Solubility of Sodium Cefotaxime in Different Solvents

982J.Chem.Eng.Data2007,52,982-985

SolubilityofSodiumCefotaximeinDifferentSolvents

HaitaoZhang,JingkangWang,*YingChen,andMeijingZhang

SchoolofChemicalEngineeringandTechnology,TianjinUniversity,Tianjin300072,People’sRepublicofChina

Thedissolutionofsodiumcefotaximein15solventswereinvestigated.Onlyfivesolvents(formamide,N,N-dimethylformamide,dimethylsulfoxide,water,andN-methylpyrrolidone)showedgoodsolvencyforthesolid.ThesolubilitiesofsodiumcefotaximeinN,N-dimethylformamide,formamide,andN-methylpyrrolidoneweredeterminedbetweenthetemperaturerangefrom(278.15to308.15)K,inwatertheyweremeasuredbetween(278.15and303.15)K,andindimethylsulfoxidetheyweredeterminedbetween(293.15and308.15)K.Alasermonitoringobservationtechniquewasusedtodeterminethedissolutionofthesolidphaseinasolid-liquidmixture.Thesolubilitiesofsodiumcefotaximeinallsolventsmeasuredincreasewithtemperature,andthesolubilitiesofsodiumcefotaximealsodependonthepolarityofthesolventtosomeextent.Theexperimentalsolubilitydatawerecorrelatedwithasemiempiricalequation.

Introduction

Solubilityisanimportantphysicochemicalpropertyandisparticularlyusefulinawidevarietyofphenomenarelevanttothechemicalandpharmaceuticalindustries,suchasthesolventselectionforareactionandforseparationprocesses.Sodiumcefotaximesaltisabroadspectrumthird-generationcepha-losporinantibiotic.1-3Untiltoday,onlysolubilityinsomepuresolventssuchasmethanol,ethanol,acetone,n-hexane,dichlo-romethane,diethylether,andethylacetateandbinary2-propanol+watersolventmixtureshavebeenreportedintheliterature.4,5Duringmanufacturing,toselectthepropersolventandtodesignanoptimizedseparationprocessforthepharmaceutical,itisnecessarytoknowitssolubilityinmoresolvents.Inthiswork,thesolubilitiesofthetitlecompoundinN,N-dimethylformamide,formamide,N-methylpyrrolidone,water,anddimethylsulfoxideweremeasuredusingasyntheticmethod.6-14Alasermonitoringobservationtechniqueemployinganisothermalmethodwasintroducedtodeterminethedissolutionofthesolute.Inaddition,thesolubilitiesofsodiumcefotaximeindimethylcarbonate,toluene,isopropanol,n-butanol,isobutanol,benzylalcohol,chloroform,pyridine,tetrahydrofuran,and1,4-dioxanewerealsoinvestigatedinthiswork.

Figure1.Chemicalstructureofsodiumcefotaxime.

http://wendang.chazidian.comparisonoftheExperimentalSolubility(ω)ofPotassiumChloride(1)inWater(2)withtheLiteratureData

T/K

283.15293.15198.15303.15313.15333.15

100ω1

100ω1(ref17)

relativedeviation/%

23.8223.830.04

25.5625.55-0.04

26.3627.1228.6226.3427.1428.57-0.080.078-0.18

31.1931.210.06

ExperimentalSection

Materials.Awhitecrystallinepowderofsodiumcefotaxime(C16H16N5O7S2Na,molecularweight477.44,Figure1)obtainedfromShenzhenJiuxinPharmaceuticalCo.,Ltd.,China,withamelting/decompositionpointof273.5°C,measuredusingaNETZSCHDSC204differentialscanningcalorimeter,waspurifiedbyrecrystallizationfrommethanolbyadrowningoutmethodwithethylacetateastheanti-solvent.Itwasdriedinvacuoat40°Cfor24handstoredinadesiccator.Itsmassfractionpurity,determinedbyHPLC,wasbetterthan99.0%.Agilent1200HPLCandZorbaxEclipseXDB-C18column(250×4.6mm,5µm)wereutilized.p-Acylaminophenolwasemployedastheinternalstandard.Themobilephasewithaflowrateof1.5mL?min-1wasphosphate-bufferedsaline+methanol(75:25),andtheUVdetectionwasat236nm.

