搜索
PharmaceuticsPassageA:PharmaceuticalFactorsAffectingDrugBioavailabilityInordertodesignadrugproductthatwilldelivertheactivedruginthemostbioavailableform,thepharmacistmustconsider(1)thetypeofdrugproduct(e.g.solution,suspension,suppository);(2)thenatureoftheexcipientsinthedrugproduct;and(3)thephysicochemicalpropertiesofthedrugmolecule.Asdiscussedpreviously,thebioavailabilityoftheactivedruginasoliddosageformisdependentonseveralfactors,including(1)disintegrationofthedrugproductandreleaseoftheactivedrugparticles;(2)dissolutionofthedrug;and(3)absorptionorpermeationofthedrugacrossthecellmembranes.DisintegrationItwasgenerallyrecognizedsomeyearsagothatasoliddrugproducthadtodisintegrateintosmallparticlesandreleasethedrugbeforeabsorptioncouldtakeplace.Forthepurposeofmonitoringuniformtabletdisintegration,theUniteStatePharmacopoeia(USP)establishedanofficialdisintegrationtest.Soliddrugproductsexemptedfromdisintegrationtestsincludetroches,tabletswhichareintendedtobechewed,anddrugproductsintendedtosustainedreleaseorprolongedorrepeataction.Theprocessofdisintegrationdoesnotimplycompletedissolutionofthetabletand/orthedrug.CompletedisintegrationisdefinedbytheUSP-XXVTas“thatstateinwhichanyresidueofthetablet,exceptfragmentsofinsolublecoating,remainingonthescreenofthetestapparatusinthesoftmasshavenopalpablyfirmcore”.TheofficialapparatusforthedisintegrationtestandprocedureisdescribedintheUSP-XXVT.Separatespecificationsaregivenforuncoatedtablet,plainuncoatedtablet,buccaltabletsandsublingualtablets.Althoughdisintegrationtestsallowforprecisemeasurementoftheformationoffragments,granules,oraggregatesfromsoliddosageforms,noinformationisobtainedfromthesetestsontherateofdissolutionoftheactivedrug.However,thedisintegrationtestsdoserveasacomponentintheoverallqualitycontroloftabletmanufacture.DissolutionDissolutionistheprocessbywhichachemicalordrugbecomesdissolvedinasolvent.Inbiologicalsystems,drugdissolutioninanaqueousmediumisanimportantpriorconditionofsystemicabsorption.Therateatwhichdrugswithpooraqueoussolubilitydissolvefromanintactordisintegratedsoliddosagesforminthegastrointestinaltractoftencontrolstherateofsystemicabsorptionofthedrug.Noyes,Whitneyandotherinvestigatorsstudiedtherateofdissolutionincludeofsoliddrugs.Accordingtotheirobservations,thestepsindissolutionincludetheprocessofdrugdissolutionatthesurfaceofthesolidparticles,thusformingasaturatedsolutionaroundtheparticle.Thedissolveddruginthesaturatedsolutionknownasthe“stagnantlayer”diffusestothebulkofthesolventfromregionsofhighdrugconcentrationtoregionsoflowdrugconcentration.TheoverallrateofdrugdissolutionmaybedescribedbytheNoyes-Whitneyequation.dc／dt＝DAK(Cs－C)／hWheredc／dt＝rateofdrugdissolution,D＝diffusionrateconstant,A＝surfaceareaoftheparticle,Cs＝concentrationofdruginthestagnantlayer,C＝concentrationofdruginthebulksolvent,K＝oil／waterpartitioncoefficient,andh＝thicknessofthestagnantlayer.Therateofdissolution,(dc／dt)×(1／A),istheamountofdrugdissolvedperunitareatime(e.g.g／cmpermin)。ItcanbeseenfromtheNoyes-Whitneyequationthatdissolutionkineticsmaybeinfluencedbythephysicochemicalcharacteristicsofthedrug,theformulation,andthesolvent.Druginthebody,particularlyinthegastrointestinaltract,isconsideredtobedissolvinginanaqueousenvironment.Inadditiontothesefactors,thetemperatureof(themediumandtheagitationratealsoaffecttherateofdrugdissolution.Invivo,thetemperatureismaintainedataconstant37℃,andtheagitationofstirringrateisheldtoaspecifiedconstant.Anincreaseintemperaturewillincreasethekineticenergyofthemoleculesandincreasethediffusionconstant,D.Ontheotherhand,anincreaseinagitationofthesolventmediumwillreducethethickness,h,ofthestagnantlayer,allowingformorerapiddrugdissolution.PhysicochemicalNatureoftheDrugThenatureofthephysicalandchemicalpropertiesofthesoliddrugparticleshasagreateffectondissolutionkinetics.Theeffectivesurfaceareaofthedrugmaybeincreasedenormouslybyareductionintheparticlesize.Becausedissolutionisthoughttotakeplaceatthesurfaceofthesolute,thegreaterthesurfacearea,themorerapidtherateofdrugdissolution.Thegeometricshapeoftheparticlealsoaffectsthesurfacearea,andduringdissolutionthesurfaceisconstantlychanging.Incalculation,itisusuallyassumedthattheparticlehasretaineditsgeometricshape.Thedegreeofaqueoussolubilityofthedrugalsoaffectstherateofdissolution.Generally,theionizablesaltofthedrugismorewatersolublethanthefreeacidorfreebase.Bychemicalmanipulation,thepharmacistcansynthesizevarioussaltsofthedrug,providingarangeofsolubilityfromverywaterinsoluble.Moreover,ifthedrugisintheanhydrousstate,therateofdissolutionisusuallyfasterthanwiththehydroussalt.Thedrugmayalsoexistinmorethanoneofthecrystallineformsknownaspolymorphs.Thesepolymorphs,whichhaveidenticalchemicalstructures,demonstratedifferentdissolutionkinetics.Ingeneral,crystallinestructuresaremorerapidandthermodynamicallymorestablethantheamorphousformsofthedrug.Thustheamorphousformsofthedrugdemonstratefasterdissolutionratesthanthecrystallineforms.FormulationFactorsAffectingDrugDissolutionThevariousexcipientsindrugproductmayalsoaffectdissolutionkine