新药杂质评估03Evaluating Impurities in Drugs 03.docx
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新药杂质评估03EvaluatingImpuritiesinDrugs03
EvaluatingImpuritiesinDrugs(PartIIIofIII)
InPartIIIofathree-partarticle,theauthorsexaminevariousdegradationroutesofAPIs,impuritiesarisingfrominteractionsinformulations,metaboliteimpurities,variousanalyticalmethodstomeasureimpuritie,andwaystocontrolimpurities.
Apr2,2012
By:
KashyapR.Wadekar, PonnaiahRavi, MitaliBhalme, S.SrinivasaRao, K.VigneshwarReddy, L.SampathKumar, E.Balasubrahmanyam
PharmaceuticalTechnology
Volume36,Issue4,pp.76-86
ControllingandmonitoringimpuritiesinAPIsandfinisheddrugproductsisacrucialissueindrugdevelopmentandmanufacturing.PartIofthisarticle,publishedintheFebruary2012issueofPharmaceuticalTechnology,discussedthevarioustypesofandsourcesofimpuritieswithspecificcasestudies
(1).PartII,publishedintheMarch2012issue,examinedchiral,polymorphic,andgenotoxicimpurities
(2).InPartIII,theauthorsexaminevariousdegradationroutesofAPIs,impuritiesarisingfromAPI–excipientinteractionduringformulation,metaboliteimpurities,variousanalyticalmethodologiestomeasureimpuritylevels,andwaystocontrolimpuritiesinpharmaceuticals.
Definitionofimpurity
ThetermimpurityreflectsunwantedchemicalsthatarepresentinAPIsorthatdevelopduringformulationoruponagingoftheAPIintheformulateddrugproduct.Thepresenceofsuchunwantedmaterial,eveninsmallamounts,couldaffecttheefficacyandsafetyofpharmaceuticalproducts.SeveralguidelinesfromtheInternationalConferenceonHarmonization(ICH)addressimpuritiesinnewdrugsubstances,drugproducts,andresidualsolvents(3–6).AspertheICHguidelinesonimpuritiesinnewdrugproducts,impuritiespresentbelowa0.1%leveldonotneedtobequalifiedunlessthepotentialimpuritiesareexpectedtobeunusuallypotentortoxic(5).Inallothercases,impuritiesshouldbequalified.Iftheimpuritiesexceedthethresholdlimitsanddataarenotavailabletoqualifytheproposedspecificationlevel,studiestoobtainsuchdatamayberequired.Severalrecentarticlesdescribeadesignedapproachandguidelinesforisolationandidentificationofprocess-relatedimpuritiesanddegradationproductsusingmassspectrometry,nuclearmagneticresonance(NMR)spectroscopy,high-performanceliquidchromatography(HPLC),andFouriertransforminfrared(FTIR)spectroscopyforpharmaceuticalsubstances(7–9).
Degradation-relatedimpurities
Figure1:
Degradationofhydrochlorothiazide.(ALLFIGURESARECOURTESYOFTHEAUTHORS)
Degradationproductsarecompoundsproducedbydecompositionofthematerialofinterestoractiveingredient.SeveralimpuritiesmayresultbecauseofAPIdegradationorotherinteractiononstorage,sostabilitystudiesneedtobeconductedtoensuredrugproductsafety(10).Hydrochlorothiazide(seeFigure1)isaclassicalexampleofadegradationimpurity.Ithasaknowndegradationpathwaythroughwhichitdegradestothestartingmaterialasdisulfonamideinitssynthesis.
Degradationproductscouldresultfromthesynthesisitself,storage,formulationofthedosageform,andaging(11).Thesedegradationpathwaysarefurtherdiscussed.
Synthesis-relatedimpurities.Impuritiesinadrugsubstanceoranewchemicalentityoriginatemainlyduringthesyntheticprocessfromrawmaterials,solvents,intermediates,andbyproducts.Therawmaterialsaregenerallymanufacturedtomuchlowerpurityrequirementsthanadrugsubstance,andthus,itiseasytounderstandwhytheycancontainanumberofcomponentsthatcaninturnaffectthepurityofthedrugsubstance.
Figure2:
Reactionschemeformirtazapineimpurity.Ph.EuristheEuropeanPharmacopoeia.DMFisdimethylformamide.EtOAcisethylacetate.
1-Methyl-3-phenylpiperazine(seeFigure2)ispresentasanunreactedstartingmaterialthatcompetesinallthestageseventuallyleadingtotheimpurityketo-piperazinederivativeofmirtazapine(seeImpurityC,Figure2).
Formulation-relatedimpurities.SeveralimpuritiesinadrugproductorAPIcanarisefrominteractionswithexcipientsusedtoformulatethedrugproduct.Intheprocessofformulation,adrugsubstanceissubjectedtovariousconditionsthatcanleadtoitsdegradationorotherdeleteriousreactions.Forexample,ifheatisusedfordryingorforotherreasons,itcanfacilitatedegradationofthermallylabiledrugsubstances.Solutionsandsuspensionsarepotentiallypronetodegradationduetohydrolysisorsolvolysis.Thesereactionsalsocanoccurinthedosageformatsolidstate,suchasinthecaseofcapsulesandtablets,whenwateroranothersolventhasbeenusedforgranulation.
