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1、晶云藥物第一屆晶型專題技術(shù)培訓(xùn)課程八課程八：課程八Pharmatech：：：手性藥物分子的結(jié)晶提純手性藥物分子的結(jié)晶提純主主講人：主講人講人：：：陳敏華博士，首席執(zhí)行官CrystalCrystalPharmatech蘇州晶云藥物科技有限公司Email：contact@crystalpharmatech.com電話：0512-69561921Pharmatech1Crystal提綱?手性藥物結(jié)晶拆分在原料藥生產(chǎn)中的重Pharmatech要性?手性藥物結(jié)晶拆分的原理及工藝研發(fā)的Crystal流程和策略：三元相圖的應(yīng)用?實(shí)例分析:對(duì)于不同種類的對(duì)映異構(gòu)體和非對(duì)映異構(gòu)體進(jìn)行手性拆分
2、不同策略的成功應(yīng)用Pharmatech2Crystal手性化合物常用術(shù)語Enantiomers:stereoisomerswhicharemirrorimagesofeachother(Rvs.S)PharmatechEnantiomericexcess(ee)=(R-S)/(R+S)(0.92or92%)Racemate:anequimolarmixtureofapairofenantiomersCrystalDiastereomersordiastereoisomers:stereoisomerswhicharenotmirrorimagesofeachother(R,
3、S)vs.(R,R)Diastereomericexcess(de)Stereoisomers:mirrorimageenantiomers,geometric(cis/trans)isomers,anddiastereoisomersPharmatech3Crystal對(duì)映異構(gòu)體分類RacematePharmatechConglomerateRacemicPseudoracemateCrystalCompoundPhysicalmixtureofpureenantiomericOnephasecrystallineSolidcrystalsadditionalcompou
4、ndsolutionRRRR+SSSSR-SR-SRSSRRRRRSSSSR-SR-SSRRSRRRRSSSSR-SR-SRSRSPharmatech4Crystal手性藥物的一些事實(shí)?Pharmatech市場(chǎng)上50%的藥物是手性分子?70%的正在研發(fā)的藥物是手性分子Crystal?全球銷量最好的10個(gè)藥物中，9個(gè)是手性分子?對(duì)于手性藥物來說，生產(chǎn)和制備光學(xué)純的對(duì)映異構(gòu)體非常重要，因?yàn)椴煌膶?duì)映異構(gòu)體可能有非常不同的生物活性Pharmatech5Crystal美國(guó)藥監(jiān)局對(duì)于新的手性藥物開發(fā)的指南PharmatechCrystalPharmatechhttp://www.fd
5、a.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htm6Crystal不同對(duì)映異構(gòu)體具有相同活性的一些手性藥物?BothenantiomersofdobutaminearePharmatechpositiveinotropes;?Bothibuprofenenantiomersareanti-Crystalinflammatoryagents;?Bothenantiomersofwarfarinandphenprocoumonareanticoagulants;?Theenant
6、iomersofbupivicainebothproducelocalanesthesia;http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htmPharmatech7Crystal不同對(duì)映異構(gòu)體具有不同生物活性的手性藥物?Granulocytopeniaisrelatedtothed-isomerofPharmatechlevodopa;vomitingiscausedbythed-isomeroflevamisole;andmyastheniagra
7、visCrystalsymptomswerenolongerobservedwhenthed-isomerwasremovedfromd,lcarnitine.Pharmatech8CrystalHypotheticalInteractionbetweenthe2EnantiomersofAChiralDrugandItsBindingSitePharmatechCrystalPharmatechhttp://www.psychiatrist.com/pcc/pccpdf/v05n02/v05n0202.pdf9C