*Correspondingauthor.Phone:+86-22-27405754.Fax:+86-22-27314971.E-mail:

wz_tju@http://wendang.chazidian.com.

N,N-Dimethylformamide,formamide,N-methylpyrrolidone,dimethylsulfoxide,dimethylcarbonate,toluene,isopropanol,1-butanol,isobutanol,benzylalcohol,chloroform,pyridine,tetrahydrofuran,and1,4-dioxane(purchasedfromTianjinChemicalReagentCo.,China)usedfortheexperimentswereofanalyticalreagentgradeandwereusedwithoutanytreatmentbeforeuse.Theirmassfractionpuritieswerebetterthan99.5%.Distilleddeionizedwaterwasalsoused.

ApparatusandProcedure.Thesolubilityofsodiumcefo-taximewasmeasuredbytheisothermalmethod.Theapparatusforsolubilitymeasurementisthesameasthatdescribedintheliterature15,16andisonlybrieflydescribedhere.A100mLjacketedvesselwithwatercirculatedfromawaterbathwasusedtodeterminethesolubility;thetemperaturewascontrolledtobeconstant(fluctuateswithin0.05K)throughthethermo-statedbath(type501A,China).Thedissolutionofthesolutewasexaminedbythelaserbeampenetratingthevessel.Thelasermonitoringsystemconsistedofalasergenerator,aphoto-electrictransformer,andalightintensitydisplay.Continuousstirringwasachievedwithamagneticstirbar.Topreventtheevaporationofthesolvent,acondenservesselwasintroduced.Amercury-in-glassthermometerwithanuncertaintyof0.05Kwasinsertedintotheinnerchambersofthevesselsforthemea-surementofthetemperature.Themassesofthesamplesand

10.1021/je600564qCCC:$37.00©2007AmericanChemicalSociety

PublishedonWeb03/08/2007

JournalofChemicalandEngineeringData,Vol.52,No.3,2007983

Table2.PhysicalPropertiesofSolventsUsedinThisWorka

solvent

N,N-dimethylformamideformamide

N-methylpyrrolidonewater

dimethylsulfoxideisopropanoln-butanolisobutanolbenzylalcoholchloroformtoluenepyridine1,4-dioxanetetrahydrofurandimethylcarbonate

a

nD201.4311.4481.4681.3331.4781.3781.3991.3961.5401.4471.4971.5101.4221.4071.370

F/g?cm-30.9451.1331.0280.9981.0960.7860.8100.8021.0461.4890.8670.9831.0340.8891.073

??

36.71111.032.0080.1048.9017.90

17.10(298.15K)17.9513.104.9002.24012.402.2507.5802.600

η/mPa?s0.8023.7641.6501.0021.9962.4312.9504.000

7.760(288.15K)0.5630.5870.9521.3000.5500.625

γ/mN?m-135.2058.3541.0072.5843.0021.7024.6023.00

40.41(298.15K)27.1428.5336.8836.9026.4028.90

Allvaluesmeasuredat293.15K,exceptwhereindicated.nD20,refractiveindex;F,density;??,dielectricconstant;η,viscosity;γ,surfacetension.

Table3.MoleFractionSolubilitiesofSodiumCefotaximeinPureSolvents

T/K278.15280.15283.15285.15288.15290.15293.15295.15298.15300.15303.15305.15308.15278.15280.15282.15283.15285.15287.15288.15290.15292.15293.15295.15297.15298.15

102xexptlA

102(xexptl-xcalcdAA)

T/K278.15

280.15283.15285.15288.15290.15293.15295.15298.15300.15303.15305.15308.15293.15295.15297.15298.15300.15302.15303.15305.15307.15308.15

102xexptlA

102(xexptl-xcalcdAA)

T/K278.15

280.15283.15285.15288.15290.15293.15295.15298.15300.15303.15305.15308.15

102xexptlA

102(xexptl-xcalcdAA)

