TheArtofDrugSynthesisTheArtofDrugSynthesisBatchsizesforCompoundsduringdrugdevelopmentBatchsizesforCompoundsduriHowtospeedupR&DProcessEffectivechemicalprocessR&Dspeedsadrugtomarket:Inthediscoverylaboratory:payattentiontothepracticesofprocessresearchislikelytoimproveyieldsoflaboratoryreaction,reproducesmall-scalerunsmoreeasily.

Observationmayleadtobetterprocessinthelaterdevelopment:minimizingbyproducts,easingwork-upsandpurification.HowtospeedupR&DProcessMinimizeriskduringscale-upSafeoperation

Safetyhazardassessmentsarerequiredbeforeinapilot:Forexample:differentialscanningcalorimetrystudiestoanticipateexothermicprocess.Riskmaycause:InjurytopersonnelLossofequipmentDamagetoacompany’sreputation,etcMinimizeriskduringscale-upSomeitemsshouldbeconsideredduringscale-upStationaryequipmentimmobilevesselsAgitationusuallymoreeffectivethaninlabTimetoconductanoperationasthevolumeincrease10-fold,thetimetoconductanoperationwillatleastdouble

SomeitemsshouldbeconsidereWhatweshoulddo?Almostalloperationsonscalearepossibleifmoneyandtimearenotissues;ofcourse,moneyrarelyflowsfreely,andtimeisoneofthemajorissuesfordevelopingdrugs.

Operationsarealmostalwayschangedinprogressingfromthediscoveryroutetoscale-up.

Thebestapproachforrapidsuccessfulscale-upistoscaledownoperationtothelab,andthendevelopprocessesthatcanbescaledupbymimickingconditionsthatwillsubsequentlybeencounteredonscaleWhatweshoulddo?AlmostalTheimpactofextendedadditionsonscale------example1Swernoxidationdevelopedinlabat-15oCwithyield55%Onapilotbatchesat-15oCwithyield34%(thereducedyieldwasattributetodecompositionoftheactivatedintermediatesduringtheextendedadditiontimes)Onapilotbatchesat-40oCwithyield51%TheimpactofextendedadditioTheimpactofextendedadditionsonscale------example2POCl3wasaddedasthelimitingreagentWhentheadditionwascarriedoutover2~3minutes,theamountofdimericImpurityformedwasabout3%Whentheadditionwasextendedto30minutes,thedimerwasabout13%TheimpactofextendedadditioConsiderationforsuccessfulscale-uptotoxbatchesandphase1material

Apurityof98%isreasonable,theFDAwillreadilypermitcompaniestoupgradetheroutineoftheirAPI(activepharmaceuticalingredient)specificationsafteranticipatedoptimization,butarequesttodowngradethedrugsubstancepurityspecificationwilllikelynotbeencouragedTox/Phase1batchesareoftenpreparedinakilolab,andmostoperationsthatareusedinthediscoverylabcanbeusedthere.Expensivereagents,lowyield,laboratorymanipulationssuchastriturationanddryingoverNa2SO4,preparativechromatographyareoftentoleratedConsiderationforsuccessfulsConsiderationforphase2materialandbeyondIn-processcontrols(IPC)aredevelopedtoensurequalityandproductivityandtheseareessentialforanewdrugapplication(NDA).

Detailedanalyticalmethodsandspecificationsaredeveloped

Ruggedoperationsaredeveloped(simpleandforgivingwithwideoperatingrange)

Scalableprocessaredeveloped(sothattechnologytransfertolargerequipmentcanproceedefficiently)

