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：contact@crystalpharmatech.com电话：0512-69561921CrystalPharmatechCrystalPharmatech2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http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htmCrystalPharmatechCrystalPharmatech7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;http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htmCrystalPharmatechCrystalPharmatech8•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CrystalPharmatechCrystalPharmatech9HypotheticalInteractionbetweenthe2EnantiomersofAChiralDrugandItsBindingSitehttp://www.psychiatrist.com/pcc/pccpdf/v05n02/v05n0202.pdfCrystalPharmatechCrystalPharmatech10•Althoughitisnowtechnologicallyfeasibletopreparepurifiedenantiomers,developmentofracematesmaycontinuetobeappropriate.However,currentlyavailableinformationsuggeststhatthefollowingshouldbeconsideredinproductdevelopment:–Appropriatemanufacturingandcontrolproceduresshouldbeusedtoassurestereoisomericcompositionofaproduct,withrespecttoidentity,strength,qualityandpurity.Manufacturersshouldnotifycompendiaofthesespecificationsandtests.–Pharmacokineticevaluationsthatdonotuseachiralassaywillbemisleadingifthedispositionoftheenantiomersisdifferent.Therefore,techniquestoquantifyindividualstereoisomersinpharmacokineticsamplesshouldbeavailableearly.Ifthepharmacokineticsoftheenantiomersaredemonstratedtobethesomeortoexistasafixed-ratiointhetargetpopulation,anachiralassayoranassaythatmonitorsoneoftheenantiomersmaybeused,subsequently.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidan...
