp02*a-
`titm of th:: drug mm a mimllar EKTUCIUTQ (Rm. and -ill in
`prmein tkgrmulationt. prevent aggregation duct Ii) liquidf
`air or liquidfsoliil intarfacial interactions.
`Tablr: IV prozwides exantplfis of FDA—appmv<":<:l parc':I1-
`txaral products containing surface active agents. While
`many different types uf surfactants mist l',~i€3l~ only an
`extreme few have precedence that use in parenteral
`;}1“0iluCtS. Fm example, for zatatwiiizatiorx of proteins
`against "_;3ml°3lem5 0f aggrcgatimn. (ml); polymiyethylefie
`sorbitan monooleate {ptalyserbatc SD’)
`is an FDA-
`agprmsed surfactant (I8); Olhfll” surfactants which have
`bfitifl used in parenteral products are pulcuxamer 188
`{poiyoxyethylt:né:~pc>lyuxypropylet§:3 ct>pc,siymer}, pt}IyssJr—
`bate 20 and 40 {p0lyC)X}tCEl'l}'lCt}'l€3-pi?«l3iDX:g'p{0p}?l€tIl3
`{pfiflljfv
`axyazhylaane sotbitan momfatty acid xzstars). Crcmapimr
`EL??? and Emulphor EL 3'31)?‘ {pE3lyB£hi)X)'lZHtZd fatty acid
`sisters; and oils). Which surfactant is mtaat effective as a
`smlubilizer or sttabillzcr £3 rcsften a matter of empirical
`
`336
`
`ll‘1\'{3Stlg3ll0I1 («=ll”;~. Detailed mwzws of micslle struc-
`tures. characterization techniques, and phattnacetattcal
`applicatians have been publisheé {42, 43}.
`The toxicity Gf surfactants repmtett in the literature
`print to P983 are summarizecl by Attw«::n::>d and Florence
`{:13}. Reviews on that pharntaczsrslez-g}* of polysmbate 80
`{:44} anti the incidence of clinical aide effects at Creme-
`phcrt ZZZL3
`(42) have: {teen published. Children and
`newborns may be particularly selnsitiva to these agents
`and administraticm to this populatitm is disctmsed (46).
`
`D.
`
`£:‘5e=* of Campiansséng Agents
`
`Cemplexation ml’ water insoluble drugs usually in-
`volves tha irscorpmatitm at Ihfi drug within tha inner
`core sf the complexing agent so that the outer hydro»
`philic gmups of tha mmplexing agent interacts with
`water rendering the complex soluble.
`An example: cf successful applicatimt of this techncl~
`ugy is sxmphecilfl a lipid complex formed between
`amphotericin B and sodium chalesterjl sulfate, 3 nam-
`rally occurring cholesteml metahalitre (»-1?’). In solution,
`ttn: cczmplex is postulated to be a stable r;lisc—like
`structure that remains intact in the systemic circulation.
`«Comparative Sltitlifis in animals with micellt: solubiilzecl
`ampltateticin B (Fungi:mne:®) have Shawn a significant
`reductian in systemit:
`toxicity as a result Of altered
`systemic distribution and elimination c:hat"acte1“isti4;:s (48).
`Naturally occurring Cyclodextrins, partiziularly l3—cycI:)—
`clextrin, are able to complex water l§lS0lt3blE drugs and
`reznds.-:r them mlttbltz in water. However. $3-cyclcaclextrin
`have bean associated with rmtal EOXiCli‘j.'t1pII)n parenteral
`administtatianl The taxicity has been attributed the low
`acgumus soltzbility of B-cycladextrin and precipitation in
`the: kidney. Newer cyclodaxtrins are chemically modified
`tn irnprtwe water solubility and increase their usefttlness
`{:19}. Brewster at al. {SQ} have described the preparation
`anti successful use of cltrsmically modified tryflltldexlrins
`such as 2-hydroxypropyl-fiwcyclcdextrin in sttlubilizing
`anti even stabilizing various praising and ptsptidtss.
`An example where the drug was nut
`incorporated
`within same kind at matrix. but combined with an
`adéitivc to obtain basically a solubls salt complex
`itwolveci ascorbic acid (51). Similarly, trometttamine has
`been repurtvzd to strllubilize ztameplrac. an anionic drug,
`by micelle {asscsciatitm colloid) fozrmation {$23, The
`aquwus solubility of metronidazale was reported to be
`enhanced by the water scluble vitamins nicotinamide,
`ascerbic acid or pyridoxine EC] (32). A cage;-ilk: struc-
`ture tamed by the vttarninsz armgmcl muleculex nf merm-
`rzidazole was pzagtulatedl
`
`E. Emulsiztlrz Systenzs
`
`If a molecule has sutficicnt lipid soltzbilitjyg rzmulsions
`may be employed. Typical emulsions contain triglyceride-
`rich vegetable ails and lecithin and may also contain
`tmrzionic surface active agents as emulsifying agents.
`Inmluble drugs may be incarparated into commercial
`fat cmulsitatts car
`through emulsificaticgn 0f the sail-
`solu‘-zailized drug. The farmer is uaually not successful
`
`PDA Jaurnal of Phannaceuticat Science 3. Technulogy
`
`Astrazeneca Ex. 2052 p. 8
`
`

`
`because drugs influence the stability of these Ct3l‘t‘l.l‘l’it3I‘-«
`trial emulsions (53+).
`Emulsion formulas have shown advantages (Wet high
`coeolvent levels by reducing local venous irritation (54).
`While emulsions hold potential as carriers for lipoollllic
`drugs, great eltallenges exist in; 1} eificient incorpora-
`tion of the drug into the oispersed phase, 2} validatio