Considerationforphase2mateReagentSelectionCost/purity/availabilitySpecializedequipmentneededToxicity:restrictingexposurerequiresadditionalPPE(personalprotectiveequipment)andmonitoringChemicalhazard:liabilityworsewithscale-upReagentSelectionCost/purity/aRemovingaBocgroupAreactioncommonlydevelopedinthediscoverylabisremovingaBocgroupFromanamineusingtrifluoroaceticacid(TFA),ProblemwithTFA:highlycorrosive,difficulttocontainandrecover(bp72oC)posesincinerationproblemsduetothegenerationofHFStrongacidsusedinsteadofTFAincludeHCl,H2SO4,methanesulfonicacidandtoluenesulfonicacidRemovingaBocgroupAreactionSolventSafetyEaseofwork-upEaseofremovingsolventfromfinalproductSolventSafetySolventavoidedonscalesolventUndesirablecharacteristicAlternativesolventEt2OflammableMTBE(i-Pr)2OperoxidesMTBEHMPAtoxicityNMPpentaneflammableHeptanehexaneElectrostaticdischargeheptaneCHCl3Mutagenicity(誘變性),toxicityCH2Cl2,PhCH3withCH3CNPhHCarcinogen(致癌性)PhCH3dioxanecarcinogenTHFHOCH2CH2ORTeratogen(致畸性)1,3-propanediolSolventavoidedonscalesolveSolventcommonlyusedonscaleWaterDMSOMIBKMTBEMeOHDMFDMEPhCH31,2-Propanediolt-BuOHEtOAcEt3NEtOHNMPTHFXylenesAcOHAcetonei-PrOAcHeptanen-BuOHPhClCyclohexanei-PrOHCH2Cl22-Me-THFMethylcyclohexaneAcetonitrilePyridinei-BuOAcSolventcommonlyusedonscaleWork-upandisolationMinimalrelianceonchromatographyNoconcentrationstodrynessMinimalnumberofrepeatedsteps,forexample,extractionsFacilesolventdisplacements;thatis,chaselowerbpsolventwithahigherbpsolventControlledcrystallizationpreferredoverprecipitationCrystallizationsusedtoupgradekeyintermediatesMinimaldilution,tominimizeVmaxandincreaseproductivityWork-upandisolationMinimalrReactionruggednessExothermsandgasevolution:liabilityworsewithscale-upCryogenic（低溫）

