Course-5-Amorphous

1药物晶型研究和固态研发中的无定形晶云药物第二届晶型专题技术培训主讲人：张炎锋博士，技术总裁CrystalPharmatech苏州晶云药物科技有限公司Email：[e-mail]电话：[phone]提纲•为什么要研究无定形?•无定形基础知识•无定形固态分散物制剂•无定形固态分散物制剂的制备•无定形的检测和表征•无定形的稳定性问题3为什么要研究无定形？4制药行业面临的挑战•Revenuesareunderpressure–Changeintargetfocus–Patentsexpiring–Increasedregulatorystandards•Drugdiscoveryshiftstartinginthe1990s:–Invitrobiologyscreeningapproachchange–Popularityofcombinatorialchemistryincreased–NewChemicalEntities(NCEs)aregettinglesssoluble–Result:solubilityand/ordissolutionlimitedabsorptioninvivo•Significantcandidateterminationinclinicalstudies–PK/Bioavailability–Formulation–Compoundsarenotachievingadequateexposure5DissolutionComparison:amorphous(inPVPSD)vscrystallineBicalutamide.Comparisonofcanineinvivoexposureforcrystallineandamorphousdrug(inHPMCASSDDs)crystallineamorphousamorphouscrystalline无定形可以提高药物溶出和生物利用度ANDREWS,GPetal.,JournalofPharmaceuticalSciences,Vol.99,1322–1335(2010)Friesen,DTetal,MOLECULARPHARMACEUTICSVOL.5,NO.6,1003–1019(2008)Bioavailability:fractionofadministereddoseofadrugthatreachessystemiccirculation6无定形可以规避创新药对晶型专利的保护，提早将仿制药推向市场180-daysmarketingexclusivity缬更昔洛韦7市场上的无定形药物•MarketedDrugProducts–Accolate(zafirlukast,安可来,ASTRAZENECA)–Accupril(quinaprilhydrochloride,喹那普利)–Ceftin(cefuroximeaxetil,头孢呋辛酯,GSK)–Humulin*(insulin,优泌林)–Rezulin(troglitazone,曲格列酮)–Sporanox(itraconazole,斯皮仁诺,J&J)*Partiallyamorphousdesignedforrapidonset+extendedrelease(crystallinefraction)8BCSIHighsolubilityHighpermeabilityBCSIIIHighsolubilityLowpermeabilityBCSIILowsolubilityHighpermeabilityBCSIVLowsolubilityLowpermeability药物分子的BCS分类Dosenumber:D0=(M0/V0)/CsDosevolume:Vd=M0/CsLargeD0,Morechallenging9药物研发中不同制剂方法的选择DoseNumberD0Non-conventionalFormulationSprayDryingHotMeltExtrusion(HME)Nano-suspensionHighConventionalFormulationLowFreezeDryingRotaryEvaporationAmorphousSolidDispersionsLowConventionalFormulationLowNon-conventionalFormulationHighNano-suspensionAmorphousSolidDispersions10AmorphousCrystalSupercooledLiquidLiquidTKTgTmEnthalpy无定形的基础知识11Moleculesinaordered,repeatingpatternMoleculesinarandomarrangementwithsomelocalorder•Equilibriumstate•Morestable•Lowersolubility•Lowerdissolutionrate•Non-equilibriumstate•Typicallylessstable•Higherapparentsolubility•Higherdissolutionrate晶相和无定形12晶型vs.无定形:XRPD100%amorphous100%crystallineMixedsystem13晶型vs.无定形:DSC/mDSC-0.4-0.3-0.2-0.10.0HeatFlow(W/g)1201101009080Temperature(°C)AmorphousBatch#3AmorphousfreeCrystallinePartiallyamorphousAmorphousGlasstransition14GlassCrystalSupercooledLiquidLiquidfastcoolingslowcoolingTemperatureTKTgTmTgfTgsEnthalpyTg:glasstransitiontemperatureTk:KauzmanntemperatureTm:meltingpointUponcooling,molecularmotionsinliquidsslowdown.Ifcrystallizationisavoidedbelowitsfreezingpoint,theliquidwillexistinasupercooledstate.Uponfurthercooling,themoleculesinthesupercooledliquidwillrearrangesoslowlythattheyappear‘frozen’onthelaboratorytimescale.Thisfallingoutofequilibriumoccursacrossanarrowtransformationrangewherethecharacteristicrelaxationtimeisoftheorderof100seconds.Thistransformationisnormallyreferredastheglasstransition.Thesloweraliquidiscooled,thecolderitcanbecomebeforefallingoutofequilbirrium.EnthalpyDebenedetti,P.G.;Stillinger,F.H.Nature,2001,410,259-267超冷却液体和无定形固体15AmorphousDrugPolymer无定形固态分散物制剂16什么是无定形固态分散物?•Asinglephaseamorphoussolidsolutionofdrug,polymer,optionalsurfactants,etc.asdeterminedbycommonanalyticaltechniquessuchasXRPD,DSC,ssNMR.•Methodstoobtainsoliddispersionsinclude:spraydrying,hotmeltextrusionandfreezedrying,etc.AmorphousDrugPolymer17“Molecularlydispersedsupersaturation”•Amorphousnanoparticles•Bilesaltmicelles•etc.Largerparticles500nmSoliddispersionDissolutionParticleSizes(Recrystallization)-5nm-500nm无定形固态分散物：药物释放18无定形分散物中辅料的选择•Polymers–Carriersforthedrug–Inhibitcrystallizationbothindosageformandin-vivo•Surfactants–Solubilizersoremulsifyingagents•Organicsolvents–Neededtodissolveallcomponents19•Increaseaqueoussolubility–Usewatersolublemacromolecules–Useamorphouspolymers•Improvephysicalstability(inhibitcrystallization)–Usemacromolecules•Reducedmobility(longrelaxationtimes)•Producesinglephasesolidsolutionswithdrugs•UsepolymerswithhighTg•Frustrationagainstcrystallization无定形分散物中高分子的选择20无定形分散物中高分子的选择Reference:Amorphoussoliddispersionsasenablingformulationsfordiscoveryandearlydevelopment,AmericanPharmaceuticalReview,Jan/Feb201121无定形分散物中表面活性剂的选择Reference:Amorphoussoliddispersionsasenablingformulationsfordiscoveryandearlydevelopment,AmericanPharmaceuticalReview,Jan/Feb201122无定形分散物工艺中溶剂的选择Reference:Amorphoussoliddispersionsasenablingformulationsfordiscoveryandearlydevelopment,AmericanPharmaceuticalReview,Jan/Feb201123AmorphousDrugPolymer无定形固态分散物制剂的制备24怎样得到无定形？HotMeltExtrusionLiquidN2MeltMeltQuenchingSprayDryingBallMillingAmorphousCrystalSupercooledLiquidLiquidFreezeDrying25SprayDrieddrug/PVP-PVAAtomizationGasEvaporationofSolventHeatinHotterregionCoolerregionSprayDropletSpraySolutionHotCoolProcessingGas喷雾干燥法26喷雾干燥工艺参数对产品质量的影响•Morphology•Homogeneity•Particlesizedistribution•NozzleSize•AtomizationGasRate•Sprayrate•CapSize•Solidloading•Disso