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首页 手性药物分子的结晶拆分-陈敏华博士.pdf

手性药物分子的结晶拆分-陈敏华博士.pdf

手性药物分子的结晶拆分-陈敏华博士.pdf

上传者: lwjxz 2011-07-20 评分 0 0 0 0 0 0 暂无简介 简介 举报

简介:本文档为《手性药物分子的结晶拆分-陈敏华博士pdf》,可适用于自然科学领域,主题内容包含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符等。

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:contactcrystalpharmatechcom电话:CrystalPharmatechCrystalPharmatech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CrystalPharmatechCrystalPharmatechEnantiomers:stereoisomerswhicharemirrorimagesofeachother(RvsS)Enantiomericexcess(ee)=(RS)(RS)(or)Racemate:anequimolarmixtureofapairofenantiomersDiastereomersordiastereoisomers:stereoisomerswhicharenotmirrorimagesofeachother(R,S)vs(R,R)Diastereomericexcess(de)Stereoisomers:mirrorimageenantiomers,geometric(cistrans)isomers,anddiastereoisomers手性化合物常用术语CrystalPharmatechCrystalPharmatechRSRSRSRSRSRSRRRRRRRRRRRRSSSSSSSSSSSSRSSRSRRSRSRSRacematePhysicalmixtureofpureenantiomericcrystalsOnephasecrystallineadditionalcompoundSolidsolution对映异构体分类ConglomerateRacemicCompoundPseudoracemateCrystalPharmatechCrystalPharmatech•市场上的药物是手性分子•的正在研发的药物是手性分子•全球销量最好的个药物中个是手性分子•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CrystalPharmatechCrystalPharmatech美国药监局对于新的手性药物开发的指南http:wwwfdagovDrugsGuidanceComplianceRegulatoryInformationGuidancesucmhtmCrystalPharmatechCrystalPharmatech不同对映异构体具有相同活性的一些手性药物•Bothenantiomersofdobutaminearepositiveinotropes•Bothibuprofenenantiomersareantiinflammatoryagents•Bothenantiomersofwarfarinandphenprocoumonareanticoagulants•Theenantiomersofbupivicainebothproducelocalanesthesiahttp:wwwfdagovDrugsGuidanceComplianceRegulatoryInformationGuidancesucmhtmCrystalPharmatechCrystalPharmatech•Granulocytopeniaisrelatedtothedisomeroflevodopavomitingiscausedbythedisomeroflevamisoleandmyastheniagravissymptomswerenolongerobservedwhenthedisomerwasremovedfromd,lcarnitine不同对映异构体具有不同生物活性的手性药物CrystalPharmatechCrystalPharmatechHypotheticalInteractionbetweentheEnantiomersofAChiralDrugandItsBindingSitehttp:wwwpsychiatristcompccpccpdfvnvnpdfCrystalPharmatechCrystalPharmatech•Althoughitisnowtechnologicallyfeasibletopreparepurifiedenantiomers,developmentofracematesmaycontinuetobeappropriateHowever,currentlyavailableinformationsuggeststhatthefollowingshouldbeconsideredinproductdevelopment:–Appropriatemanufacturingandcontrolproceduresshouldbeusedtoassurestereoisomericcompositionofaproduct,withrespecttoidentity,strength,qualityandpurityManufacturersshouldnotifycompendiaofthesespecificationsandtests–PharmacokineticevaluationsthatdonotuseachiralassaywillbemisleadingifthedispositionoftheenantiomersisdifferentTherefore,techniquestoquantifyindividualstereoisomersinpharmacokineticsamplesshouldbeavailableearlyIfthepharmacokineticsoftheenantiomersaredemonstratedtobethesomeortoexistasafixedratiointhetargetpopulation,anachiralassayoranassaythatmonitorsoneoftheenantiomersmaybeused,subsequentlyhttp:wwwfdagovDrugsGuidanceComplianceRegulatoryInformationGuidancesucmhtm美国药监局对于新的手性药物开发的指南CrystalPharmatechCrystalPharmatechSomeExamplesofChiralPsychiatricDrugsCrystalPharmatechCrystalPharmatech得到纯手性药物的主要途径chiralresolvingagentsDiastereomericsaltsCrystallizationdissolutionSaltswithdesirableeePurecompoundindesirableformCompounds(ee)AsymmetricsynthesisEnantiomericmixtures(ee)CrystallizationdissolutionCompoundswithdesirableeeCrystalPharmatechCrystalPharmatech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CrystalPharmatechCrystalPharmatech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CrystalPharmatechCrystalPharmatechSSolventR三元相图的基础知识•QrepresentsS,solventandR•TrepresentsS,solventandR•AnypointonthedashedlinewillrepresentasystemwithsameratioofStoRQTCrystalPharmatechCrystalPharmatechSSolventRABCsolidSsolidRS,R,SolventAddsolventsolidSsolidRsolutionSeparatethesolutionandsolidphaseQPST用三元相图示意手性分子结晶溶解提纯的工艺流程CrystalPharmatechCrystalPharmatechDSolventUA'ASE(a)SDUA'AE(b)rSolventE'A'ASrA'AA'ASolventD(c)UA'ASrA'AA'ASolventD(c)U对映异构体的三元相图ConglomerateRacemiccompoundPseudoracemateCrystalPharmatechCrystalPharmatechSSolventREConglomerate系统的三元相图varΠ=CianceGibbsPhaseRule:C=FixPressurevarΠ=CianceVarianceinGreyFGBluesolidlinerepresentsthesaturatedsolutioncurveRegionERS:BothRandSaresaturatedRegionEFS:RisunsaturatedandSissaturatedRegionAF’E’EF:BothRandSareunsaturatedAF’CrystalPharmatechCrystalPharmatechSSolventRRSE’RegionEDS:BothRSandSaresaturatedRegionEFS:RScompletelydissolvesinsolutionandSissaturatedRegionE’DE:RSissaturatedandeitherRorSisunsaturatedRegionAF’E’EF:BothRSandSareunsaturatedFDF’varΠ=CianceGibbsPhaseRule:C=FixPressurevarΠ=CianceBluesolidlinerepresentsthesaturatedsolutioncurveVarianceinGreyAERacemicCompound系统的三元相图CrystalPharmatechCrystalPharmatechDevelopTPDConglomerateRacemiccompoundeeofstartingsolids>eeofeutecticpointeeofeutecticpoint>minimumeerequiredforproduct>eeofstartingsolidsMinimumeerequiredforproduct>eeofeutecticpoint>eeofstartingsolids(Enrichedinsolid)(Enrichedinsolid)(Enrichedinsupernatant)XRPD,DSC,TGDeterminethethermodynamicallymoststableformofracemateDetermineTypeofracemateSolidSolutionMakeracemate(a)(b)(c)对映异构体的结晶提纯工艺开发流程CrystalPharmatechCrystalPharmatechConglomerateSystemVmin=)(eeUeuDSolventUA'ASE())(eeeeUDDDVeupureeupureYield(atVVmin)=Yieldmax=eeee()()()M三元相图的深入理解:ConglomerateCrystalPharmatechCrystalPharmatechRacemiccompoundsystem(whenthestartingsolidhaseehigherthanthatofeutectic)Vmin=)(eeUeu))(())((maxeueueeeeeeeeYield=SDSolventUA'AEE'rpYield(