orveryhightemperaturesrequirespecializedequipmentTightcontrolofreactionconditions,forexample,temperatureorpH,requiresattentionExcludingmoistureoroxygenmayrequireadditionalconsiderationsRapidadditionsandshortreactiontimesrequirenonstandardequipmentReactionruggednessExothermsaRuggedprocessconditionsRuggedprocessconditionsaresoughttodefinesafeoperatingrangesandimproveprocessreliability.Whentimeisavailable,abusetestsareruntodefinetherangesofacceptableprocessing.Unnecessaryoperationsareeliminatedtodecreaseprocessingcycletimesandproducemorematerialonscale.OneexampleiseliminatingtheoperationofdryingrichorganicextractsoverNa2SO4;thisstepisoftenredundant,becauseH2Oisremovedbyazeotropicdistillationwithsolventscommonlyusedforextractions.RuggedprocessconditionsRuggeUnitoperation123WhenCH3SO2Clwasaddedtoamixtureof1andEt3N,routineconditionsforpreparingamesylate,thesoleproductwastheoxazoline3.BysimplyaddingtheEt3NgraduallyafteraddingtheCH3SO2Cl,thusminimizingtheamountoffreebasepresentinthereactionmixture,theratioofmesylatetooxazolinewas95:5Unitoperation123WhenCH3SO2ClRemoveofby-productIntheoxidationofthediarylacetylenetothediketone,aniceexampleofanoxidationthatdoesnotuseinorganicoxidantsortransitionmetalcatalysts,thereactionisheatedat105–110oCtoremovethebyproductdimethylsulfidebyco-distillationwithsolvents.Removingthisbyproductisnecessarytocompletetheoxidation.Eventhoughthisprocessisheatedsignificantlyabovetheboilingpointofdimethylsulfide,thisbyproductisnoteffectivelyremovedfromthereactionmixturesinthelaboratoryunlessdistillationoccurs.Otherapproachesmaybeusefulonscaletoremovedimethylsulfide,suchasaddingasurfactanttodecreasethesurfacetensionofthemixture,spargingwithnitrogen,chargingthereactortoaboutone-thirdofthetotalvolumetoincreaseheadspace,oroptimizingreactorgeometryandagitationRemoveofby-productIntheoxiVolatilizingtheacetonebyproductdrivesthereactiontocompletionandminimizestheformationofthesymmetricalureabyproductsVolatilizingtheacetonebyproYieldLowyieldsrequirethatmoreintermediatesbepreparedformultistepprocessesLowyieldsindicateareasforimprovementsYieldLowyieldsrequirethatmRouteConvergentroutespreferred,inprincipleIfchiral,locationofresolutionsteporintegrityofinducedstereocentersMinimalnumberofstepsgenerallypreferredRouteConvergentroutespreferrRouteDesignandProcessOptimizationtoMinimizeCOGCostofgoodsusedonlyoneorganicsolventRouteDesignandProcessOptimTheImportanceofPhysicalStatesThephysicalformsofintermediatesandAPIscansignificantlyaffect(1)theeaseofunitoperationssuchasfiltrationanddrying;(2)theabilitytoupgradematerial,usuallybycrystallization;(3)thestabilityofprocessstreamsandisolatedcompounds;(4)theeaseandreliabilityofformulatingtheAPI;(5)thebioavailabilityoftheAPIinthedrugproduct.TheImportanceofPhysicalStaSomethingshouldbeconsideredProtectinggroupsareoftenchosentoaffordcrystallineintermediates.Foamsandviscousliquidsareavoided,asitisdifficulttoprepareandtransferthesematerialsonscale.Compoundsmeltingbelow50oCwillbedifficulttocrystallizeSomethingshouldbeconsideredAnalyticalSolidshavemeltingpointsdescribedFinalformwelldefined(salt,polymorph)Spectraandchromatographyinformationavailable,withdetailedmethodsAnalyticalSolidshavemeltingSUMMARYAsdrugdevelopmentisanexpensiveprocess,peoplearealwaystryingtobalancethebenefitsofprocessresearchagainstthetimeandresourcesneededforthatresearch.Duringthedevelopmentofadrugcandidate,thecriteriaforasuccessfulroutechange:Topreparematerialearlyinadrugdevelopmentcampaign,thebestroutewillbethemostexpedientone,ButforamarketedAPIthebestrouteistheonethatismosteconomicalforlarge-scaleoperations.(工藝學問題)

Somedifficultiesmaybeanticipatedandinvestigatedinthelaboratory,suchastheeffectsofextendedprocessing;otherdifficultiesmaybeencounteredonlyuponscale-uptomultikilobatches.Byinvestingtimeandmoneyearlyinprocessresearchtodevelopadrugcandidate,developmentproblemscanbeavoidedandmaterialcanbepreparedinatimelymanner.SUMMARYAsdrugdevelTheArtofDrugSynthesisTheArtofDrugSynthesisBatchsizesforCompoundsduringdrugdevelopmentBatchsizesforCompoundsduriHowtospeedupR&DProcessEffectivechemicalprocessR&Dspeedsadrugtomarket:Inthediscoverylaboratory:payattentiontothepracticesofprocessresearchislikelytoimproveyieldsoflaboratoryreaction,reproducesmall-scalerunsmoreeasily.

