美国药典 36版 905 UNIFORMITY OF DOSAGE UNITS

Accessedfrom1.202.191.189bysttage1onMonFeb2522:04:21EST2013USP36PhysicalTests/〈905〉UniformityofDosageUnits431SubstitutingtheexperimentallyobtainedvaluesforTo−Tm,amongdosageunits.Therefore,therequirementsofthis∆Hf,andToinequation(2)yieldsthemolefractionofthechapterapplytoeachdrugsubstancebeingcomprisedintotaleutecticimpurity,which,whenmultipliedby100,dosageunitscontainingoneormoredrugsubstances,un-givesthemolepercentageoftotaleutecticimpurities.lessotherwisespecifiedelsewhereinthisPharmacopeia.DeviationsfromthetheoreticallinearplotalsomaybeTheuniformityofdosageunitscanbedemonstratedby◆duetosolidsolutionformation(KD≠0),sothatcaremusteitheroftwomethods,ContentUniformityorWeight◆Varia-betakenininterpretingthedata.tion(seeTable1).ThetestforContentUniformityofprepara-Toobservethelineareffectoftheimpurityconcentrationtionspresentedindosageunitsisbasedontheassayoftheonthemelting-pointdepression,theimpuritymustbesolu-individualcontentofdrugsubstance(s)inanumberofbleintheliquidphaseormeltofthecompound,butinsolu-dosageunitstodeterminewhethertheindividualcontentisbleinthesolidphase,i.e.,nosolidsolutionsareformed.withinthelimitsset.TheContentUniformitymethodmaybeSomechemicalsimilaritiesarenecessaryforsolubilityintheappliedinallcases.◆melt.Forexample,thepresenceofioniccompoundsinneu-ThetestforWeight◆Variationisapplicableforthefollow-tralorganiccompoundsandtheoccurrenceofthermalde-ingdosageforms:compositionmaynotbereflectedinpurityestimates.Theextentofthesetheoreticallimitationshasbeenonlypartiallyexplored.Solutionsenclosedinunit-dosecontainersandintosoftImpuritiespresentfromthesyntheticrouteoftenaresimi-(W1)lartotheendproduct,hencethereusuallyisnoproblemofcapsules;solubilityinthemelt.ImpuritiesconsistingofmoleculesofSolids(includingpowders,granules,andsterilesolids)thesameshape,size,andcharacterasthoseofthemajor(W2)thatarepackagedinsingle-unitcontainersandcontaincomponentcanfitintothematrixofthemajorcomponentnoactiveorinactiveaddedsubstances;withoutdisruptionofthelattice,formingsolidsolutionsorSolids(includingsterilesolids)thatarepackagedinsin-inclusions;suchimpuritiesarenotdetectablebyDSC.Puritygle-unitcontainers,withorwithoutactiveorinactiveestimatesaretoohighinsuchcases.Thisismorecommon(W3)addedsubstances,thathavebeenpreparedfromtruewithless-orderedcrystalsasindicatedbylowheatsofsolutionsandfreeze-driedinthefinalcontainersandarefusion.labeledtoindicatethismethodofpreparation;andInaddition,themethodisreliablewhenthepurityoftheHardcapsules,uncoatedtablets,orfilm-coatedtablets,majorcomponentisgreaterthan98.5mol%andthemater-containing25mgormoreofadrugsubstancecompris-ialsarenotdecomposedduringthemeltingphase.ing25%ormore,byweight,ofthedosageunitor,inImpuritylevelscalculatedfromthermogramsarerepro-(W4)thecaseofhardcapsules,thecapsulecontents,exceptducibleandgenerallyreliablewithin0.1%foridealcom-thatuniformityofotherdrugsubstancespresentinpounds.lesserproportionsisdemonstratedbymeetingthere-CompoundsthatexistinpolymorphicformcannotbequirementsforContentUniformity.usedinpuritydeterminationunlessthecompoundiscom-pletelyconvertedtooneform.Ontheotherhand,DSCandThetestforContentUniformityisrequiredforalldosage◆DTAareinherentlyusefulfordetecting,andthereforemoni-formsnotmeetingtheaboveconditionsfortheWeight◆toring,polymorphism.Variationtest.1Procedure—TheactualprocedureandthecalculationstobeemployedforeutecticimpurityanalysisaredependentTable1.ApplicationofContentUniformity(CU)andWeightontheparticularinstrumentused.Consultthemanufactur-Variation(WV)TestsforDosageFormser’sliteratureand/orthethermalanalysisliteraturefortheDose&Ratioofmostappropriatetechniqueforagiveninstrument.InanyDrugSubstanceevent,itisimperativetokeepinmindthelimitationsofsolidsolutionformation,insolubilityinthemelt,polymor-≥25mg<25mgphism,anddecompositionduringtheanalysis.andorDosageFormTypeSubtype≥25%<25%UncoatedWVCUTabletsFilmWVCUCoatedOthersCUCUHardWVCUSuspension,Capsulesemulsion,〈905〉UNIFORMITYOFDOSAGESoftorgelCUCUUNITSSolutionsWVWVSinglecompo-Thisgeneralchapterisharmonizedwiththecorrespond-nentWVWVingtextsoftheEuropeanPharmacopoeiaandtheJapaneseSolidsinSolutionPharmacopoeia.Portionsofthegeneralchaptertextthataresingle-unitfreeze-MultiplenationalUSPtext,andarenotpartoftheharmonizedtext,containersdriedin◆compo-aremarkedwithsymbols(◆)tospecifythisfact.finalcon-◆nentsNOTE—Inthischapter,unitanddosageunitaresynony-tainerWVWVmous.