新药杂质评估03Evaluating Impurities in Drugs 03.docx

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