Solubility of 16r,17r-Epoxyprogesterone in Six Different Solvents

1750J.Chem.Eng.Data2005,50,1750-1752

Solubilityof16r,17r-EpoxyprogesteroneinSixDifferentSolvents

QiangNieandJingKangWang*

SchoolofChemicalEngineeringandTechnology,TianjinUniversity,Tianjin300072,People’sRepublicofChina

Thesolubilitiesof16R,17R-epoxyprogesteroneinmethanol,ethanol,acetone,ethylacetate,aceticacid,and1,4-dioxaneweremeasuredusinganisothermalmethodfrom283Kto323K.Alasermonitoringobservationtechniquewasusedtodeterminethedissolutionofthesolidphaseinasolid+liquidmixture.Thesolubilityof16R,17R-epoxyprogesteroneintheabovesolventsincreasedintheordermethanol<ethanol<ethylacetate<acetone<aceticacid<1,4-dioxane.

Introduction

Solubilityisanimportantphysicochemicalpropertyandisparticularlyusefulinawidevarietyofphenomenarelevanttothechemicalandpharmaceuticalindustries,suchasthesolventselectionforareactionandforsepara-tionprocesses.16R,17R-Epoxyprogesteroneisanimportantsteroid(Figure1)thatservesasanintermediateformanyhormonepharmaceuticals,suchashydrocortisoneandmegestrol.1Itisalsoconvertedtoanotherimportantintermediate,11R-hydroxy-16R,17R-epoxyprogesterone,throughbioconversionformanufactureofmorepharma-ceuticals.2,3Butbecauseofthelimitationoftheconversionratio,theproductisamixtureoftwocompounds.Multiplecrystallizationprocessesareneededtoobtainthepureproduct.Toselectthepropersolventandtodesignanoptimizedseparationprocess,itisnecessarytoknowtheirsolubilityindifferentsolvents.4Thesolubilitydataof11R-hydroxy-16R,17R-epoxyprogesteroneinsomesolventshasbeenreportedinourpreviouswork,5butthesolubilityof16R,17R-epoxyprogesteronehasnotbeenreportedinanysolvent.Inthiswork,thesolubilitiesofthetitlecompoundinmethanol,ethanol,acetone,ethylacetate,andaceticacidweremeasuredusingasyntheticmethod.6-9Alasermonitoringobservationtechniquewasusedtodeterminethedissolutionofthesoluteatconstanttemperatures.ExperimentalSection

Materials.Acrystallinepowderof16R,17R-epoxyproges-terone(C21H28O3,relativemolarmass328.45)wasobtainedfromTianjinTianyaoPharmaceuticalCo.Ltd.,China.ItsmassfractiondeterminedbyHPLC,isbetterthan99.0%.Itwasdriedinvacuoat50°Cfor24handstoredinadesiccator.Themeltingpointis(205.5(0.5)°C.Nopolymorphictransitionwasfoundinthetreatmentofthematerial.Themethanol,ethanol,acetone,ethylacetate,andaceticacid(purchasedfromTianjinChemicalReagentCo.,China)usedforexperimentswereofanalyticalreagentgradeandwithoutanytreatmentbeforeuse.Theirmassfractionsarebetterthan99.5%.

ApparatusandProcedures.Thesolubilityof16R,17R-epoxyprogesteronewasmeasuredbytheisothermalmethod.A150mLjackedvesselwasusedtodeterminethesolubility.Thetemperaturewascontrolledtofluctuatewithin0.05Kthroughathermostatedbath(Wanda/sida

*Towhomcorrespondenceshouldbeaddressed.E-mail:srcict_tju@http://wendang.chazidian.com.Fax:+

86-22-27374971.

Figure1.Chemicalstructureof16R,17R-epoxyprogesterone.

instrumentHC2010,China).Thedissolutionofthesolutewasexaminedbythelaserbeampenetratingthevessel.Topreventtheevaporationofthesolvent,acondenservesselwasintroduced.Themassesofthesamplesandsolventsweredeterminedusingananalyticalbalance(MetlerToledoAB204-N,Switzerland)withanaccuracyof0.0001g.