atVVmin)=()()()Vminrepresentsthevolumeofsolvent(expressedinmlofsolvent)tobeaddedtoonemilligramofsolidtoreachpointMDpurerepresentsthesolubilityofdesiredenantiomerinmgofsolidpermlofsolventM())(eeeeUDDDVeupureeupureCrystalPharmatechCrystalPharmatechRacemiccompoundsystem(whenthestartingsolidhaseelowerthanthatofeutectic)eueuUDeeVmax=VDeueeYield(atVVmax)=Yield(atV=Vmax)=)()(eeeeeeeeeueu()()()Vmaxrepresentsthevolumeofsolvent(expressedinmlofsolvent)tobeaddedtomgofsolidtoreachpointMeerepresentstheeeofstartingsolidswhoseeeistobeupgradedeeeurepresentstheeeofeutecticpointDeuandUeurepresenttheconcentrationofdesiredenantiomerandundesiredenantiomer(mgofsolidspermlofsolvent)attheeutecticpointrespectivelyVrepresentsthevolumeofsolvent(inml)addedtoonemgofsolidSDSolventUA'AEE'prMCrystalPharmatechCrystalPharmatech案例分析CrystalPharmatechCrystalPharmatechDesiredenantiomer:(S,S)Undesiredenantiomer:(R,R)Byasymmetricsynthesis,APIsolidswitheecanbeproduced,howtoupgradetheeetoaboveCompoundI案例分析:Aracemiccompoundsystem(withhigheeforeutecticpoint)NHCHOCHCHONFFFClNCrystalPharmatechCrystalPharmatech纯对映异构体vs消旋体的物理性质DifferentDSCDifferentXRPDMostlikely,theracemateisracemiccompoundTobeconfirmedbysolubilityternaryphasediagramCrystalPharmatechCrystalPharmatechSmgRmg:IPAC:Heptane(v:v)mlmgmlSmgmlREutecticpoint:eemgmlSmgmlREracemateAeeupgradeofCompoundIFormBCrystalPharmatechCrystalPharmatechTernaryphasediagramofFormBin:IPAC:Heptane(v:v)atCeeeePPeeCrystalPharmatechCrystalPharmatechBasedontheaboveequations,givenastartingmixturewitheeof,VmaxisandyieldisatV=VmaxThismeansbyaddingmlof:(v:v)IPAC:HeptanesolventtomgofstartingenantiomericmixturewitheeatC,atequilibrium,theeewillbeupgradedtowithayieldeeUDee)()(=eeVmax=VeeYieldVVmax=Optimalprocesstoupgradeeein:IPAC:Heptane(v:v)atCFeasibilityandstrategy:Theeeofeutecticpoint()ishigherthanthatofstartingsolids(~)Therefore,theeecanbeupgradedtoamaximumvalueofinthesupernatantbydissolutionDeterminetheoptimalsolventsolidratioandthecorrespondingyield:CrystalPharmatechCrystalPharmatechChiralamide(penultimate)APIeeeeDissolutionFilterrecrystallizationAPI>eeReactioncrystallizationReactioncrystallization(eeupgradebydissolutionofAPI)Chiralamide(penultimate)API>ee>eeReactioncrystallizationReactioncrystallization(eeupgradebycrystallizationofpenultimate)eeupgradeinchiralamidecrystallizationstepwasachievedwhenanewanhydrouscrystallineformofchiralamideenantiomerwasdiscoveredPriortothediscoveryoftheanhydrouscrystallineform,chiralamidecrystallizedasamixtureofMTBEsolvateandamorphous,withnoeeupgradeNeweeupgradeprocesswasimplementedinthemanufacturingprocess中间体新晶型的发现改变了手性分子的结晶提纯工艺CrystalPharmatechCrystalPharmatechD(mg)Ethanol(ml)U(mg)CompositionoftotalsystemCompositionofSupernatantED