N,N-dimethylformamide

4.07270.21174.13000.05704.3607-0.05134.6185-0.03404.7428-0.29325.37430.06505.6962-0.04886.0021-0.05206.62020.07326.90220.00407.56780.11187.8517-0.00108.4511-0.0329

water1.8026-0.00741.8095-0.00551.82160.00161.83040.00741.83510.00511.83940.00101.8415-0.00051.85390.00291.86180.00081.87580.00881.87990.00191.8851-0.00491.8884-0.0086

formamide

4.8303-0.26575.0265-0.20005.2955-0.13355.61840.04705.96460.17266.15170.20406.43590.24796.51580.15906.74340.12546.87720.07707.0191-0.06697.1863-0.09807.3271-0.2669dimethylsulfoxide7.3768-0.03007.4391-0.02707.5085-0.02007.5490-0.01307.69730.06607.76550.06307.79110.05117.83280.01507.8537-0.04407.8797-0.0590

N-methylpyrrolidone

0.0254-0.08160.0935-0.05650.1523-0.09470.1915-0.15050.2788-0.27620.3829-0.37910.5241-0.69290.8686-0.78841.1798-1.43423.80160.27367.36551.86858.29570.936710.297-1.0344

solventswereweighedusingananalyticalbalance(MetlerTo-ledoAB204-N,Switzerland)withanuncertaintyof0.0001g.

Duringexperiments,predeterminedexcessamountsofsodiumcefotaximeandsolventofknownmasswereplacedinthejacketedvessel.Thecontentsofthevesselwerestirredcontinu-ouslyataninvariableandrequiredtemperature,andthesolventwasaddedtothevesselsimultaneouslyinbatcheswiththeintervalofadditionof30min.Theadditionalsolventofknownmasswasabout50mgeachbatch.Whenthelastportionofsolutejustdisappeared,theintensityofthelaserbeampenetrat-ingthevesselreachedthemaximum,andthesolventmassconsumedinthemeasurementwouldberecorded.Togetherwiththemassofthesolute,thesolubilitywouldbeobtained.

Thesaturatedmolefractionsolubilityofthesolute(x1)insolventcanbeobtainedasfollows:

x1)

m1/M1

m1/M12/M2

(1)

Toverifytheuncertaintyofthemeasurement,oneotherexperimentwasdoneinwhichthesolubilityofKClinwaterwasmeasured.Thesolubilityofpotassiumchlorideinwaterintheliterature17andinthispaperareshowninTable1.Consideringotherfactors,theuncertaintyoftheexperimentalsolubilityvaluesisabout0.5%.

Theresultsindicatedthedeviationbetweentheliteraturevaluesandtheexperimentvalueswerelessthan0.2%.Alldeterminationswererepeatedtwomoretimes,andthemeanvalueswereusedtocalculatethemolefractionsolubility.

ResultsandDiscussion

Inthiswork,15solvents(asshowninTable2)wereemployedtodeterminethedissolutionbehaviorofsodiumcefotaxime.Theresultsindicatethatmostofthesolventsselectedinthispaperincludingdimethylcarbonate,toluene,isopropanol,n-butanol,isobutanol,benzylalcohol,chloroform,pyridine,tetrahydrofuran,and1,4-dioxanearenotgoodsolventsforthetitlecompound.Thesolubilitiesofsodiumcefotaximeinthemareless0.0001gofsodiumcefotaximeper100gofsolvent,andthevaluesaretoolowtobedetectedbythemethod

Inwhichm1andm2representthemassofsoluteandsolvent;M1andM2arethemolecularweightofsoluteandsolvent,respectively.

