An application of high performance liquid chromatographic assay for the kinetic analysis

DepartmentofPharmaceuticalChemistry1,FacultyofPharmacy,PoznanUniversityofMedicalSciences;PozLab2,ContractResearchOrganization,Pozna´n,Poland

Anapplicationofhighperformanceliquidchromatographicassayforthekineticanalysisofdegradationoffaropenem

J.Cielecka-Piontek1,A.Krause2,M.Paczkowska1

ReceivedJanuary17,2012,acceptedFebruary16,2012

JudytaCielecka-Piontek,DepartmentofPharmaceuticalChemistry,FacultyofPharmacy,PoznanUniversityofMedicalSciences,Grunwaldzka6,60-780Pozna´n,Polandjpiontek@ump.edu.plPharmazie67:912–916(2012)

doi:10.1691/ph.2012.2016

AnisocraticRP-HPLC-DADprocedurewasdevelopedandvalidatedforkineticanalysisofdegradationoffaropeneminbulkdrugsubstanceandintablets.ItinvolvedtheuseofaC-18analyticalcolumn(5␮mpar-ticlesize,250mm×4.6mm),flowrate1.3ml/minand50␮linjectionvolume.Themobilephaseconsistedofacetatebuffer(pH3.5)–acetonitrile(70:30v/v).Thedeterminationwascarriedoutatthewavelengthof323nm.Kineticstudiesoffaropenemdegradationinaqueoussolutionsincludedhydrolysis,oxidation,photolysisandthermaldegradation.Aderivativespectrophotometrywasusedasanalternativemethodtocomparetheobservedrateconstants.1.Introduction

Derivativesofpenemarearapidlydevelopinggroupof␤-lactamantibiotics(Dalhoffetal.2003).Beta-lactamanalogderivatives–carbapenemsandthiopenems–haveabroadspectrumofantibacterialactivity(includingactionagainstPseudomonasaeruginosaandEnterobactericae),desiredphar-macokineticparametersandproducelowsideeffects(Walshetal.2007;Zhaneletal.2007).Thegreatestlimitationofather-apyusingpenemsistheirsignificantenzymaticandchemicalinstability(Cielecka-Pionteketal.2011).

Regardingcarbapenems,theproblemofenzymaticinstabilitywassolvedbytheintroductionofamethylgroupatC3intotheazabicyclo[3.2.0]heptan-7-onesstructure.Unfortunately,thechemicalinstabilityofcarbapenemscontinuestolimittheirapplicationtoparenteraladministration.Therefore,thestabil-ityofcarbapenemsisbeingwidelystudied,includingtheirmetabolisminthehumanbody(Kipperetal.2009;Suther-landetal.2007;Kamedaetal.2010),theinfluenceofstorage(Mendezetal.2006,2008;Zaj˛acetal.2007;Cielecka-Pionteketal.2008;Zaj˛acetal.2006)andpreparationofintravenoussolutions(Grantetal.2000;Pateletal.1997;Keeletal.1997;Psathasetal.2008).

ThechemicalinstabilityofthiopenemswasimprovedbytheintroductionofasulphuratomatC4intothethiazolidinemoi-etyofthebi-cyclic4:5fusedring,incontrasttocarbapenemswheresuphuratomwassubstitutedwithacarbonatom.ThesulphuratomaffectstheentirestructureshapeandbychangingtheC-S-Cbandangleresultinginreducedintra-ringstress,thusdecreasingsusceptibilitytodegradationunderaffectingfactorsbothinsolidandaqueousmedia(Schureketal.2007).Fur-thermore,inthechemicalstructureoffaropenem,thechiraltetrahydrofuransubstituentatpositionC2isresponsibleforitsimprovedchemicalstabilityandreducedneurotoxicity(Dalhoffetal.2003,2006)

Atpresent,faropenem(Fig.1)istheonlyderivativeofthiopen-emsapprovedfortherapeuticuse(Hamilton-Milleretal.2003).912

InJapan,faropenemiscurrentlyavailableasorallyadministeredsodiumsalt(FAROM®),whileitsesterprodrug(faropenemdaloxate)isinPhaseIIIofclinicaltrialsintheUSA(Dalhoffetal.2003).Somechromatographicmethodshavebeenreportedforquantificationoffaropenem,mainlyinbiologicalmatrices(Nirogietal.2005;Gaoetal.2008;Wenetal.2006;Huetal.2006).Tothebestofourknowledge,onlyonescientificpub-licationdescribesananalyticalmethodforthedeterminationoffaropeneminpharmaceuticalmatrix,butitdoesnotreportamethodwhichissuitableforkineticanalysisoffaropenemdegradation(Menonetal.2009).