(mg)Ethanol(ml)U(mg)CompositionoftotalsystemCompositionofSupernatantEeeupgradeofCompoundIIDIPASalt案例分析:Aracemiccompoundsystem(withloweeforeutecticpoint)Eutecticpoint:ee:C(R):mgmlRC(S):mgmlSC(R):mgmlTemp:CNSOOOFClCHOCrystalPharmatechCrystalPharmatech)(eeUeuFeasibilityandstrategy:eeofeutecticpointis,lowerthanthatofstartingsolids(toee)Therefore,eecanbeupgradedtointhesolidphasebyaddingVminormoreamountofsolventstothesolids=(ee)Basedonabove,givenastartingenantiomericmixturewithee,VmincanbedeterminedtobeandtheyieldisatV=VminThismeansthatbyaddingmlofEtOHtomgofstartingenantiomericmixturewitheeatC,atequilibrium,theeeofDwillbeupgradedtointhesolidphasewithayieldofVmin=OptimalprocesstoupgradeeeofDIPASaltinethanolatC))(())((maxeueueeeeeeeeYield=Determinetheoptimalsolventsolidratioandthecorrespondingyield:CrystalPharmatechCrystalPharmatech案例分析三:AconglomerateSystemeeupgradeofcompoundIIIfreebaseD(mg):(v:v)IPA:Heptane(ml)U(mg)CompositionofsupernatantD(mg):(v:v)IPA:Heptane(ml)U(mg)CompositionofsupernatantCCC(R)=mgatCEutecticpoint:C(S)=mgmlC(R)=mgmlC(R)=mgEutecticpoint:C(S)=mgmlC(R)=mgmlNHNONNNFFFFFFCrystalPharmatechCrystalPharmatecheecanbeupgradedtointhesolidphasebyaddingVminormoresolventstothestartingsolidBasedontheTPDatC,thesolubilityofpureconglomerateismgofRandmgofSpermlofsolventandthatofpureenantiomerRismgpermlofsolventTherefore,similarVminandyieldatVVmincanbecalculatedbasedonequations()and())(eeUeuVmin==(ee)Yieldmax=eeeeOptimalprocesstoupgradeeeofCompoundIIIfreebasein:(v:v)IPA:HeptaneatCorCFeasibilityandstrategy:Determinetheoptimalsolventsolidratioandthecorrespondingyield:CrystalPharmatechCrystalPharmatechDSolventUE非对映异构体的三元相图varΠ=CianceGibbsPhaseRule:C=FixPressurevarΠ=CianceVarianceinBoldTheternaryphasediagramisnotsymmetricduetodifferentsolubilityoftwodiastereomersCrystalPharmatechCrystalPharmatechVmin=)(deUeu())(dedeUDDDVeupureeupureYield(atVVmin)=))(())((eueudedededeYield(atV=Vmin)=YieldisdefinedastheratioofdesireddiastereomerinthesolidphasetothedesireddiastereomerinthetotalsystemderepresentsthediastereomericexcessDefinetheoptimalratioandpredicttheyieldbasedontheternaryphasediagramCrystalPharmatechCrystalPharmatechOHNHOHNH(R,S)()cis(S,R)()cisMW=CompoundIVAPICAIFourpossibleisomersofcompoundIVCAIsaltAPI(R,R,R)CAI(R,S):DdAPI(S,S,S)CAI(R,S):UdAPI(R,R,R)CAI(S,R):DuAPI(S,S,S)CAI(S,R):UuAssumingthecrudefreeacidhasee~andCAIsalthasee~,thenuponsaltformation,therewillbe:Dd:Ud:Du:Uu:APIhasthreechiralcenters案例分析四:非对映异构体的手性提纯CrystalPharmatechCrystalPharmatechTernaryPlotDdmgSolvent(:(v:v)toluene:heptaneplusvariousimpurities)mlUdmgTotalcompositionSupernatantMotherliquorfromprocessEutecticC(Dd):mgmlC(Ud):mgmlde:PureDd:C(Dd)~mgmlTemperature:CStartingSolvent:Washedmotherliquor