Solubility of Pravastatin Sodium in Water, Methanol, Ethanol, 2-Propanol,

2466J.Chem.Eng.Data2008,53,2466–2468

SolubilityofPravastatinSodiuminWater,Methanol,Ethanol,2-Propanol,1-Propanol,and1-Butanolfrom(278to333)K

ChunyanJia,QiuxiangYin,*JingjingSong,GuangyangHou,andMeijingZhang

SchoolofChemicalEngineeringandTechnology,TianjinUniversity,Tianjin300072,People’sRepublicofChina

Thesolubilitiesofpravastatinsodiuminwater,methanol,ethanol,2-propanol,1-propanol,and1-butanolfrom(278to333)Kweremeasured.Alasermonitoringobservationtechniquewasusedtodeterminethedissolutionofthesolidphaseinthesolid+liquidmixture.Theexperimentaldatawerecorrelatedwithasemiempiricalequation.Thesolubilitiesinthesixsolventsdecreaseinthefollowingorder:water>methanol>ethanol>1-propanol>1-butanol>2-propanol.

Introduction

Pravastatin([1S-[1R(??*,γ*)2R,6R,8??(R*),8aR]]-1,2,6,7,8,8a-hexahydro,??,γ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-heptanoicacid),whosechemicalstructureisshowninFigure1,isamemberoftheclassofpharmaceuticalcompoundscalledstatins.Statinscurrentlyarethemosteffectivemedicationsforloweringserumcholesterollevelsinpatientswithatherosclerosisandhypercholesteremia.Pravastatinsodium,themonosodiumsaltofpravastatin,canexistinhydrated,anhydrous,solvated,andunsolvatedforms1(CASRN81131-70-6).

Previously,pravastatinsodiumwasavailableonlyintheamorphousform.Inrecentyears,thepreparationofpravastatinsodiuminthecrystalformhasbeenreported.1,2Incomparisonwiththeamorphousform,thecrystallinesubstanceshavemanyadvantages:theirphysicalaswellaschemicalpropertiesarebetterde?ned,andtheyaremorestable.

Ithasbeenfoundthatdifferentpolymorphicformsofpravastatinsodiumcanbeobtainedinthecrystallizationprocessbyusingdifferentsolvents.1Toselectthepropersolventandtodesignanoptimizedresearchprocess,itisnecessarytoknowthesolubilityofpravastatinsodiumindifferentsolvents.Inthiswork,itssolubilitiesofthetitlecompoundinwater,methanol,ethanol,2-propanol,1-propanol,and1-butanolattemperaturesbetween(298and333)Kweremeasuredusingtheisothermalmethod.3-6Alasermonitoringobservationtechniquewasusedtodeterminethedissolutionofthesolute.

Table1.SolubilityofPravastatinSodiuminDifferentPureSolventsfrom(278to333)KT/K278.4283288293298303277.8283287.9293297.8278283288293298303278283288293298278283288293298303278.1283288293298303

103x19.1111.9316.2421.6528.5234.3122.4624.4826.9530.0932.623.13.253.463.664.064.290.6050.6840.7530.8180.9032.082.162.192.272.382.741.081.181.271.441.591.78

100(x1-xcalcd/x1)

1.3-1.91-0.880.964.251.212.651.671.341.14-2.14.832.130-0.01-3.33-0.361.363.492.670.2-1-10.6-0.780.48-1.37-7.3-8.2-3.070.52-0.261.61-1.53-5.65

T/K

103x140.8947.7255.2864.1972.384.1437.3241.7549.2158.868.674.634.935.696.927.939.421.031.11.411.641.93.434.496.212.1615.78

100(x1-xcalcd/x1)

-0.436-1.94-2.060.161.166.98-1.37-3.64-0.942.530.061.776.844.50-1.91-1.33-3.340.8-4.33-3.36-1.872.09-4.88-1.173.926.61-4.16

water

308313318323328333methanol

302.9308313318324ethanol

3083133183233283332-propanol

303308318322.9327.91-propanol

3083133183283331-butanol

308313318.2323328

ExperimentalSection

Materials.CrystallinepowderpravastatinsodiumofformAwithamassfractionhigherthan99.5%obtainedfromShanghaiTianweiPharmaceuticalCo.Ltd.(Mw446.52,molecularformulaC23H35NaO7),China,wasusedasreceivedwithoutfurtherpuri?cation.Water,methanol,ethanol,2-propanol,1-propanol,and1-butanol(purchasedfromTianjinChemicalReagentCo.,China)usedforexperimentswereofanalyticalreagentgradeandweredehydratedwithmolecularsievesbeforeuse.Theirmassfractionwashigherthan99.5%.Distilleddeionizedwaterwasused.