984JournalofChemicalandEngineeringData,Vol.52,No.3,2007

Figure2.Molefractionsolubilitiesofsodiumcefotaxime(x1)indifferentsolventsatdifferenttemperatureranges:9,N,N-dimethylformamide;b,formamide;2,N-methylpyrolidone;f,water;[,dimethylsulfoxide.

usedhere.Onlyfivesolvents(formamide,N,N-dimethylform-amide,dimethylsulfoxide,water,andN-methylpyrrolidone)showgoodsolvencyforthesolid.ThesolubilityofsodiumcefotaximeinN,N-dimethylformamide,formamide,N-meth-ylpyrrolidonewasdeterminedbetweenthetemperaturerangefrom(278.15to308.15K.However,toavoiddecompositionofsodiumcefotaximeinwateratahighertemperature,thesolubilityofsodiumcefotaximeinwaterwasonlymeasuredbetween(278.15and303.15)K.Atatmosphericpressure,themeltingpointofdimethylsulfoxideis291.69K,andsothesolubilitiesofsodiumcefotaximeindimethylsulfoxidewereonlydeterminedbetween(293.15and308.15)K.

ThemeasuredsolubilitiesofsodiumcefotaximeinthefivepuresolventsatdifferenttemperaturerangearelistedinTable3andFigure2.Itcanbeseenthatthesolubilitiesofsodiumcefotaximeinallfivesolventsincreasewithtemperature.Thesolubilitiesofsodiumcefotaximeinwaterincreaseslowlywithtemperature,http://wendang.chazidian.comrmamide,N,N-dimethylformamide,anddimethylsulfoxide,thesolubilitiesofsodiumcefotaximealmostlinearlyincreasewithtemperature.However,itisinterestingthatthesolubilitiesofsodiumcefotaximeinN-methylpyrrolidonedisplayanexponentialupwardtrendwiththeenhancementoftemperature.PerhapsitcanbeattributedtothechangeoftheinteractionbetweenthemoleculeofsodiumcefotaximeandthemoleculeofN-methylpyrrolidonewiththeincreaseintemperature.

Onthebasisoftheresults,thesolubilityofsodiumcefotaximealsodependsonthepolarityofthesolventtosomedegree.Thesolubilityincreaseswiththeenhancementofthepolarityofthesolvent.FromTable2,itcouldbeseenthatthevalue18ofdielectricconstantsofthefivesolventsthatdisplaygoodsolvencyforsodiumcefotaximeallexceed30at20°C.Intheothersolventsinvestigatedsuchasethylacetate,tolueneand1,4-dioxane,whosepolarityismuchlower,thesoluteisalmostinsoluble.Thesolid-liquidequilibriumbehaviormaybeexplainedbydiscussingtheinteractionbetweenthehomoge-neoussolute,thesolvent,andtheheterogeneousmoleculesinsolution.

Theprocessofdissolutionisdeterminedbyacombinationofenthalpyandentropyfactors.Thechemicalstructureandthepolarityalsoinfluencethedissolutionofsolute.Iftheinterac-tionsinthesoluteandsolventaresimilar,thentheenergyofinteractionbetweenhomogeneousandheterogeneousmoleculesisnearlyidentical,whichfacilitatesthedissolutionofthemoleculesofthesolute.Ifthechemicalstructuresofthesolute

Table4.Curve-FittingParametersforSolubilitiesofSodiumCefotaximeinPureSolvents

solvent

abc103σxN,N-dimethylformamide-79.0871427.312.5621.18formamide

-78.2332336.711.8791.82N-methylpyrrolidone-62.242-8789.015.4588.63water

-77.2303000.711.0920.05dimethylsulfoxide

-76.484

2957.3

11.230

0.46

andsolventmoleculesdiffergreatlyinpolarity,thenswellinganddissolutiondonoteasilyhappen.Thisisreflectedintheempiricalrulethat“likedissolveslike”.