Observationmayleadtobetterprocessinthelaterdevelopment:minimizingbyproducts,easingwork-upsandpurification.HowtospeedupR&DProcessMinimizeriskduringscale-upSafeoperation

Safetyhazardassessmentsarerequiredbeforeinapilot:Forexample:differentialscanningcalorimetrystudiestoanticipateexothermicprocess.Riskmaycause:InjurytopersonnelLossofequipmentDamagetoacompany’sreputation,etcMinimizeriskduringscale-upSomeitemsshouldbeconsideredduringscale-upStationaryequipmentimmobilevesselsAgitationusuallymoreeffectivethaninlabTimetoconductanoperationasthevolumeincrease10-fold,thetimetoconductanoperationwillatleastdouble

SomeitemsshouldbeconsidereWhatweshoulddo?Almostalloperationsonscalearepossibleifmoneyandtimearenotissues;ofcourse,moneyrarelyflowsfreely,andtimeisoneofthemajorissuesfordevelopingdrugs.

Operationsarealmostalwayschangedinprogressingfromthediscoveryroutetoscale-up.

Thebestapproachforrapidsuccessfulscale-upistoscaledownoperationtothelab,andthendevelopprocessesthatcanbescaledupbymimickingconditionsthatwillsubsequentlybeencounteredonscaleWhatweshoulddo?AlmostalTheimpactofextendedadditionsonscale------example1Swernoxidationdevelopedinlabat-15oCwithyield55%Onapilotbatchesat-15oCwithyield34%(thereducedyieldwasattributetodecompositionoftheactivatedintermediatesduringtheextendedadditiontimes)Onapilotbatchesat-40oCwithyield51%TheimpactofextendedadditioTheimpactofextendedadditionsonscale------example2POCl3wasaddedasthelimitingreagentWhentheadditionwascarriedoutover2~3minutes,theamountofdimericImpurityformedwasabout3%Whentheadditionwasextendedto30minutes,thedimerwasabout13%TheimpactofextendedadditioConsiderationforsuccessfulscale-uptotoxbatchesandphase1material

Apurityof98%isreasonable,theFDAwillreadilypermitcompaniestoupgradetheroutineoftheirAPI(activepharmaceuticalingredient)specificationsafteranticipatedoptimization,butarequesttodowngradethedrugsubstancepurityspecificationwilllikelynotbeencouragedTox/Phase1batchesareoftenpreparedinakilolab,andmostoperationsthatareusedinthediscoverylabcanbeusedthere.Expensivereagents,lowyield,laboratorymanipulationssuchastriturationanddryingoverNa2SO4,preparativechromatographyareoftentoleratedConsiderationforsuccessfulsConsiderationforphase2materialandbeyondIn-processcontrols(IPC)aredevelopedtoensurequalityandproductivityandtheseareessentialforanewdrugapplication(NDA).

Detailedanalyticalmethodsandspecificationsaredeveloped

Ruggedoperationsaredeveloped(simpleandforgivingwithwideoperatingrange)

Scalableprocessaredeveloped(sothattechnologytransfertolargerequipmentcanproceedefficiently)

Considerationforphase2mateReagentSelectionCost/purity/availabilitySpecializedequipmentneededToxicity:restrictingexposurerequiresadditionalPPE(personalprotectiveequipment)andmonitoringChemicalhazard:liabilityworsewithscale-upReagentSelectionCost/purity/aRemovingaBocgroupAreactioncommonlydevelopedinthediscoverylabisremovingaBocgroupFromanamineusingtrifluoroaceticacid(TFA),ProblemwithTFA:highlycorrosive,difficulttocontainandrecover(bp72oC)posesincinerationproblemsduetothegenerationofHFStrongacidsusedinsteadofTFAincludeHCl,H2SO4,methanesulfonicacidandtoluenesulfonicacidRemovingaBocgroupAreactionSolventSafetyEaseofwork-upEaseofremovingsolventfromfinalproductSolventSafetySolventavoidedonscalesolventUndesirablecharacteristicAlternativesolventEt2OflammableMTBE(i-Pr)2OperoxidesMTBEHMPAtoxicityNMPpentaneflammableHeptanehexaneElectrostaticdischargeheptaneCHCl3Mutagenicity(誘變性),toxicityCH2Cl2,PhCH3withCH3CNPhHCarcinogen(致癌性)PhCH3dioxanecarcinogenTHFHOCH2CH2ORTeratogen(致畸性)1,3-propanediolSolventavoidedonscalesolveSolventcommonlyusedonscaleWaterDMSOMIBKMTBEMeOHDMFDMEPhCH31,2-Propanediolt-BuOHEtOAcEt3NEtOHNMPTHFXylenesAcOHAcetonei-PrOAcHeptanen-BuOHPhClCyclohexanei-PrOHCH2Cl22-Me-THFMethylcyclohexaneAcetonitrilePyridinei-BuOAcSolventcommonlyusedonscaleWork-upandisolationMinimalrelianceonchromatographyNoconcentrationstodrynessMinimalnumberofrepeatedsteps,forexample,extractionsFacilesolventdisplacements;thatis,chaselowerbpsolventwithahigherbpsolventControlledcrystallizationpreferredoverprecipitationCrystallizationsusedtoupgradekeyintermediatesMinimaldilution,tominimizeVmaxandincreaseproductivityWork-upandisolationMinimalrReactionruggednessExothermsandgasevolution:liabilityworsewithscale-upCryogenic（低溫）

