溶出度方法學(xué)驗證

溶出度方法學(xué)驗證第一頁，共三十八頁，編輯于2023年，星期日Dissolutioniseverywhere!DissolutionstudiesProductQualityAssuranceDosageformdevelopmentIVIVCBiowaiversDrugreleaseregulatoryrequirementsStabilitytestingVariationsSUPACFormulationBioequivalenceManufacturingScaleupFormulationkineticsReleasemechanismsIn-vivopredictionsProductsimilarity2第二頁，共三十八頁，編輯于2023年，星期日

Dissolution AninterplayofthreegroupsoffactorsFORMULATIONDESIGNAPIPROPERTIESTHETESTPROCEDURE3第三頁，共三十八頁，編輯于2023年，星期日INTRODUCTIONTheneedfordissolutiontestingHistoricalperspectiveNarrowtherapeuticrangesBoundarytheoryofdissolutionIntrinsicdissolutionThestartofmoderndissolutiontestingDrugabsorptionAdissolutiontechnologistsview4第四頁，共三十八頁，編輯于2023年，星期日Whydissolution?Chemicalparametersdonottellthewholestory

Whichisbetter?

Atabletwithassayof100%whichreleasesonly50%oftheactivesubstance OR

Atabletwithassayof90%whichreleases100%oftheactivesubstance50%90%5第五頁，共三十八頁，編輯于2023年，星期日Whydissolution?QualitycontrolTwobatchesofthesameproductwithacceptableassayandcontentuniformitybut --------------------BatchIreleases90%activesubstancein20minutesBatchIIreleases60%in20minutes6第六頁，共三十八頁，編輯于2023年，星期日Therapeuticlevels-instantreleaseTOXICLEVELTHERAPEUTICLEVELSUBTHERAPEUTICLEVEL90%Release20min60%Release20minconcentrationtime7第七頁，共三十八頁，編輯于2023年，星期日Therapeuticlevels-slowreleaseTOXICLEVELTHERAPEUTICLEVELSUBTHERAPEUTICLEVEL90%Release20min60%Release20minconcentrationtime8第八頁，共三十八頁，編輯于2023年，星期日Therapeuticlevels-narrowtherapeuticrangeTOXICLEVELTHERAPEUTICLEVELSUBTHERAPEUTICLEVELconcentrationtimeTherapeuticrange9第九頁，共三十八頁，編輯于2023年，星期日Whatisanarrowtherapeuticindex?ThereislessthanatwofolddifferenceintoxicconcentrationsandminimumeffectiveconcentrationsinthebloodSafeandeffectiveuseofthedrugproductsrequirecarefultitrationandpatientmonitoringFornarrowtherapeuticrangeproductsthiscanbeanargumentagainstsubstitutionItisreallyanargumentagainstswitchingsuppliersonceatherapyhasbeenstartedLevothyroxineCarbamazepineWarfarin10第十頁，共三十八頁，編輯于2023年，星期日“ResultsoftestsconductedbytheMHRA’sMedicinesTestingLaboratory,suggestthattheTEVAproductmaydifferfromotherproductsintheamountoflevothyroxinethatisreleasedovertime(dissolution)”11第十一頁，共三十八頁，編輯于2023年，星期日

DisintegrationDissolution…………..…..…..DisintegrationX1934-Switzerland'sPharmacopeiaHelveticawasthefirstregulatorybodytointroduceadisintegrationtestfortablets.1950-DisintegrationbecameanofficialUSPMethod,USP14.12第十二頁，共三十八頁，編輯于2023年，星期日Anhistoricpublication!“ThesedifferencesarenotdetectedbythetestfordisintegrationrategivenintheBritishandU.S.pharmacopoeias”(Shawetal.,1972;Wagneretal.,1973).13第十三頁，共三十八頁，編輯于2023年，星期日Digoxin:Dissolution-limited