Duringthedevelopmentofanalyticalproceduresfordeter-minationofpenems,ensuringsuitableselectivityisvitalforcalculatingreliableratesofdegradation.Theinfluenceofdif-ferentfactors(e.g.,methanolyticdegradation)ontherateofdegradationofapenemderivative(Vailayaetal.2005)andontheformationofcarbapenemdegradationproducts(Sajonzetal.2005;Elragehyetal.2008;Xiaetal.2009)hasbeenproved.Therefore,theaimofthisstudywastodevelopanLCmethodforcalculatingthekineticparametersoffaropenemdegradationinbulkdrugsubstanceandinpharmaceuticalpreparationsduringacceleratedstabilitystudies.

2.Investigations,resultsanddiscussion

Amethodforthedeterminationofthefaropeneminpuresub-stanceandinpharmaceuticalpreparationsinthepresenceofdegradationproductsformedundervariousstressconditionswasdeveloped.AnanalysisofstressedsampleswasperformedwithanHPLCsystemusingaC-18columnandthemobilephasecomposedof30volumesofacetonitrileand70volumesofacetatebuffer(pH3.5).Detectionwascarriedoutat323nm.Themobilephaseflowratewas1.3ml/min.TheHPLC-DADmethodwasdevelopedandvalidatedwithregardtoselectiv-ity,linearity,accuracy,precision,limitofdetectionandlimitofquantitation.Undertheproposedchromatographicconditions,

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Fig.1:Chemicalstructureoffaropenem

Fig.2:TheHPLCchromatogramsoffaropenem:A-substanceinbulk,after

degradationinNaOH(0.05M),343K(180min),B-substanceinbulkafterdegradationinH2O2(30%),313K(6min),C-pharmaceuticaldosageformafterdegradationinH2O2(30%),303K(13min),D–pharmaceuticaldosageformafterdegradationinNaOH(0.05M),313K(0.5min)(F–faropenem)

theselectivityofthemethodwasconfirmedbyexaminingthespectrophotometricpurityoffaropenempeaks(>98.5%).Prod-uctsformedduringacidicandalkalinedegradation,oxidationandphotolysisaswellastabletexcipientsdidnotinterfereatanylevelofdetermination.Theruntimeoftheanalysiswas8.5min.Typicalretentiontimesoffaropenemwereabout6.5min,whilethepeaksoriginatingfromdegradationproductsandexcipientselutedafterthefaropenempeak(∼8.0min)(Fig.2).

ThecalibrationcurvewasdescribedbytheEq.y=ac;y=(46310±1500)c(b=98.50).Thebvalues,calculatedfromtheEq.y=ac+b,werenotsignificant.Thecalibrationplotswerelinearinthefollowingconcentrationrange5.0–400.0␮g/ml(n=10,r=0.9993).

Recoverywasperformedatthreelevels:80,100and120%ofthelabelclaimofthesubstance.Goodrecoverieswereobtainedforeachconcentration,confirmingthatthemethodwasaccu-rate.Themeanrecoveryfrompuresubstancewas99.94%andfrompharmaceuticalpreparation101.18%(n=3).Theintra-dayandinter-dayprecisionvaluesoffaropenemconcentrationsmeasuredat80,100and120%ofthelabelclaim,demonstratedthattheRSDvalues(Table1)forthedeterminationoffaropeneminpuresubstanceandinpharmaceuticalpreparationwereintherange1.31–2.97%,indicatingthatthemethodwasprecise.Undertheappliedchromatographicconditions,theLODandLOQoffaropenemwere0.84␮g/mland2.58␮g/ml,respec-tively.Therobustnessoftheprocedurewasevaluatedbychangingthefollowingparameters:thecompositionandpHofthemobilephase,themobilephaseflowrateintherangePharmazie67(2012)

Fig.3:First-derivativespectraoffaropenemafterheatingofFAROM®preparation

to343KduringthedegradationinHCl(0.4M)from0to45min(A)andduringthedegradationoffaropeneminbulksubstanceinNaOH(0.2Mfrom0to2h(B)

of1.0–1.5ml/min,andthetemperatureintherange23–27◦C(±1◦C).Withachangeofeachparameter,itseffectonreten-tiontime,peakresolution,peakshapeandpeakarea(heightandwidth)wasevaluated.Nosignificantchangesintheseparation,shapesofareasandretentiontimeofthepeakswereobservedwhenthetemperatureandflowrateweremodified.ThechangesinpHandthetypeoftheorganicfractioninmobilephaseinflu-encedsignificantlytheretentiontimeandshapeofthepeaks.TheatypicaleffectsoftailingandsymmetricallackofpeakwereobservedforthemobilephasewhenatitspHabove3.7.Theintroductionofacetonitrileresultedinashortertimeofanalysis,symmetrical,non-tailingpeaksandgaveresultsofdegradationanalysiscomparablewiththesedeterminedwiththealternativemethod.

