Course-4-Formulation

1制剂中的晶型控制和评估主讲人：李盈博士，亚太区商务发展副总裁CrystalPharmatech苏州晶云药物科技有限公司Email：[e-mail]电话：[phone]晶云药物第二届晶型专题技术培训2提纲•晶型研究在制剂开发中的重要性•制剂中晶型的定性和定量分析•制剂工艺中原料药的晶型转变•原料药在制剂中的歧化反应•制剂中的成像•总结3药物剂型TabletsCapsulesSolutionsSuspensionsIntravenous(IV)SoftgelCapsulesInhalersImplants/stentSuppositoriesPatchesEmulsionsDepotOther4常见辅料及功能ComponentFunctionsCommonExamplesDiluent/Filler•Bulkuptheformulation•CompensateAPIproperties•inertLactoseDicalciumphosphateMicrocrystallinecelluloseBinder•Adhesive•Usuallywatersoluble•WetordryHydroxypropylcellulosePolyvinylpyrolidonePregelstarchDisintegrant•Hydrophilic•waterswellablepolymerSodiumstarchglycolateCroscarmellosesodiumLubricant•HydrocarbontailwithpolarheadgroupMagnesiumstearateSodiumstearylfumarateOthers•Antioxidant•Solubilizer,surfactant•Flowaid•Filmformer•Waxingagent•Colorants,sweeteners•BHT,BHA,propylgallate•Poloxamer,polyoxy40hyrdro-genatedcastoroil,sodiumlaurylsulfate•Colloidalsilicondioxide•HPC,HPMC,PVA•Carnaubawax5API+Excipients+MixingGranulationMillingCompactionCoatingDosageFormFormulationProcess1.Stability2.MechanicalStrength3.ContentUniformity4.Dissolutionrate5.Scalability制剂大致生产流程晶型研究在制剂开发中的重要性•制剂中原料药晶型的变化会引起–性能的变化(生物利用度、稳定性、可生产性等)–药品的质量问题，比如批次的不合格•对制剂工艺中晶型的深入理解有助于–预测工艺中可能发生的原料药晶型转变–增强制剂工艺的可重复性,提高产品质量–药物申报和专利保护6制剂开发中的晶型问题–如何监控制剂中晶型的相互转变？–如何对制剂中药物晶型进行定性和定量分析？–晶型的粒径分布对溶出率，生物利用度，及制剂工艺的影响？–如何判定晶型对药物溶出度，生物利用度的影响？–如何预测和评估晶型在制剂中的化学和物理稳定性？–晶型在湿法制粒过程是否稳定？–如何预测和评估无定形药物在制剂中的重结晶风险？–如何确定盐类晶型在制剂中是否发生歧化反应？制剂中固态分析手段89制剂中晶型的定性定量分析10定性和定量分析•Whenmultipleformsareknown:–needtest/assaytoshowcontrolofprocess–assaycanbequalitativeorquantitative–canbeanissueinAPIanddrugproduct•Differentlevelsofuseandvalidationthroughoutdevelopment–Earlydevelopment:qualitative/visual–Latedevelopment:increaselevelofvalidation•Univariatevs.multivariateapproachesNewmanandByrn,DrugDiscoveryToday,2003,8,898-905用固态核磁共振定量•Higheststrengthtablet8.1%w/wdrug•IRandRamandidnothaveneededsensitivity•XRPDhadsignificantoverlapwithForm1andexcipients;Form2didnotshowdrugsignificantoverlap•13CSSNMRhadsufficientsensitivityandresolution–Limittestmethoddeveloped–4000scans;20hrdataacquisition;10%w/wLOD;0.8%drug11Katrincicetal.IntJPharm.2009,366,1-13•Improvedmethoddevelopedwith19FNMR–19FNMRismoresensitivethan13C–Reduceslonganalysistimes–Transfertoothersitesmaybelimited•Limitofdetectionof19Fmethod1.5%w/wForm1–Absolutedetectionlimit0.12%w/wForm1–4.2hracquisitiontime•Canbeusedforlowerdosetablets–0.3%w/wdrugintablets(1mgdrugin300mgtablets)12Katrincicetal.IntJPharm.2009,366,1-13用固态核磁共振定量13制剂及制剂工艺中原料药的晶型转变14制剂工艺中原料药晶型的转变Formchangescanoccur–Mixed/dissolved/suspendedinsolvent–Drying–Milling–Compaction–RHexposure•InteractionsbetweendrugsubstanceandexcipientscancauseformchangesZhangetal.AdvDrugDeliveryRev.2004,56,371-39015制剂工艺中原料药晶型的转变•Caninvolveonecomponentormore•Canbesolid-solidorsolid-liquid-solidBasicProcessStateofAggregationSpecificProcessTransformations(Onecomponent)Solid-solidPolymorphictransformationsCrystallizationoftheamorphousformandviceversaIncongruentmelting(meltingfollowedbycrystallizationofamorestableform)SolutionmediatedpolymorphictransformationSolid-liquid-solidPhysicalinteractions(multicomponent)Solid-solidEutecticreactionSolid-liquid-solidFormationofamolecularcompoundorasolidsolution(includingsolvateformation)cocrystals,saltsSolid-solidorSolid-liquid-solidHydrateformationinhumidairPhysicaldecompositions(multicomponent)Solid-solidorSolid-liquid-solidDesolvationdissociationTypesofthemostimportantphasetransitionsduringprocessingofpharmaceuticalsaaDoesnotconsiderachemicalchangeMorrisetal.AdvDrugDeliveryRev.2001,48,91-11416如何通过工艺改进避免晶型转变•TransformationscanbecontrolledandcircumventedbyselectingtheappropriateprocessZhangetal.AdvDrugDeliveryRev.2004,56,371-390Multi-stepdryblending•Milldrugwithlactosemonohydratetoreduceparticlesizeandimproveflowproperties•Form1convertstoForm2duringmilling17Katrincicetal.Int.J.Pharm.2009,366,1-13案例一：亚稳态晶型的制剂开发Form2waschosenfordevelopmenteventhoughitwasn’tthestableformatRT•Millingandhygroscopicitywereimportant•ShowedthatForm2wasstablefor1yearunderstabilityconditions18案例二：原料药和辅料在制剂中形成共晶AMG517•Anumberofcrystallineformsfoundforfreebase•Numeroussolvatesalsoisolated•Saltformationnotfeasible–Disproportionatedinaqueoussolution–ResultingpHwaslowandacidmediatedcleavageoccurredatetherbond•FormAselectedforearlydevelopment–Insolubleinwater•Asuspensionin10%(w/v)PluronicF108(R)inOraPlus(R)wasselectedforpre-clinicalformulation19Baketal.JPharmSci.2008,97,3942-3956•Athighdoses,foundabsorptionlimitedbysolubility–Duetonewsolidforminsuspension•OraPlus(R)contains0.1%sorbicacidasapreservative•Newformwas1:1AMG517:sorbicacidcocrystal•Found12additionalcocrystalsinsubsequentstudies•Knowwhatisinyoursolutions–canalsohappenwithbuffers20Baketal.JPharmSci.2008,97,3942-3956案例三：选择适当的制剂方法以避免晶型转变•Capsulesandtabletspreparedbywetgranulationordryblending–Clinicalformulations:1:10and1:15drug:excipient–Prototypeformulation:1:2.8drug:excipient•Dryblendshowednochangeincrystallinity•Wetgranulationresultedinmostlyamorphousdrug