(de,gl)CrystalPharmatechCrystalPharmatechTernaryPlotDd(mg)SolventfromML()(ml)Ud(mg)SupernatantcompositionTotalsystemEutectic:Dd:mgmlUd:mgmlde:Startingsolvent:Motherliquor(de,gl)Temperature:CCrystalPharmatechCrystalPharmatech•Eutecticdeofthediastereomericsystemisrelativelyindependentofthesolventcompositionimpurityconcentrationanditisverylow~•Loweutecticdesuggeststhermodynamicallytheundesireddiastereomercanberejectedinthesupernatantandpuredesireddiastereomercanbeobtainedinthesolidsuponcrystallization•Theoptimalsolventsolidratioandtheyieldcanbepredefinedandcalculated通过结晶提纯的可行性和策略CrystalPharmatechCrystalPharmatech总结•三元相图是理解手性药物结晶提纯工艺的强有力的工具。•根据对映异构体或者非对映异构体系统的三元相图一个手性药物分子通过结晶或者溶解的方法得到提纯的可行性可以立刻确定同时三元相图可以协助我们找到最优化的结晶工艺条件。•手性药物的手性提纯可以在原料药最后一步的结晶工艺中实现也可以通过中间体的结晶工艺实现。有时通过对手性药物中间体的结晶可能可以将一个很难提纯的手性药物通过很简单的方法得以提纯。•手性药物的结晶提纯有时会受到结晶动力学的很大影响不要忽略。CrystalPharmatechCrystalPharmatech晶云药物晶云药物晶云药物晶云药物可以帮助您开发出手性药物结晶提纯手性药物结晶提纯手性药物结晶提纯手性药物结晶提纯的工艺如果您有这方面的任何问题请随时和我们联系咨询!苏州晶云药物科技有限公司Email:contactcrystalpharmatechcom电话:CrystalPharmatechCrystalPharmatech药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息研发领域专业研发领域专业研发领域专业研发领域专业研发领域专业研发领域专业研发领域专业研发领域专业CROCROCROCROCROCROCROCRO晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司CrystalPharmatechIncCrystalPharmatechIncCrystalPharmatechCrystalPharmatech公司使命公司使命公司使命公司使命公司使命公司使命公司使命公司使命为全球各制药公司提供药物晶型研药物晶型研药物晶型研药物晶型研究究究究和药物固态研发药物固态研发药物固态研发药物固态研发领域的最佳技术方案并成为该领域的领导者。CrystalPharmatechCrystalPharmatech公司简介公司简介公司简介公司简介公司简介公司简介公司简介公司简介国内第一家专注于药物晶型研究的公司国内第一家专注于药物晶型研究的公司国内第一家专注于药物晶型研究的公司国内第一家专注于药物晶型研究的公司为全球制药公为全球制药公为全球制药公为全球制药公司提供药物晶型筛选和研究领域的专业技术服务司提供药物晶型筛选和研究领域的专业技术服务司提供药物晶型筛选和研究领域的专业技术服务司提供药物晶型筛选和研究领域的专业技术服务研发团队晶型研究经验丰富研发团队晶型研究经验丰富研发团队晶型研究经验丰富研发团队晶型研究经验丰富技术力量雄厚技术力量雄厚技术力量雄厚技术力量雄厚博士博士博士博士硕士硕士硕士硕士本科本科本科本科核心团队成员过去在美国默克核心团队成员过去在美国默克核心团队成员过去在美国默克核心团队成员过去在美国默克罗氏等全球领先的制药罗氏等全球领先的制药罗氏等全球领先的制药罗氏等全球领先的制药公司直接负责和从事药物晶型研究和药物固态研发公司直接负责和从事药物晶型研究和药物固态研发公司直接负责和从事药物晶型研究和药物固态研发公司直接负责和从事药物晶型研究和药物固态研发拥拥拥拥有在该领域有在该领域有在该领域有在该领域多年的丰富实战经验多年的丰富实战经验多年的丰富实战经验多年的丰富实战经验曾共同负责和管理曾共同负责和管理曾共同负责和管理曾共同负责和管理过超过过超过过超过过超过个药物分子的晶型研究个药物分子的晶型研究个药物分子的晶型研究个药物分子的晶型研究拥有拥有拥有拥有多项药物晶型多项药物晶型多项药物晶型多项药物晶型专利专利专利专利在各类国际学术期刊发表过在各类国际学术期刊发表过在各类国际学术期刊发表过在各类国际学术期刊发表过多篇文章多篇文章多篇文章多篇文章配备了全球领先的晶型筛选和研究的各种固态分析仪器配备了全球领先的晶型筛选和研究的各种固态分析仪器配备了全球领先的晶型筛选和研究的各种固态分析仪器配备了全球领先的晶型筛选和研究的各种固态分析仪器致力于提供研发方案致力于提供研发方案致力于提供研发方案致力于提供研发方案而不是仅仅提供实验数据而不是仅仅提供实验数据而不是仅仅提供实验数据而不是仅仅提供实验数据CrystalPharmatechCrystalPharmatech晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器固态核磁共振固态核磁共振固态核磁共振固态核磁共振(ssNMR)(ssNMR)(ssNMR)(ssNMR)XXXX射线粉末衍射仪射线粉末衍射仪射线粉末衍射仪射线粉末衍射仪(XRPD)(XRPD)(XRPD)(XRPD)热重分析仪热重分析仪热重分析仪热重分析仪(TGA)(TGA)(TGA)(TGA)差示扫描量热仪差示扫描量热仪差示扫描量热仪差示扫描量热仪(DSC)(DSC)(DSC)(DSC)Cry

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