(Yu,Pharm.Res.16:1884-1888(1999))FractionofdoseabsorbedParticlediameter(μm)1.00.80.60.40.200 20 40 60 80 10014第十四頁，共三十八頁，編輯于2023年，星期日Whatshouldwereallybelookingfor?Theidealistofindamodel,eitherphysicaland/ormathematicalthatmimicsorcanpredictwhatishappeninginthegastrointestinaltract.Inspiteofmanymodelswearealongwayfromachievingthis.15第十五頁，共三十八頁，編輯于2023年，星期日Thedissolutionprocess第十六頁，共三十八頁，編輯于2023年，星期日Disintegration-dissolutionmodelDISINTEGRATIONFractiondissolvedTabletsurface(t) Largefragments(l)Smallfragments(s)Totaldissolution=Ft+Fl+Fs+Fs*FtFlFsFs*(belowxμ)DISINTEGRATIONTIMEDTPriortodisintegrationtime17第十七頁，共三十八頁，編輯于2023年，星期日ThedissolutionprocessDissolutionofasolidsubstanceisoneoftheheterogeneousprocesses

occurringontheboundarybetweentwophases,whichiscalledthephaseinterface.Itisthereactiononthesolidsurfaceanditcanbedividedintothefollowingsteps:diffusionofinteractingsubstancestothesurface,adsorptiononthesurface,reactiononthesurface,desorptionfromthesurface,diffusionofproductsfromthesurface.1234518第十八頁，共三十八頁，編輯于2023年，星期日ThefirstdissolutiontestJ.Am.ChemSoc.1897,19(12):930-93419第十九頁，共三十八頁，編輯于2023年，星期日Noyes-WhitneyEquationTheKconstantincludesvariousfactorswhichrelatetotheexperimentalcondutionssuchasstirringratesRateisproportionalto:-StagnantLayerGradient(Cs–Ct)DiffusivityDSurfaceAreaS.RateinverselyproportionaltoDiffusionlayerthicknessAplotofW/S[massdissolvedperunitarea]vst[ime]willapproachzeroasCtapproachesCsCstAmountdissolved/unitarea20第二十頁，共三十八頁，編輯于2023年，星期日Fick’sFirstLaw(Diffusion)ThedrivingforceofdiffusionisthespatialconcentrationgradientaccordingtoFirstFick'sLawDissolutionofthesolidsubstanceiscontrolledbytheslowestreactionstage,whichisthediffusionofdissolvedandhydratedcompoundfromthesolidsurface.Thediffusiontransportsthedissolvedsubstanceacrossathindiffusionlayer,wheretheconcentrationofdissolvedsubstancecontinuouslydecreasesfromtheconcentrationofsaturatedsolution(Sc)atthesolidsurfacetotheconcentrationlevel(c)inthebulksolution.21第二十一頁，共三十八頁，編輯于2023年，星期日Fick’sLawSolidcompressedchemicalsubstanceplacedinthesolventWithnostirringatalltherateofsolutiondependsonsimplediffusionDistancefromsurfaceAstimeprogressesTherateofsolutionisextremelyslowasitdependsonlyondiffusion22第二十二頁，共三十八頁，編輯于2023年，星期日where:dn[mol]istheamountofthedissolvedsubstancewithintimeintervaldtDisthediffusioncoefficientSrepresentsthetotalsurface(phaseinterface)ofthedissolvedsolidsubstancedc/dxistheconcentrationgradientWhenthemixingisefficient,thediffusionlayerisverythin(0.02-0.05nm)theconcentrationgradientmaybereplacedbyasinglelinearapproximationdc/dx=(c-cs)/δFortheamountofdissolvedsubstancewecanthenwritedn=VdcwhereVisthetotalvolumeofthesolutionanddcistheconcentrationincrement23第二十三頁，共三十八頁，編輯于2023年，星期日DiffusionLayerModelinaStirredSystemStirringthedissolutionmediumhasadramaticeffectondissolutionrate.Additionaltermsarerequiredtocharacterisedissolutionwithstirringspeed.SolidsurfaceDiffusion/StagnantlayerDiffusionLayerBoundaryBulkSolutionCs=SaturationconcentrationCt=Drugconcentrationinbulksolutionattimeth=DiffusionlayerthicknessCsCth(constantforsetagitationrate)BulkSolidSolidsurface24第二十四頁，共三十八頁，編輯于2023年，星期日Effectofstirringspeed