Thismethodisbasedonsequentiallyaddingknownmassesofsolutetoastirredsolutionkeptatafixedtemperature.Predeterminedamountsofsoluteandsolvent(about100.0g)weretransferredintothejacketedvessel.Theamountofsolventwasasmallexcess.Afterbeingstirredatafixedtemperaturefor1h,anadditionalsoluteofknownmass(about10mg)wasintroducedintothevesselwithcontinuousstirring.Thisprocedurewasrepeateduntilthelastadditionofsolutecouldnotdissolvecompletelywithintheintervalofadditionof30min.Then,thetotalamountofthesoluteadded(includingthelastaddition)wasusedtocomputethesolubility.Thedissolutionofthesolutewasmonitoredbyalaserbeam.Whenthesolutedissolvedcompletely,thesolutionwasclear,andthelaserintensitypenetratedthroughthesolutionattaineditsmaximum.Whenthelaserintensitydidnotexceed90%ofthemaximum,thesolutewasbelievednottobedissolvedcompletely.Theamountofsoluteleadingtothelaserintensitydecrease10%fromthemaximumislessthan1.0mg.Theuncertaintyinthesolubilityvaluesisestimatedtobe1.0%.Alldeterminationswererepeatedtwomoretimes,andthemeanvalueswereusedtocalculatethemolefractionsolubility.ResultsandDiscussion

Themeasuredsolubilityof16R,17R-epoxyprogesteroneinpuremethanol,ethanol,acetone,ethylacetate,aceticacid,and1,4-dioxaneatdifferenttemperaturesarelisted

10.1021/je050195wCCC:$30.25©2005AmericanChemicalSociety

PublishedonWeb07/26/2005

JournalofChemicalandEngineeringData,Vol.50,No.5,20051751

Table1.MoleFractionSolubility(x1)of

16r,17r-EpoxyprogesteroneinPureSolvents

Tx1-xcalcd1

Tx1-xcalcd1

K102x1x1

K

102x1x1Ethanol286.100.1340.067308.850.340

-0.006288.150.1450.048312.650.4000.003293.350.171-0.023317.550.4870.004297.700.211-0.009322.700.5960.008303.050.258-0.039328.450.729-0.004Methanol282.500.1000.043307.750.290-0.005288.700.1330.038312.800.349-0.021293.100.1590.016317.650.424-0.012297.900.192-0.003322.450.5160.001302.950.2400.005327.600.6270.009Acetone285.350.895-0.017310.051.8380.002288.500.985-0.016314.152.035-0.003293.351.150-0.003317.602.225-0.003298.951.3720.012322.352.507-0.003304.851.6240.018327.452.8530.001EthylAcetate285.450.752-0.035308.151.4220.014288.700.819-0.039312.751.5800.008293.850.968-0.008317.851.765-0.002297.951.1020.014322.801.9850.002302.751.2570.023328.452.230-0.010AceticAcid293.601.2350.020310.752.426-0.004295.751.3570.022313.552.7080.000298.251.4790.003316.653.022-0.007301.301.646-0.016319.253.333-0.004303.951.817-0.026322.153.7590.012306.852.1210.014326.054.245-0.0031,4-Dioxane288.452.2650.002312.754.519-0.043293.452.6580.0004317.255.5620.041298.253.0970.004322.506.3030.026302.753.525-0.003328.257.104-0.002307.75

3.996

-0.024332.55

7.822

-0.013

inTable1.Thesolubilityinallsixsolventsincreaseswithtemperature.16R,17R-Epoxyprogesteroneisslightlysolubleinmethanolandethanolwiththeequilibriummolefractionx≈10-3,whereasthesolubilityinacetone,ethylacetate,aceticacid,and1,4-dioxanearemuchhigher,withx≈10-2.Thesolubilityof16R,17R-epoxyprogesteronealsode-pendsonthepolarityofthesolventtosomedegree.Thesolubilityincreaseswiththedecreaseofthepolarityofthesolvent.Thesolubilityinstronglypolarethanolandmethanol(dielectricconstantsof22.4and32.6,respec-tively,at20°C)10ismuchlowerthanthatinweaklypolarethylacetateand1,4-dioxane(dielectricconstantsare6.02and2.21,respectively,at20°C).10Thesolubilitybehaviormaybeexplainedbydiscussingtheinteractionbetweenthehomogeneoussolute,thesolvent,andtheheteroge-neousmoleculesinsolution.