orveryhightemperaturesrequirespecializedequipmentTightcontrolofreactionconditions,forexample,temperatureorpH,requiresattentionExcludingmoistureoroxygenmayrequireadditionalconsiderationsRapidadditionsandshortreactiontimesrequirenonstandardequipmentReactionruggednessExothermsaRuggedprocessconditionsRuggedprocessconditionsaresoughttodefinesafeoperatingrangesandimproveprocessreliability.Whentimeisavailable,abusetestsareruntodefinetherangesofacceptableprocessing.Unnecessaryoperationsareeliminatedtodecreaseprocessingcycletimesandproducemorematerialonscale.OneexampleiseliminatingtheoperationofdryingrichorganicextractsoverNa2SO4;thisstepisoftenredundant,becauseH2Oisremovedbyazeotropicdistillationwithsolventscommonlyusedforextractions.RuggedprocessconditionsRuggeUnitoperation123WhenCH3SO2Clwasaddedtoamixtureof1andEt3N,routineconditionsforpreparingamesylate,thesoleproductwastheoxazoline3.BysimplyaddingtheEt3NgraduallyafteraddingtheCH3SO2Cl,thusminimizingtheamountoffreebasepresentinthereactionmixture,theratioofmesylatetooxazolinewas95:5Unitoperation123WhenCH3SO2ClRemoveofby-productIntheoxidationofthediarylacetylenetothediketone,aniceexampleofanoxidationthatdoesnotuseinorganicoxidantsortransitionmetalcatalysts,thereactionisheatedat105–110oCtoremovethebyproductdimethylsulfidebyco-distillationwithsolvents.Removingthisbyproductisnecessarytocompletetheoxidation.Eventhoughthisprocessisheatedsignificantlyabovetheboilingpointofdimethylsulfide,thisbyproductisnoteffectivelyremovedfromthereactionmixturesinthelaboratoryunlessdistillationoccurs.Otherapproachesmaybeusefulonscaletoremovedimethylsulfide,suchasaddingasurfactanttodecreasethesurfacetensionofthemixture,spargingwithnitrogen,chargingthereactortoaboutone-thirdofthetotalvolumetoincreaseheadspace,oroptimizingreactorgeometryandagitationRemoveofby-productIntheoxiVolatilizingtheacetonebyproductdrivesthereactiontocompletionandminimizestheformationofthesymmetricalureabyproductsVolatilizingtheacetonebyproYieldLowyieldsrequirethatmoreintermediatesbepreparedformultistepprocessesLowyieldsindicateareasforimprovementsYieldLowyieldsrequirethatmRouteConvergentroutespreferred,inprincipleIfchiral,locationofresolutionsteporintegrityofinducedstereocenters