手性分子结晶拆分-晶云药物

1课程八课程八课程八课程八：：：：手性药物分子的结晶提纯手性药物分子的结晶提纯手性药物分子的结晶提纯手性药物分子的结晶提纯晶云药物第一届晶型专题技术培训主讲人主讲人主讲人主讲人：：：：陈敏华博士，首席执行官CrystalPharmatech苏州晶云药物科技有限公司Email：[e-mail]电话：[phone]CrystalPharmatechCrystalPharmatech2提纲•手性药物结晶拆分在原料药生产中的重要性•手性药物结晶拆分的原理及工艺研发的流程和策略：三元相图的应用•实例分析:对于不同种类的对映异构体和非对映异构体进行手性拆分不同策略的成功应用CrystalPharmatechCrystalPharmatech3Enantiomers:stereoisomerswhicharemirrorimagesofeachother(Rvs.S)Enantiomericexcess(ee)=(R-S)/(R+S)(0.92or92%)Racemate:anequimolarmixtureofapairofenantiomersDiastereomersordiastereoisomers:stereoisomerswhicharenotmirrorimagesofeachother(R,S)vs.(R,R)Diastereomericexcess(de)Stereoisomers:mirrorimageenantiomers,geometric(cis/trans)isomers,anddiastereoisomers手性化合物常用术语CrystalPharmatechCrystalPharmatech4R-SR-SR-SR-SR-SR-SRRRRRRRRRRRR+SSSSSSSSSSSSRSSRSRRSRSRSRacematePhysicalmixtureofpureenantiomericcrystalsOnephasecrystallineadditionalcompoundSolidsolution对映异构体分类ConglomerateRacemicCompoundPseudoracemateCrystalPharmatechCrystalPharmatech5•市场上50%的药物是手性分子•70%的正在研发的药物是手性分子•全球销量最好的10个药物中，9个是手性分子•对于手性药物来说，生产和制备光学纯的对映异构体非常重要，因为不同的对映异构体可能有非常不同的生物活性手性药物的一些事实CrystalPharmatechCrystalPharmatech6美国药监局对于新的手性药物开发的指南不同对映异构体具有相同活性的一些手性药物•Bothenantiomersofdobutaminearepositiveinotropes;•Bothibuprofenenantiomersareanti-inflammatoryagents;•Bothenantiomersofwarfarinandphenprocoumonareanticoagulants;•Theenantiomersofbupivicainebothproducelocalanesthesia;•Granulocytopeniaisrelatedtothed-isomeroflevodopa;vomitingiscausedbythed-isomeroflevamisole;andmyastheniagravissymptomswerenolongerobservedwhenthed-isomerwasremovedfromd,lcarnitine.不同对映异构体具有不同生物活性的手性药物CrystalPharmatechCrystalPharmatech9HypotheticalInteractionbetweenthe2EnantiomersofAChiralDrugandItsBindingSite•Althoughitisnowtechnologicallyfeasibletopreparepurifiedenantiomers,developmentofracematesmaycontinuetobeappropriate.However,currentlyavailableinformationsuggeststhatthefollowingshouldbeconsideredinproductdevelopment:–Appropriatemanufacturingandcontrolproceduresshouldbeusedtoassurestereoisomericcompositionofaproduct,withrespecttoidentity,strength,qualityandpurity.Manufacturersshouldnotifycompendiaofthesespecificationsandtests.–Pharmacokineticevaluationsthatdonotuseachiralassaywillbemisleadingifthedispositionoftheenantiomersisdifferent.Therefore,techniquestoquantifyindividualstereoisomersinpharmacokineticsamplesshouldbeavailableearly.Ifthepharmacokineticsoftheenantiomersaredemonstratedtobethesomeortoexistasafixed-ratiointhetargetpopulation,anachiralassayoranassaythatmonitorsoneoftheenantiomersmaybeused,subsequently.美国药监局对于新的手性药物开发的指南CrystalPharmatechCrystalPharmatech11SomeExamplesofChiralPsychiatricDrugsCrystalPharmatechCrystalPharmatech12得到纯手性药物的主要途径+chiralresolvingagentsDiastereomericsaltsCrystallization/dissolutionSaltswithdesirableeePurecompoundindesirableformCompounds(0%ee)AsymmetricsynthesisEnantiomericmixtures(80-96%ee)Crystallization/dissolutionCompoundswithdesirableeeCrystalPharmatechCrystalPharmatech13如何进行手性药物结晶提纯工艺的开发？现状现状现状现状•开发工艺耗时太长，很多随机的实验•缺少对手性分子晶型和所属体系的系统了解•对手性结晶提纯的工艺的可重复性和可放大性没有把握，缺少对工艺风险的预测（不知道结晶提纯根据的是动力学还是热力学原理）利用三元相图指导结晶工艺开发利用三元相图指导结晶工艺开发利用三元相图指导结晶工艺开发利用三元相图指导结晶工艺开发•可以全面理解结晶提纯的原理和过程•了解通过结晶工艺提高手性纯度的可能性•确定最佳的结晶工艺条件，预测能够提纯到的最高手性纯度以及对应的产率CrystalPharmatechCrystalPharmatech14两篇利用三元相图指导手性药物结晶提纯工艺开发的文献CrystalPharmatechCrystalPharmatech15S0102030405060708090100Solvent0102030405060708090100R0102030405060708090100三元相图的基础知识•Qrepresents50%S,20%solventand30%R.•Trepresents80%S,0%solventand20%R.•AnypointonthedashedlinewillrepresentasystemwithsameratioofStoR.QTCrystalPharmatechCrystalPharmatech16S0102030405060708090100Solvent0102030405060708090100R0102030405060708090100ABCsolidSsolidRS,R,SolventAddsolventsolidSsolidRsolutionSeparatethesolutionandsolidphaseQPST用三元相图示意手性分子结晶/溶解提纯的工艺流程CrystalPharmatechCrystalPharmatech17DSolventUA'ASE(a)SDUA'AE(b)rSolventE'A'ASrA'AA'ASolvent123D(c)UA'ASrA'AA'ASolvent123D(c)U对映异构体的三元相图ConglomerateRacemiccompoundPseudoracemateCrystalPharmatechCrystalPharmatech18SSolventREConglomerate系统的三元相图2var+Π−=CianceGibbsPhaseRule:C=3FixPressure1var+Π−=CianceVarianceinGreyFG212BluesolidlinerepresentsthesaturatedsolutioncurveRegionERS:BothRandSaresaturated.RegionEFS:RisunsaturatedandSissaturated.RegionAF’E’EF:BothRandSareunsaturated.AF’CrystalPharmatechCrystalPharmatech19SSolventRR-SE’RegionEDS:BothR-SandSaresaturated.RegionEFS:R-ScompletelydissolvesinsolutionandSissaturated.RegionE’DE:R-SissaturatedandeitherRorSisunsaturated.RegionAF’E’EF:BothR-SandSareunsaturated.FDF’2var+Π−=CianceGibbsPhaseRule:C=3FixPressure1var+Π−=Ciance21122BluesolidlinerepresentsthesaturatedsolutioncurveVarianceinGreyAERacemicCompoun