右旋布洛芬的低温热容

右旋布洛芬的低温热容 January 物理化学学报(WuliHuaxueXuebao) ActaP.一Chim.Sin.,2005,21(1):l,5 LowTemperatureHeatCapacityof(S)-ibuprofen Xu.FenSUN,Li—XianTAN,Zhi—ChengLI,Rui—Lian TIAN,Qi—FengZHANG,Tao rMaterials&ThermochemistryLaboratory,DalianInstituteofChemicalPhysics.ChineseAcade myofSciences Dalianl16023;lHunanInstituteofDrugDetection.Changsha410001) AbstractMolarheatcapacitiesof()一 ibuprofenwerepreciselymeasuredwithasmallsampleprecisionautomated adiabaticcalorimeteroverthetemperaturerangefrom80to370K.Experimentalheatcapacitieswerefitt edintoapolyno— mialequationofheatcapacities(Cp)withreducedtemperature(X),[X=-厂 fTJ】.Thepolynomialequationsfor (S)一ibuprofenwereCp,(s)=一39.483X4—66.649X3+95.196+210.84X+l72.98insolidstateand. (L)= 7.191X3+4.2774+56.365X+498.5inliquidstate.Thethermodynamicfunctionsrelativetothereferenc etempera- tureof298.15K,厅一9815andSr一9815,werederivedforthe()一 ibuprofen.Afusiontransitionat=(324.15? 0.02)Kwasfoundfromthe—Tcurve.Themolarenthalpyandentropyofthefusiontransitionweredeterm inedto be(18.05?0.31)kJ’mol一and(55.71?0.95)J’mol’K一1,respectively.Thepurityofthe()一 ibuprofenwasdeter- minedtobe99.44%onthebasisoftheheatcapacitymeasurement.Finally,theheatcapacitiesof()一 ibuprofenand racemicibuprofenwerecompared. Keywords:()一ibuprofen,Adiabaticcalorimetry.Heatcapacity lbuprofenhasachiralcarbonaceousatom.Itisgenerally recognizedthat(S)一ibuprofenistheenantiomerofibuprofen. The()一ibuprofen.awhitecrystalpowderandnonsteroidalanti— inflammatorydrughavinganalgesicandantipyreticactivities, showsameltingprocessoverthetemperaturerangefrom51to 53?iii.Clinicstudyshowedthatthe(S)-ibuprofenpossessesa pharmacologicaleffect160timeshigherthanthatof2一 (4一isobutylpheny1)一(一)一propionicacid.Thedosesof150 mgand300mgofthe()一ibuprofenarebiologicallyequivalent tothoseof200mgand400mgofracemicibuprofen,respec— tively.The()一ibuprofenhasthesuperioritytoracemicibupro— feninsafetyandpharmacologicaleffect.Itisthemostactive speciespharmaceuticallyfromboththeclinicalandbiophar- maceuticalpointsofview.Methodsusedforpreparing(S)一 ibuprofen,suchaschiralseparationbychiralchromatographyor chiralHPLC,chemicalsplittingmethod,biologicalcatalysis andhydrolysis,havebeenpresentediniterature. Thethermodynamicpropertiesofdrugs,e.g.heatcapa— cies,aresignificantforthedrugproductionandclinicalappli— cations.Asfarasthedeterminationofheatcapacitiesofdrugsis concerned,therearemanypublicationswhichuseddifferent methodssuchasmodulatedtemperaturedifferentialscanning calorimetry(DSC)[781,standarddifferentialscanningcalorime— try.Asoneknows,adiabaticcalorimetryisaveryaccurate methodforheatcapacitydetermination.However,onlyvery fewpapers”..reportedtheheatcapacitymeasurementsof drugsbytheadiabaticcalorimetry. Theliteraturereportedthatthemeltingpoint,meltingen— thalpyandentropyofthe()一ibuprofenwere327K.17.9kJ’ mol一and54.8J’mol’K一1.respectively..Inthepresent work,low—temperatureheatcapacitiesofthe(S)一ibuprofenwere studiedindetailbyasmallsampleprecisionautomatedadiabatic calorimeter.Thepurityofibuprofenwasdeterminedinthelight oftheheatcapacitymeasurements. 1Experimental ReceiVed:June11,2004;Revised:July15,2004.Correspondent:SUN.Li—Xian(E—mail:lxsun@dicp.ac.cn;Tel:0411—84379123) ‘TheProjectSupportedbyNsFc(20373072) 2ActaPs.