Kineticstudiesofdegradationoffaropeneminhydrochloricacid(0.4M,343K)insodiumhydroxidesolution(0.2M,343K),afteroxidation(30%H2O2,313K)andafterphotolysiswereconductedbyusingtwochromatographictechniques–ourcurrentmethodandareportedone(Menonetal.2009)andderivativespectrophotometry.Derivativespectrophotometryiswidelyusedasstability-indicatinganalyticalmethodforthedeterminationofpenemanalogs(Elragehyetal.2008;Cielecka-Pionteketal.2011,2010;Hassanetal.2009).

Linear,selectivechangesofamplitudevaluesofthefirst-derivativeoftheindirectspectraoffaropeneminthepresenceofits␭degradationproductswereregistered(afterthecrossingpoint,Piontek=323nm)etal.using2012).

apeak-to-zerotechnique(Fig.3)(Cielecka-Thekineticmechanismoffaropenemdegradationinaqueoussolutionswasdescribedbyapseudo-first-orderreactionandwasexpressedasfollows:

lnPF=lnPF−kobstlnDF=lnDF−kobst

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Table1:Validationparametersoffaropenem

Intra-dayandinter-dayprecision(n=6)studies

Puresubstance

Pharmaceuticalformulation

Intra-dayprecision50.0(␮g/ml)100.0(␮g/ml)200.0(␮g/ml)Inter-dayprecision100.0(␮g/ml)

Spikedconcentration(␮g/ml)50(∼80%)100(∼100%)200(∼120%)

RDS2.521.312.952.75

Recoverystudies(n=3)Measuredconcentration±S.D(␮g/ml),RSD(%)Puresubstance49.78±0.04,99.56101.32±0.82,100.32199.±0.03,99.94

%RDS52.562.052.972.91

Pharmaceuticalpreparation50,98±0.02,101,96101.23±0.03,101.23200.67±0.04,100.35

TheobservedrateconstantswereequaltotheslopesoftheplotslnPF=f(t)andlnDF=f(t)withthenegativesign(−kos);wherePFistheareaofthefaropenempeakandDF–thevalueofthefirstderivativeat323nm.ThevaluesoftheobservedrateconstantsdeterminedwitheachmethodareshowninTable2.

Thedifferencesinthevaluesoftheobservedrateconstantsdeterminedbyusingfirst-derivativespectrophotometryandthepresentedchromatographicprocedurewerenotstatisti-callysignificant.Thedifferencesinthekineticparametersoffaropenemdegradationwereobservedonlywhencomparingtheresultsobtainedbyusingthechromatographictechniques.Thatmaybeexplainedbythefactthatthepresenceofmethanolincreasestherateoffaropenemdegradationand/orinfluencestheformationofmethanolysisproducts.Asimilarmethanolyticeffectwasalsopresentinananalysisofotheranalogsofapenemderivative(Vailayaetal.2005).Theinfluenceofcatalyticeffectsofdegradationproducts,(3-vinyl-4-thia-1-azabicyclo[3.2.0]hept-2-en-7-oneand3-(tetrahydrofuran-2-yl)-4-thia-1-azabicyclo[3.2.0]hept-2-en-7-one),formingduringhydrolysis,oxidation,photolysisandthermolysisontherateofdegradationoffaropenemwasexcluded.However,asimilareffectwasobservedduringthedegradationofpenemderiva-tives.Itwasconfirmedthatthecatalyticeffectofdegradationproductsandtheamountoftheundissociatedformofthecar-boxylicgroupinamoleculeincreasedtherateofdegradation(Itoetal.2005).