Themoleculeofsodiumcefotaximehasa2-amino-4-thiazolylsidechainandR-methoxyiminogroup,anditsmolecularpossessesmanypolargroupssuchasamido,sulfonyl,andcarbonylgroups(Figure1).TheinteractionsinthesolutewerenotonlyvanderWaalsforcesbutalsothehydrogenbondforce.Therefore,itwouldrequiremoreenergytodestroytheinterac-tionbetweenthesolutemoleculesinordertodispersetothesolvent.However,theinteractioninthenonpolarsolventssuchasethylacetate,toluene,and1,4-dioxaneismainlythevanderWaalsforce.Theinteractionbetweennonpolarsolventmol-eculesandsolutemoleculescannotoffsettheenergylossindestroyingthenormalinteractionsinsolventandsodiumcefotaximecrystals.Therefore,thetitlecompoundinnonpolarsolvents(ethylacetate,toluene,and1,4-dioxaneinthisstudy)arealmostinsoluble.However,inthestrongpolarsolvents(N,N-dimethylformamide,formamide,N-methylpyrrolidone,water,anddimethylsulfoxideinthispaper),theinteractionbetweenthesolventmoleculesismainlythehydrogenbondforce.Whensodiumcefotaximeaddedtothesolvent,thesolutemoleculesandthesolventmoleculescouldeasilyformintermolecularhydrogenbonding,andtheinteractioninthesolutemoleculeswouldbeenbroken.Afterthemixingofsoluteandsolventmolecules,thetotalenergyofthewholesystemdoesnotchangetoomuch.So,thedissolubilityofsodiumcefotaximeinstrongpolarsolventsisbetterthaninnonpolarsolvents.Owingtotheinsufficientpolarityofisopropanolandchloroform,thesolubilityofsodiumcefotaximeisverylow.

ConcerningtheexponentialupwardtrendofthesolubilitiesofsodiumcefotaximeinN-methylpyrrolidone,itisperhapsattributedtothespecialcharacteristicoftheinteractionofthesolventandthetitlecompound.Theprobabilityofformingamolecularcomplexinsolutionmaybeanotherexplanationforthesharpincreaseofthesolubilityofsolute.Butitshouldbepointedoutthattheaboveexplanationsareonlyonemeasureofmanyfactorsaffectingthedissolutionbehavior.Furtherdiscussionofthedissolutionofanorganicsoluteinanorganicsolventiscomplicatedandbeyondthescopeofthisarticle.Thetemperaturedependencesolubilitiesinthefivepuresolventswerecorrelatedbythesemiempiricalequationdeducedfromthesolid-liquidphaseequilibrium:12,19

lnx1)a+

b

T/K

+cln(T/K)(2)

inwhichx1isthemolefractionsolubilityofsodiumcefotaxime;Tistheabsolutetemperature;anda,b,andcaretheparameters.Thevaluesofparametersa,b,andcandtherootmeansquaredeviations(rmsd)arelistedinTable4.Thermsdofthemolefractionisdefinedasfollows:

20

(xexptlσi-xcalcdi

)2x)

{∑

ni)1

n-1

1/2

(3)

JournalofChemicalandEngineeringData,Vol.52,No.3,2007985

wherenisthenumberofexperimentalpoints,xcalcdrepresentsthesolubilitiescalculatedfromeq2,andxexptl

i

representstheexperimentalsolubilityvalues.Itcanbeseeni

thatthecorrelatedsolubilitiesshowgoodagreementwiththeexperimentalvalues.Inthemeantime,itisnoticeablethatthermsdforN-methylpyrrolidonepresentsahighvalueascomparedtoothersolventswiththecorrelatedequationusedhere.

Conclusions

(i)Thesolubilitiesofsodiumcefotaximein15solventswereinvestigated,andtheresultsindicatethatmostofthesolventsarenotgoodsolventsforthetitlecompound.Onlyfivesolvents(formamide,N,N-dimethylformamide,dimethylsulfoxide,water,andN-methylpyrrolidone)showgoodsolvencyforthesolid.(ii)Thesolubilitiesofsodiumcefotaximeinthefivesolventsmeasuredincreasewithtemperature.Thesolubilityofsodiumcefotaximealsodependsonthepolarityofthesolventtosomedegree.Thetitlecompoundisalmostinsolubleinnonpolarsolvents.

(iii)Theexperimentalsolubilitydatawerecorrelatedwithasemiempiricalequation.Thesystemsshowsatisfactoryagree-mentbetweentheexperimentalsolubilitiesandthecalculatedvalues.

Acknowledgment

TheauthorsaregratefultoShenzhenJiuxinPharmaceuticalCo.,Ltd.(China)forsupplyingsodiumcefotaxime.

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