Therearetwotypicalconditionsinsolid-andsolution-statedegradationstudies.TypicalconditionsfortheAPIinasolidstatemightbe80°C,75%relativehumidity(RH);60°CatambientRH;40°Cat75%RH;andlightirradiation.TypicalconditionsforanAPIinthesolutionstatemightbe:
pH1–9inbufferedmedia;withperoxideand/orfree-radicalinitiator;andlightirradiation.
Figure3:
Degradationpathwayofketorolac.
Figure3showsthedegradationpathwayofketorolacinthesolidandsolutionstates(12–14).
Dosageform-relatedimpurities.Impuritiesrelatedtothedosageformaresignificantbecausemanytimesprecipitationofthemainingredientrequiresvariousfactors,suchaspHorleaching,tobealtered(15).Forexample,theprecipitationofimipraminehydrochloridewithsodiumbisulfiterequiresasubsequentpHalterationoflidocainehydrochloridesolutioninthepresenceof5%dextroseinsaline.
Method-relatedimpurities.Aknownimpurity,1-(2,6-dichlorophenyl)indolin-2-oneisformedinthediclofenacsodiumampuls.FormationofthisimpuritydependsontheinitialpHofthepreparationandtheconditionsofsterilization(i.e.,autoclavemethod,123°C±2°C)thatenforcestheintermolecularcyclicreactionofdiclofenacsodium,formingindolineonederivativeandsodiumhydroxide(16).
Environmental-relatedimpurities.Environmental-relatedimpuritiesmayresultfromthefollowing:
∙Temperature.Manyheat-labilecompounds,whensubjectedtoextremetemperature,losetheirstability.Keepingthisinmind,extremecareshouldbeexercisedtopreventthemfromdegradation.
∙Light(ultravioletlight).Exposuretolightresultsinaphotolyticreaction.Severalstudiesreportedthatergometrineandergometrineinjectionsareunstableundertropicalconditionsuchaslightandheat(17–19).
∙Humidity.Humidityisoneoftheimportantfactorswhenworkingwithhygroscopiccompounds.Humiditycanbedeleterioustobulkpowdersandformulatedsoliddosageforms.Well-knowexamplesareranitidineandaspirin(19).
TableI:
Effectofinteractionsamongingredients
Impuritiesonaging.Generally,alongerstayontheshelfincreasesthepossibilitythatimpuritieswilloccur.Suchimpuritiescanbecausedbyseveralinteractionsasfurtherdescribed.
∙Interactionamongingredients.Vitaminsarehighlypronetoinstabilityafteraging.Forexample,thepresenceofnicotinamidecontainingfourvitamins(nicotinamide,pyridoxine,riboflavin,andthiamin)causedthedegradationofthiamintoasubstandardlevelduringaone-yearshelflife(20).TableIlistssomeexamplesofinteractionsamongingredients.
∙Hydrolysis.Manydrugsarederivativesofcarboxylicacidsorcontainfunctionalgroupssusceptibletoacid–basehydrolysis(e.g.,aspirin,atropine,andchloramphenical).
∙Oxidation.Inpharmaceuticals,themostcommonformofoxidativedecompositionisauto-oxidationthroughafree-radicalchainprocess.Drugsthatarepronetooxidationincludemethotrexate,adinazolam,catecholamine,conjugateddienes(i.e.,vitaminA),andnitrosoandnitritederivatives.Olanzapineisespeciallypronetooxidativedegradationinthepresenceofoxygen(seeFigure4)(21).
∙Photolysis.PhotolyticcleavageonagingproductsoccurswithAPIsordrugproductsthatarepronetodegradationonexposuretoUVlight.Forexample,theophthalmicformulationofciprofloxacindrops0.3%,whenexposedtoUVlightandundergoesphotolysistoformethylenediamine,ananalogofciprofloxacin(22).
∙Decarboxylation.Carboxylicacid(–COOH)tendstolosecarbondioxidefromcarboxylgroupswhenheated.Forinstance,aphotoreactionofarufloxacinenterictabletcoatedwithcelluloseacetatephthalateandsubcoatedwithcalciumcarbonatecauseshydrolysisofcelluloseacetatephthalate.Thisreactionliberatesaceticacid,whichonreactingwithcalciumcarbonate,producescarbondioxideasabyproduct.
∙pH.ItiswellunderstoodthatpH,particularlyextremelevelsofpH,canencouragehydrolysisoftheAPIwhenionizedinanaqueoussolution.Thissituationnecessitatesbuffercontrolifsuchadosageformisrequired.
∙Packagingmaterials.Impuritiesmayresultfrompackagingmaterials(i.e.,containersandclosures(23).
Figure4:
Olanzapineimpuritiesduetoair,heating,andformulation.
Twoimpuritiesinolanzapinehavebeenidentifiedas1and2(seeFigure4)(24).Thestructuresindicatethatthetwoimpuritiesaredegradationproductsresultingfromoxidationofthethiopheneringofolanzapine.
Fromaregulatoryperspective,forceddegradationprovidesdatatosupportthefollowing(25):
∙Identificationofpossibledegradants
∙Degradationpathwaysandintrinsicstabilityofthedrugmolecule
∙Validationofstabilityforindicatinganalyticalprocedures
∙Facilitationofthedevelopmentofanalyticalmethodstoevaluatestability
∙UnderstandingthedegradationoftheAPItoarationalproduct.
∙Screeningforpossibleformationofpotentialgenotoxins.
Variousissuesareaddressedinregulatoryguidance