ApparatusandProcedure.Thesolubilityofpravastatinsodiumwasmeasuredbytheisothermalmethod,andthe

*Correspondingauthor.Fax:+86-22-27374971.E-mail:qxyin@http://wendang.chazidian.com.

2.232.93.454.084.93-0.28-6.512.16-2.91-8.56

experimentalapparatususedwassimilartothatdescribedindetailintheliterature.6Theexperimentswereperformedinacylindricaldouble-jacketedglassvesselhavingaworkingvolumeof100mL,inwhichthetemperaturewascontrolledto

10.1021/je800196kCCC:$40.75?2008AmericanChemicalSociety

PublishedonWeb09/03/2008

JournalofChemical&EngineeringData,Vol.53,No.10,20082467

x1)

m1?M1

m1?M12?M2

(1)

wherem1andm2representthemassesofthesoluteandsolventandM1andM2arethemolecularweightsofthesoluteandthesolvent,respectively.

ResultsandDiscussion

Figure1.Chemicalstructureofpravastatin

sodium.

beconstantwithin0.05Kthroughathermostattedbath(Wanda/sidainstrumentHC2010,China).Amagneticstirbarwasusedforturbulentmixingofsuspension.Thedissolutionofthesolutewasexaminedbytheintensityofthelaserbeamthatpenetratedthroughthesuspension.Thelasermonitoringsystem(purchasedfromPhysicsDepartmentofPekingUniversity)consistedofalasergenerator(typeJD-3,China),aphotoelectricswitch(typemodel271,China),andalightintensitydisplay.

Themassesofthesamplesandsolventsweredeterminedusingananalyticalbalance(MetlerToledoAB204-N,Switzer-land)withanaccuracyof0.0001g.Thismethodisbasedonsequentiallyaddingknownmassesofsolutetoastirredsolutionkeptata?xedtemperature.Predeterminedmassesofsoluteandsolventweretransferredintothejacketedvessel.Thesolventtransferredintothevesselwasoverweight.Afterstirringata?xedtemperaturefor10min,anadditionalsoluteofknownmass{about(0.1to0.3)mg}wasintroducedintothevesselwithcontinuousstirring.Thisprocedurewasrepeateduntilthesolutewascompletelydissolvedwithintheintervalofadditionof20min.Then,thetotalamountofthesoluteadded(includingthelastaddition)wasusedtocomputethesolubility.Thedissolutionofthesolutewasmonitoredbyalaserbeam.Whenthesolutedissolvedcompletely,thesolutionwasclear,andthelaserintensitythatpenetratedthroughthesolutionattaineditsmaximum.Otherwise,thesolutewasbelievednottobedissolvedcompletely.Thesamesolubilityexperimentwasconductedthreetimes,andthemeanvalueswereusedtocalculatethemolefractionsolubilityx1basedonthefollowingequation

Thesolubilitydataofpravastatinsodiuminwater,methanol,ethanol,2-propanol,1-propanol,and1-butanolfrom(278to333)KarelistedinTable1andmorevisuallygiveninFigure2.Forthesakeofthepracticalapplication,itiscommontodescribethesolid-liquidequilibriumdatawithatheoreticalsemiem-piricalexpression.Ithasbeenfoundthatthemodi?edApelblatequation7can?tthesolubilitydataverywellforseveralsolid-liquidequilibriumsystems.8-11Here,thissemiempiricalequationwastentativelyusedtocorrelatetheexperimentalsolubilitydataofpravastatinsodiuminthesixsolventsunderconsideration.