TheintroductionofasulfuratomatpositionC4intothethia-zolidinemoietyofbi-cyclic4:5fusedringinthiopenemanalogdidnotchangethekineticmechanismofdegradation,comparedtothatofcarbapenemanalogs.Changesofchemicalstructure,significantlyinfluencethestabilityofthiopenemanalogs,which

wasprovedwhenthemethanolyticeffectwasexcluded.Oursta-bilitystudiesdemonstratedthattheinfluenceofaffectingfactorsonthedegradationofthefaropeneminpuresubstance(a)andinpharmaceuticalpreparation(b),maybepresentedasfollows:oxidativefactor>alkalifactor>lightfactor>>acidicfactor

(a)

alkalifactor>oxidativefactor∼acidicfactor>>lightfactor

(b)

ThecurrentHPLCprocedurenotonlyallowsdeterminationoffaropeneminthepresenceofitsdegradationproductsbutalsoinpharmaceuticalpreparationwithexcipients.Itwasshownthatbyapplyingthisprocedureitispossibletoobtainamorereli-ablechromatographicresponse,higherspectrophotometricpeakpurityandtoanalysethekineticsoffaropenemdegradationinpuresubstanceandinpharmaceuticalpreparation.3.Experimental

3.1.Chemicalsandreagents

Faropenemreferencestandard(purity>98%)wassuppliedbyPharma-chemInternationalCo.,(China).Commerciallyavailable200mgtablets(FAROM®)manufacturedbyDaichiAsubioPharma(Japan),werepur-chasedandusedwithinshelf-lifetimedeclaredbytheproducer.AllotherchemicalsandsolventswereobtainedfromMerckKGaA(Germany)andwereofanalyticalgrade.HighqualitypurewaterwaspreparedusingaMilliporepurificationsystem(Millipore,Molsheim,France,modelExilSA67120).

Table2:Observedrateconstantsofdegradationoffaropeneminpuresubstanceandinpharmaceuticalpreparation

Analyticalmethods

HCl(0.4M,343K)

NaOH(0.2M,343K)

H2O2,30%,313K

Photodegradation

HPLC*HPLC*UV*HPLC*HPLC*UV*

(9.78±0.66)×10−8(7.24±0.26)×10−7(9.57±1.57)×10−8(6.05±0.58)×10−4(2.78±0.06)×10−3(5.81±0.40)×10−4

puresubstance,kobs[s−1](1.03±0.11)×10−5(1.33±0.18)×10−4(5.98±0.43)×10−4(1.08±0.43)×10−4(1.55±0.32)×10−5(1.10±0.12)×10−4pharmaceuticalpreparation,kobs[s−1]

(3.52±0.38)×10−3(4.±0.31)×10−4(7.18±0.11)×10−3(6.98±0.23)×10−4(3.44±0.32)×10−3(4.50±0.63)×10−4

(6.17±0.42)×10−6

(6.65±0.98)×10−5(6.11±0.30)×10−6(1.18±3.11)×10−5(2.78±0.23)×10−4(1.19±2.95)×10−5

HPLC*observedrateconstantsofdegradationoffaropenemdeterminedbyusingchromatographicprocedurepresentedinthepaperHPLC*observedrateconstantsofdegradationoffaropenemdeterminedbyusingchromatographicprocedure(Menonetal.2009)UV*observedrateconstantsofdegradationoffaropenemdeterminedbyusingderivativespectrophotometry

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3.2.Apparatusandstudyconditions

Thechromatographicseparationandquantitativedeterminationwereper-formedusingahighperformanceliquidchromatographysystemcontainingaShimadzupump,modelLC-6A,aUV-VISdetector(SPD-6AV,Shimadzu),aRheodyne7120witha50␮Lloop.ItinvolvedtheuseofaC-18analyt-icalcolumn(5␮mparticlesize,250mm×4.6mm);flowrate:1.3ml/minand50␮linjectionvolume.Themobilephaseconsistedofacetatebuffer(pH3.5)–acetonitrile(70:30v/v).Thedeterminationwascarriedoutatthewavelengthof323nm.Foranalysisofhomogeneityofpeaksofforced-degradedsamples,aphotodiodearraydetector(Merck,L-7455)wasusedinscanmodewitha200–600nmscanrange.

AUV-VISLambda20(PerkinElmed)spectrophotometerequippedwith1.0cm-in-widthquartzcellsandcontrolledviaUVWinLabsoftwarewasutilized.Thefirstderivativeoftheratio-indirectspectra(D1–thepeakampli-tudeofthefirst-derivativecurve󰀑A/󰀑␭atthecorrespondingwavelength)with󰀑␭=4nmandascalingfactorof10wasobtained.Theamplitudesofthefirstderivativepeaksoffaropenemweremeasuredat323nm.

PhotodegradationstabilitystudiesoffaropenemwereperformedusingaSuntestCPS+apparatus(Atlas®)withaSolarID65filter,wherecellswereexposedtolight(300–400nm).