一Chim.Sin.1WuliHuaxueXuebao),2005Vo1.21 1.1Sample (S).Ibuprofen(CAS51146?56?6,itscontentishigher than99.0%)wassuppliedbyHunanInstituteofDrugDetec— tion.P.R.China.ItwasseparatedbychiralHPLC.Tllesep’ aratedproductwasfurtherrecrystallizedthreetimeswithalcohol (A.R.).FrIRandC13NMRwereusedtodetermineits structure.Qualitativeanalysiswascarriedoutbypolarimeter, andquantitativeanalysiswasperformedusingtitration. 1.2Adiabaticcalorimetry Heatcapacitymeasurementwascarriedoutusingasmall sampleprecisionautomatedadiabaticcalorimeteroverthetem— peraturerangefrom80to390K.Theconstructionandprinciple ofthecalorimeterhavebeendescribedpreviouslyindetail elsewhereIl4_”1. Briefly.thecalorimeterwasbasedonNernst stepheatingmethod.AtemperatureincrementATiscaused bysupplyingaknownquantityofelectricenergyAE_Tlle electricalenergyintroducedintothesamplecellandtheexlui? libriumtemperatureofthecellaftertheenergyinputwerean? tomaticallypickedupbyusingoftheDataAcquisition/Switch Unit(Model34970A,Agilent,USA),andprocessedonlineby acomputer.Tlletotalheatcapacity(C)ofthecellcontaining sampleisgivenastheratioofthesuppliedelectricenergytothe temperatureincrement,namelyasC=AE/AHeatcapacity ofthe(S)?ibuprofensampleisderivedbysubtractingtheheat capacityoftheemptycalorimetercelldeterminedinanexperi? mentusingemptycellwithoutsamplefromthetotalheatca- pacity. Toverifythereliabilityofthecalorimeter,themolarheat capacitiesofsapphire(a—A1203,StandardReferenceMaterial 720,theNationalInstituteofStandardsandTechnology)were measuredoverthesametemperaturerange.Tlledeviationsofour experimentalts.respectively byleastsquarefittingofheatcapacitiesdataofsapphirewere within?0.2%.whiletheinaccuraciesliewithin?0.5%,as comparedwiththeheat?capacityvaluesofsapphirerecom’ mendedbyDonaldArcherforITS一90【lovertheinvestigated temperaturerange. Themassofthesamplefilledinsamplecelloftheadi? abaticcalorimeterwas1.5088g,whichwasequivalentto 7.3143mmolbasedonitsmolarmassof206.28g?mol—i. 2Resultsanddiscussion 2.1Heatcapacity Fig.1showsaplotofexperimentalmolarheatcapacitiesof ()一ibuprofentemperatureobtainedbytheadiabaticcalorime? teroverthetemperaturerangefrom88to370K.Thetemper- atureincrementforeachexperimentalpointwasabout3Kinthe wholetemperaturerange.Thesmoothmolarheatcapacitiesof (S)?ibuprofenandotherthermodynamicproperties(relativeto 298.15K)arelistedinTable1,where ?,一‰=』二dT = 』二.争dT Themolarheatcapacitiesofthesampleinsolidstate werefittedtothefollowingpolynomialofheatcapacitiest reducedtemperatm’e(X)bymeansoftheleastsquarefitting .(s)=一39.483一66.649+ 95.196+210.84X+l72.98(1) whereX={一【(+)/2】/【(Tm一)/2】},when =312KandTm.=88K,X=(T一200)/ll2,Tisthe absolutetemperature,thecorrelationcoefficientofthefitting, R2=0.9999.Thisequationisvalidinthetemperaturerange from88to312K. Themolarheatcapacitiesofthesampleinliquidstatewere fittedtothefollowingpolynomial: C…(L)=7.191+4.2774+ 56.365X+498.5(2) whereX={一【(|x+7)/2】/【(Tm啦一)/2】},when =369Kand,=326K.X=(T一347.5)/21.5.This equationisvalidinthetemperagurerangefrom326to369K andcorrelationcoefficient=0.9998. 2.2Molarenthalpyandentropyoffusion Fig.1showsthereisanendothermicpeakfrom312to326 K.Themeltingpointofthismaterialisoverthetemperature rangefrom51to53?(324.15—326.15K)accordingtothe literature….Thus,thisendothermicpeakiscausedbythefu- sionof(S)一ibuprofen.Theequilibrationtimewithinsolidand liquidphasewasabout8h. Theenthalpyoffusion.?ru.,wascalculatedas (18.05?0.31)kJ?mol一.bythefollowingformula.’ N0.1SUN.Li.Xianela1.:LowTemperatureHeatCapacityof().ibuprofen3 \ Fig.2CurveofT1/Ffor(S)-ibuprofen ?sHm/J’mol=【Q一J(s】dT一Jr_(L】d一rr_r f风dT】/n(3)J whereisthetemperaturewhichiss~ghtiylowerthanthe startingphasetransitiontemperature;Tm,themeltingpoint; . thetemperatureslightlyhigherthanthefinishingphase transitiontemperature;Cp(s),theaverageheatcapacityatthe temperature(+Tm)/2;Cp(L),theaverageheatcapacityat thetemperature(Tm+)/2;n,themolarnumberofthe sample;Q,overallenergyabsorbedbythesampleandcon? Table1Calculatedthermodynamicfunctiondataof(S)-ibuprofen 4ActaPhys.一Chim.Sin.rWuliHuaxueXuebao),2005Vo1.2l tainerinthetemperatureregionbetweenandTf;Ho,theheat capacityoftheemptysamplecel1.Theentropyoffusion?sSm couldbeobtainedas(55.71?0.95)J?mol?Kby ?Sm=AHm/Tm. 2.3Meltingpointandpurity Thepurityofthesamplewasevaluatedfromasetof equilibriummeltingtemperatureandthemeltedfractionF correspondingtothesetemperature【】.?.l】Therelationshipbe— tweenandFcanbeexpressedasfollows: = To一(1/F)(To一)(4) whereToisthemeltingpointofanabsolutelypuresubstance; Tmisthemeltingpointofthegivensample;Fistherateofthe partialheatrequiredmeltingapartofthesampletothetotalheat requiredmeltingthewholesample. Eq.(4)showsthattherelationshipbetweentheequilibrium meltingtemperatureandthereciprocalofmeltedfraction1/F islinear.Plotting/)s1/F(seeFig.2).andextrapolatingthe straightlineto1/F=1and1/F=0.thenTmandTocanbe derivedasTm=324.15KandTo=324.42K.Therefore.the meltingpointofthe()一ibuprofenis324.15K. Accordingliteratures【l8_.21】.therelationbetweenthemole fractionxoftheimpuritiesinthesampleandmeltingpointof thesamplecanbeexpressedasfollows: x=Am(一)/(5) IntermsofEq.(5).xiscalculatedtobe5.58×10-3.The purityofthe()一ibuprofenis1一x=99.44%. 2.4ComparingCpof(S)-ibuprofentllracemic ibuprofen Theheatcapacitiesofracemicibuprofenhavebeenre— ported.Fig.3isthecurvesofheatcapacitiesofracemate and(S)一ibuprofen.Itclearlyindicatesthattheheatcapacities oftheracemateand(S)一ibuprofenbelow170Karealmost thesame;andtheheatcapacitiesof()一ibuprofenarehigherthan thoseofracemicibuprofenabove170K,whethertheyaresolid orfiquid.Thehi【gherthetemperature,thelargerthedifference ofheatcapacitiesbetweentheracemateand(S)-ibuprofenis. Theabovephenomenacanbeascribedtotherelationshipof crystalstructuresandintermolecularenvironments】ofthe racemateand()一ibuprofen.Accordingtotheliterature【7】.the moleculararrangementofracemicibuprofenexhibitssomeofthe acidgroups’face—up’andothers’face—down’. sothatallthe layersofmoleculesareinterconnectedwithpairsofhydrogen bondstocarboxylgroups.However,therealeagreaternumber ofcrystallographicallyindependentmoleculesinthe()一crystals. ? E ? \ Fig.3ComparisonofCpofracemateand (S)-ibuprofen Thearrayof(S)一crystalmoleculesinvolvedinhomochiralin— teractionsprobablyspreadsthemechanicalstability/strengthof thecrystal,andmoleculesofthesainechiralityhadtobeflexed inordertomeetthespacerequirementsofthelattice.Thismay causethattheheatcapacitiesof(S)一ibuprofenishigherthan thatofracemate. 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Berlin:Springer,1995,Chaper7 21Badley,J.H.Phys.Chem.,1959,63:1991 22Xu,F.;Sun,L.X.;Tan,Z.0.84X+ 172.98;相应的液态的拟和方程为:.()=7.191Xz+4.2774X2+56.365X+498.5.并计算得到右旋 布洛芬 相对于室温(298.15K)的摩尔焓和摩尔熵.右旋布洛芬的熔点为(324.15?0.02)K.基于摩尔热 容的测量, 还可获得右旋布洛芬的纯度为99.44%.并对右旋布洛芬和消旋布洛芬的热容进行了对比研 究. 关键词:右旋布洛芬,绝热量热,热容 中图分类号:0642.3 2oo4-o6-11到收初稿,2004-07-15收到修改稿.联系人:孙立贤 (E-mail:lxsun@dicp.ac.cn;Tel:0411.84379123).’国家自然科学 基金(20373072)资助项目