Thesolubilityofasolidinaliquidmaybeexpressedinaverygeneralmannerby

?Hf,1Tf,1?Cpf,1Tf,1

lnx1)--1--1+

RTf,1TRT

?Cpf,1Tf,1

ln-lnγ1(2)RT

wherex1,γ1,?Hf,1,?Cpf,1,Tf,1,R,andTstandforthemole

fractionofsolute,activitycoef?cient,enthalpyoffusion,differenceinthesoluteheatcapacitybetweenthesolidandliquidatthemeltingtemperature,meltingtemperatureofthesolute,gasconstant,andequilibriumtemperatureinthesaturatedsolution,respectively.Forregularsolutions,theactivitycoef-?cientisgivenby

(

)

(

)

lnγ1)A+

B(T?K)

(3)

whereAandBstandforempiricalconstants.Introducingγ1frompreviousequationsintoeq2withsubsequentrearrange-mentsresultsinthe

equation

Figure2.Molefractionsolubilityofpravastatinsodiuminsixdifferentsolventsbetween(298and333)K.

2468JournalofChemical&EngineeringData,Vol.53,No.10,2008

lnx?Hf,1RT+?Cpf,1

1)

[

(1+lnTf,1R

f,1)-A-[B+(

?Hf,1RT+?Cpf,1)]

T]

1?Cpf,1

f,1-R

lnT(4)

f,1RTwhichcanbewrittenas

lnx1)a+

b

(T?K)

+cln(T?K)(5)

ThedeviationsbetweentheexperimentalandcalculatedresultsarealsopresentedinTable1.Thevaluesofparametersa,b,andcineq5andtheroot-mean-squaredeviations(rmsd)de?nedbyeq6arelistedinTable2.Itcanbeseenthatthecalculatedsolubilitiesshowgoodagreementwiththeexperi-mentalvalues.

{N

calcd21/2

rmsd)

1x1i

-x1iN(6)

i∑)1(x1i

)}

whereNisthenumberofexperimentalpointsandxcalcdandxrepresentthesolubilitycalculatedfromeq5and1thei

experi-1imentalvalue,respectively.

FromTable1,itcanbeseenthatwithinthetemperaturerangeofmeasurementsthesolubilitiesofpravastatinsodiuminwater,methanol,ethanol,2-propanol,1-propanol,and1-butanolin-creasewithincreasingtemperaturewithoutexception.Inaddi-tion,thesolubilitiesofpravastatinsodiuminwaterandmethanolaremuchhigherthanthoseintheotherfoursolvents.Referredtothefactthatthepolaritiesofthesixsolventsusedintheexperimentsdecreaseinthefollowingorder,water(100)>methanol(76.2)>ethanol(65.4)>1-propanol(61.7)>1-bu-tanol(60.2)>2-propanol(54.6),12inaccordwiththesolubilitiesorder,itcanbeconcludedthatthebiggerthepolarityofthesolventused,thehigherthesolubilityofthetitlecompound.

Table2.ParametersofEquation2forPravastatinSodiuminDifferentPureSolventssolventabc102rmsdwater437.79-23095.8-63.872.66methanol-264.949800.7740.131.99ethanol-39616190.79593.242-propanol-155.464909.7723.172.461-propanol-1197.3651088.13179.035.531-butanol

-637.02

25916.05

95.42

3.99

Thiscanbeduetotheion-dipoletypeinteractionbetweenthe

saltformsolventsandtheproticsolute.Thisinteractiongetsstrongerasthepolarityofthesolventgetslarger.AscanbeseenfromTable1,thereisasuddenincreaseofthesolubilityin1-propanolathighertemperature.Thereasonforthisismaybethattheaddedpravastatinsodiumreactedwiththesolvent.Thisistobedeterminedinthefollowingstudy.FromFigure1,itcanbeseenthatpravastatinsodiumisacompoundwithhighpolarity,whichisledbytwocarboxylsandthreehydroxylsinthemolecule.Thatistosaythesolubilitybehaviorofpravastatinsodiumjustaccordswiththeempiricalrule,“likedissolveslike”.

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JE800196K