LevichequationsInthediffusionlayermodeltheincreaseinstirringspeeddecreasesthethicknessofthestagnantlayerBulkSolutionCsCthSOLIDSURFACEBulkSolutionCsCthSlowstirringspeedFaststirringSpeedDiffusionGradientHomogenousSolutionSOLIDSURFACESTAGNANTLAYER25第二十五頁，共三十八頁，編輯于2023年，星期日Theearlydevelopment1903,BrunerandTolloczkoprovedthatdissolutionratedependedon:-

thechemicalstructure,physicalstructuresofthesolid,thesurfaceareaexposedtothemedium,agitationspeed,mediumtemperaturetheoveralldesignofthedissolutionapparatus.L.BRUNERetS.TOLLOCZKO.-UeberdieAuflosungsgeschwindigkeitfesterK?rper(Surlavitessededissolutiondescorpssolides).-Bulletindel'AcadémiedesSciencesdeCracovie,séancedu12octobre1903

p.

11026第二十六頁，共三十八頁，編輯于2023年，星期日DissolutionofdrugsubstancesIntrinsicdissolution第二十七頁，共三十八頁，編輯于2023年，星期日IntrinsicdissolutionTheintrinsicdissolutionrateistherateofdissolutionofapuredrugsubstancewhenconditionssuchassurfacearea,agitation,stirringspeed,pHandionicstrengthofthedissolutionmediumareheldconstant.AsubstancewithsolubilitySdissolvesfromaplanarsurfaceareaAItsdissolutionrate,-dm/dt[mismassandtistime]isgivenby

dm/dt=VdC/dt=-kA(S-C)

wherekistheintrinsicdissolutionrateconstantandCistheconcentrationattimet.28第二十八頁，共三十八頁，編輯于2023年，星期日Sinkconditions*andintrinsicdissolutionrateIfCs<<<<Cd,thatisthesolubilityofthesubstanceismuchgreaterthanitsconcentrationinthedissolutionmedia,thentheequationwouldsimplifyto:- W/S=KCs.t

y=m.x+c[straightline]IfSisconstant,aplotofW/S(massdissolvedperunitarea)vstwillyieldastraightlineofgradientKCs(massdissolvedperunitareaperunittime),whichistheintrinsicdissolutionrate.*SinkconditionsexistwhenCtislessthan10%ofCs29第二十九頁，共三十八頁，編輯于2023年，星期日Wood’sapparatusTabletwithonlyonefaceexposedAsdissolutionproceedstabletfaceretreatsandsurfacearearemainsconstantDifferentPolymorphicFormsPaddle30第三十頁，共三十八頁，編輯于2023年，星期日DissolutionunderNoyesWhitneysinkconditionsCstAmountdissolved/unitareaW/S=K.(Cs-Ct).tW/S=K.Cs.tLinearupto10%ofsaturationItmaybethatthe~10%linearityisrelevanttoasimpleIVIVCbutitiscertainlynotarequirementfordevelopingdiscriminatoryorQCmethodsIfCs<<<<Cd,thatisthesolubilityofthesubstanceismuchgreaterthanitsconcentrationinthedissolutionmedia,thentheequationwouldsimplifyto:- W/S=KCs.t[y=m.x+cstraightline]Weshalllookatsinkconditionslaterinthecontextofmethoddevelopment31第三十一頁，共三十八頁，編輯于2023年，星期日ApparentintrinsicdissolutionHowever,asfarasdissolutionofpowdereddrugsisconcerneditisnotpossibletomeasureintrinsicdissolutionbecauseitisnotpossibletomeasurethesurfaceareaduringthedissolutionprocessApparentIntrinsicDissolutioniswhatisdeterminedforapowdereddrugsubstanceinaspecifiedmediumThisisextremelyvariabledependingonthetestmethodItishoweverofmuchmorerelevancetoformulationworkItallowsthecomparisonbetweenAPI’sofdifferentparticlesizeorpolymorphicform32第三十二頁，共三十八頁，編輯于2023年，星期日ApparatusThereisnoacceptedstandard