16R,17R-Epoxyprogesteronehasanonpolarsteroidskel-etonmoiety.Theadditionofsomecarbonylgroupsmakesthewholesteroidmoleculehavesomeweakpolarity.ThemaininteractionsinthesolutewerevanderWaalsforces.However,bothmethanolandethanolarepolarsolvents;theinteractionbetweenthealcoholmoleculesismainlythehydrogenbondforce,themoleculesofmethanolandethanolformachainbyintermolecularhydrogenbonding.Thestrongpolarityofthealcoholsalsoincreasestherepulsionbetweenthealcoholmoleculesandthesteroidskeleton.Theinteractionbetweenalcoholmoleculesandsteroidmoleculescannotoffsettheenergylossindestroying

Table2.ParametersofEquation1for

16r,17r-EpoxyprogesteroneinPureSolventssolvent

λ

h

solvent

λ

h

ethanol0.296313131.0ethylacetate0.158213646.3

methanol0.237116028.7aceticacid1.69352213.72acetone0.27608797.54

1,4-dioxane0.96252829.67

thenormalinteractionsinalcoholsandsteroidcrystals.

Therefore,thesolubilityofthetitlecompoundinstrongpolarsolvents(alcoholsinthisstudy)isnotveryhigh.However,theinteractioninethylacetateand1,4-dioxanemainlythroughthevanderWaalsforce,sothesolvationofsteroidmoleculesiseasier.Theacetoneisalsoapolarsolvent,butnointermolecularhydrogenbondingexistsinthesolvent.Afterthemixingofsoluteandsolventmol-ecules,thetotalenergyofthewholesystemdoesnotincreasetoomuch,sothesolubilityinacetoneisgreaterthaninethanolandmethanol.Aceticacidisaspecialsolvent,althoughthesinglemoleculeofaceticacidhasstrongpolarity,butinliquidtheyaremainlyintheformofadimer.Thentheapparentpolarityofthedimerisweakened,thennotonlytherepulsionbetweenthedimerandthesteroidmoleculeisdecreasedbutalsotheinterac-tionbetweentwoheterogeneousmoleculesisenhanced.Andevenafterthedissolutionofthesteroid,thedimerstructuremaybenotdestroyed.Sothesolubilityofthesteroidinaceticacidishigh.

Buchowskietal.11firstpresentedtheλ-hequationtocorrelatethesolid-liquid-phaseequilibriumfortheas-sociatedsysteminthefollowingform:

ln[1+λ(1-x1)/x1])λh/(T-1-T-1t1)

(1)

wherex1isthemolefractionsolubilityofthesolute,Tisabsolutetemperature,andTt1isthemeltingpointtem-peratureofthesolute.λisadimensionlessparameter,indicatingthenon-idealityofthesolutionsystem.Anotherparameterhisdefinedasfollows:

hR)?Hmt+HE/x1

(2)

where?Hmtistheenthalpychangeuponmelting,HEistheexcessenthalpyinthemixingprocess,andRisthegasconstant.Theparametersvaluesareusuallycorrelatedfromtheexperimentaldataduetothelackofthefunda-mentalthermodynamicdata.

Equation1issimpleandhasonlytwoindeterminateparameters,providedthemeltingtemperatureisknown,soitattractsmuchattention.12-16Domanskahasreportedthatcorrelatingthesolid-liquidequilibriumusingtheλ-hequationisbetterthanusingtheWilsonequationforsomepolarsystems.13,14

Inthispaper,theexperimentalresultswerecorrelatedusingeq1.Themeltingpointof16R,17R-epoxyprogesteroneusedineq1is478.65K,whichwasdeterminedbyDSC.ThevaluesofparametersλandhfordifferentsolventsarelistedinTable2.Therelativedeviationsbetweentheexperimentalsolubility(x1)andthecalculatedsolubility

(xcalcd)byeq1aregiveninTable1.Itcanbeseengoodness1

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