3.3.Preparationofstockstandardsolutions

Standardstocksolutionsoffaropenemwerepreparedinwaterbydissolvingaccurateamountsofworkingstandardstoobtain100␮g/mlofsodiumsaltoffaropenem.Stockstandardsolutionswerestoredindarknessat4◦Candremainedstableduringthetimeofthestudy.3.4.Preparationoftabletsforassay

Twentytablets(FAROM®)wereaccuratelyweighedandfinelypowdered.Analiquotofpowderequivalenttothecontentof5mgoffaropenemwasaccuratelyweighed,nextitwastransferredtoa50mlvolumetricflaskwiththeadditionofabout25mlofwater.Forthestabilitystudies,theobtainedmixturewasshakenwithasolutionofanaffectingfactor.Finally,themixturewasfilteredthrough0.45micronnylonfilterpaper.3.5.Validationofthemethod

TheproposedHPLCmethodwasvalidatedaccordingtotheInternationalConferenceonHarmonizationGuidelines(ICH2003,2005)

Selectivitywasexaminedfornon-degradedanddegradedsamplesoffaropeneminpuresubstanceandinpharmaceuticalpreparation.Solutionsoffaropenemwereexposedtothestressconditionsofhydrolysis(acid,base)at343K,photolysis(sunlight)andoxidation(H2O2)at313K.

ThecalibrationplotsP=f(c)wereobtainedinthe5.0–400.0␮g/mlconcen-trationrange,wherePisthepeakareaoffaropenem.Solutionsusedtochecklinearitywereinjectedintriplicate.

Theaccuracyofthemethodwasdeterminedbyrecoveringfaropenemfromtheplacebo.Therecoverytestwasperformedatthreelevels80%,100%and120%ofthenominalconcentrationoffaropenem(50,100and200␮g/ml)duringdegradationstudies.Threesampleswerepreparedforeachrecoverylevel.Thesolutionswereanalyzedandthepercentageofrecoverieswerecalculatedfromthecalibrationcurves.

Theprecisionoftheassaywasdeterminedinrelationtorepeatability(intra-day)andintermediateprecision(inter-day).Inordertoevaluatetherepeatabilityofthemethodfivesamplesweredeterminedduringthesamedayforthreeconcentrationsoffaropenem.Intermediateprecisionwasstud-iedcomparingtheassaysperformedontwodifferentdays.

LODandLOQparameterswerecalculatedfromtheregressionequationforfaropenem:LOD=3.3Sy/a,LOQ=10Sy/a;whereSyisastandarderrorandaistheslopeofthecorrespondingcalibrationcurve.

Therobustnessoftheprocedurewasevaluatedafterchangingthefollowingparameters:thecompositionandthemobilephase(contentofacetonitrileinthe−1range25–35%),themobilephaseflowrate(intherange1.0–1.5mlmin)andabsorptionwavelength(intherange290–350nm)andthetem-perature(25±2◦C).Foreachparameterchangeitsinfluenceonretentiontime,resolution,area,shape(heightandwidth)ofpeakswasevaluated.3.6.Acceleratedstabilitytestconditions

Inordertodeterminethekineticparametersofdegradation,tabletsoffaropenemandbulksubstancewerestressedundervariousconditionstoconductacceleratedstabilitytests(ICH2003).Degradationwasinitiatedbydissolvinganaccuratelyweighed5.0mgoffaropenemorpowdercontain-ing5.0mgoffaropenemin25.0mlofthesolutionequilibratedtoadesiredtemperatureinastoppedflask.Atspecifiedtimes,samplesofthereactionsolutionsweretakenandinstantlycooledwithamixtureoficeandwater.Solutionsforoxidationstudieswerepreparedin30%H2O2at313K.

Pharmazie67(2012)Solutionsforacidicdegradationstudieswerepreparedinwaterandhydrochloricacid(0.4M)aswellasinwaterandsodiumhydroxidesolution(0.2M)at343K.Theionicstrengthofallsolutionswasadjustedtosodiumchloridesolution(4.0M).

5.0mgoffaropenemorpowdercontaining5.0mgoffaropenemwaspre-paredandexposedtolighttodeterminetheeffectoflightirradiationonthestabilityoffaropeneminthesolidstate.Allsamplesforphotostabilitystudieswereplacedinalightchamberandexposedtolightat300–400nmforaspecifiedtime.

3.7.Derivativespectrophotometry

Theobservedrateconstantsoffaropenemdegradationweredeterminedbyusingderivativespectrophotometryasanalternativemethod(Cielecka-Pionteketal.2012).Theacceleratedstabilitytestswereconductedunderthesameconditionsasthoseusedinchromatographicproceduresforpuresubstanceandinpharmaceuticalpreparation.

Acknowledgements:ThisstudywassupportedbyagrantfromtheStateCommitteeForScientificResearchPoland(n.NN405683040)

AranLunzerisacknowledgedforprovidingthesubstanceforresearch.

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