◆OthersCUCUToensuretheconsistencyofdosageunits,eachunitinabatchshouldhaveadrugsubstancecontentwithinanar-1◆EuropeanPharmacopoeiaandJapanesePharmacopoeiatextnotacceptedbytheUnitedStatesPharmacopeia:Alternatively,productslistedinitem(4)rowrangearoundthelabelclaim.Dosageunitsaredefinedabovethatdonotmeetthe25mg/25%thresholdlimitmaybetestedforasdosageformscontainingasingledoseorapartofadoseuniformityofdosageunitsbyMassVariationinsteadoftheContentUniform-ofdrugsubstanceineachunit.Theuniformityofdosageitytestiftheconcentrationrelativestandarddeviation(RSD)ofthedrugunitsspecificationisnotintendedtoapplytosuspensions,substanceinthefinaldosageunitsisnotmorethan2%,basedonprocessvalidationdataanddevelopmentdata,andiftherehasbeenregulatoryap-emulsions,orgelsinunit-dosecontainersintendedforex-provalofsuchachange.TheconcentrationRSDistheRSDoftheconcentra-ternal,cutaneousadministration.tionperdosageunit(w/worw/v),whereconcentrationperdosageunitTheterm“uniformityofdosageunit”isdefinedastheequalstheassayresultperdosageunitdividedbytheindividualdosageunitdegreeofuniformityintheamountofthedrugsubstanceweight.SeetheRSDformulainTable2.◆OfficialfromAugust1,2013Copyright(c)2013TheUnitedStatesPharmacopeialConvention.Allrightsreserved.Accessedfrom1.202.191.189bysttage1onMonFeb2522:04:21EST2013432〈905〉UniformityofDosageUnits/PhysicalTestsUSP36Table1.ApplicationofContentUniformity(CU)andWeightVariation(WV)TestsforDosageForms(Continued)HardCapsulesDose&RatioofDrugSubstanceAccuratelyweigh10capsulesindividually,takingcareto≥25mg<25mgpreservetheidentityofeachcapsule.Removethecontentsandorofeachcapsulebyasuitablemeans.AccuratelyweightheDosageFormTypeSubtype≥25%<25%emptiedshellsindividually,andcalculateforeachcapsule◆◆thenetweight◆ofitscontentsbysubtractingtheweight◆Solutionsin◆unit-doseoftheshellfromtherespectivegrossweight◆.Calculatethedrugsubstancecontentofeachcapsulefromthe◆netcontainers◆◆andintoweight◆oftheindividualcapsulecontent◆andtheresultofsoftcap-theAssay.Calculatetheacceptancevalue.sules◆WVWVOthersCUCUSoftCapsulesAccuratelyweigh10intactcapsulesindividuallytoobtain◆theirgrossweights◆,takingcaretopreservetheidentityofCONTENTUNIFORMITYeachcapsule.Thencutopenthecapsulesbymeansofasuitableclean,drycuttinginstrumentsuchasscissorsoraSelectnotfewerthan30units,andproceedasfollowsforsharpopenblade,andremovethecontentsbywashingthedosageformdesignated.withasuitablesolvent.Allowtheoccludedsolventtoevap-Wheredifferentproceduresareusedforassayoftheprep-oratefromtheshellsatroomtemperatureoveraperiodofarationandfortheContentUniformitytest,itmaybeneces-about30minutes,takingprecautionstoavoiduptakeorlosssarytoestablishacorrectionfactortobeappliedtotheofmoisture.Weightheindividualshells,andcalculatetheresultsofthelatter.netcontents.Calculatethedrugsubstancecontentineach◆capsulefromtheweight◆ofproductremovedfromtheSolidDosageFormsindividualcapsulesandtheresultoftheAssay.Calculatetheacceptancevalue.Assay10unitsindividuallyusinganappropriateanalyticalmethod.Calculatetheacceptancevalue(seeTable2).SolidDosageFormsOtherThanTabletsandCapsulesLiquidorSemi-SolidDosageFormsProceedasdirectedforHardCapsules,treatingeachunitAssay10unitsindividuallyusinganappropriateanalyticalasdescribedtherein.Calculatetheacceptancevalue.method.Carryouttheassayontheamountofwell-mixedmaterialthatisremovedfromanindividualcontainerinconditionsofnormaluse,andexpresstheresultsasdeliv-LiquidDosageFormsereddose.Calculatetheacceptancevalue(seeTable2).Accuratelyweightheamountofliquidthatisremovedfromeachof10individualcontainersinconditionsofnor-CalculationofAcceptanceValuemaluse.Ifnecessary,computetheequivalentvolumeafterdeterminingthedensity.Calculatethedrugsubstancecon-Calculatetheacceptancevaluebytheformula:tentineachcontainerfromthemassofproductremovedfromtheindividualcontainersandtheresultoftheAssay.Calculatetheacceptancevalue.inwhichthetermsareasdefinedinTable2.CalculationofAcceptanceValueCalculatetheacceptancevalueasshowninContentUni-◆WEIGHT◆VARIATIONformity,exceptthattheindividualcontentsoftheunitsarereplacedwiththeindividualestimatedcontentsdefinedCarryoutanassayforthedrugsubstance(s)onarepre-below.sentativesampleofthebatchusinganappropriateanalyti-calmethod.ThisvalueisresultA,expressedaspercentageχ1,χ2,…,χn=individualestimatedcontentsoftheunitsoflabelclaim(seeCalculationofAcceptanceValue).Assumetested,whereχi=wi×A/Wthattheconcentration(weightofdrugsubstanceper◆w1,w2,…,wn=individualweights◆oftheunitstestedweightofdosageunit)isuniform.Selectnotfewerthan30A=contentofdrugsubstance(%oflabelclaim)dosageunits,andproceedasfollowsforthedosageformobtainedusinganappropriateanalyticaldesignated.method◆W=meanofindividualweights◆UncoatedorFilm-CoatedTablets(w1,w2,…,wn)Accuratelyweigh10tabletsindividually.Calculatethecontent,expressedaspercentageoflabelclaim,ofeach◆tabletfromtheweight◆oftheindividualtabletandtheresultoftheAssay.Calculatetheacceptancevalue.OfficialfromAugust1,2013Copyright(c)2013TheUnitedStatesPharmacopeialConvention.Allrightsreserved.Accessedfrom1.202.191.189bysttage1onMonFeb2522:04:21EST2013USP36PhysicalTests/〈905〉UniformityofDosageUnits433CRITERIAequaltoL1%.Iftheacceptancevalueis>L1%,testthenext20units,andcalculatetheacceptancevalue.There-Applythefollowingcriteria,unlessotherwisespecified.quirementsaremetifthefinalacceptancevalueofthe30◆dosageunitsis≤L1%,andnoindividualcontentofany◆dosageunitislessthan[1−(0.01)(L2)]Mnormorethan◆Solid,Semi-Solid,andLiquidDosageForms[1+(0.01)(L2)]Masspecified◆intheCalculationofAccep-◆tanceValueunderContentUniformityorunderWeight◆Vari-Therequirementsfordosageuniformityaremetiftheac-ation.Unlessotherwisespecified,L1is15.0andL2is25.0.ceptancevalueofthefirst10dosageunitsislessthanorTable2VariableDefinitionConditionsValueMeanofindividualcontents(χ1,χ2,…,χn),expressedasaper-Xcentageofthelabelclaimχ1,χ2,…,χnIndividualcontentsoftheunitstested,expressedasapercentageofthelabelclaimnSamplesize(numberofunitsinasample)kAcceptabilityconstantIfn=10,thenk=2.4Ifn=30,thenk=2.0sSamplestandarddeviationRSDRelativestandarddeviation(the100s/Xsamplestandarddeviationex-pressedasapercentageofthemean)M(case1)tobeappliedwhenReferencevalueIf98.5%≤X≤101.5%,thenM=X(AV=ks)T≤101.5M=98.5%IfX<98.5%,then(AV=98.5–X+ks)M=101.5%IfX>101.5%,then(AV=X–101.5+ks)M(case2)tobeappliedwhenReferencevalueM=XIf98.5≤X≤T,thenT>101.5(AV=ks)M=98.5%IfX<98.5%,then(AV=98.5–X+ks)M=T%IfX>T,then(AV=X–T+ks)Acceptancevalue(AV)Generalformula:(Calculationsarespecifiedaboveforthedifferentcases.)L1MaximumallowedacceptanceL1=15.0unlessotherwisespecifiedvalueL2MaximumallowedrangeforOnthelowside,nodosageunitL2=25.0unlessotherwisespecifieddeviationofeachdosageunitresultcanbelessthan[1–testedfromthecalculatedvalue(0.01)(L2)]M,whileonthehighofMside,nodosageunitresultcanbegreaterthan[1+(0.01)(L2)]M.(ThisisbasedonanL2valueof25.0.)TTargetcontentperdosageunitatthetimeofmanufacture,ex-pressedasapercentageofthelabelclaim.Unlessotherwisestat-ed,Tis100.0%,orTistheman-ufacturer’sapprovedtargetcontentperdosageunit.OfficialfromAugust1,2013Copyright(c)2013TheUnitedStatesPharmacopeialConvention.Allrightsreserved.Accessedfrom1.202.191.189bysttage1onMonFeb2522:04:21EST2013434〈911〉Viscosity/PhysicalTestsUSP36.wateroroilbathstabilizedatthetemperaturespecifiedin〈911〉VISCOSITY—CAPILLARYtheindividualmonograph,andcontrolthetemperatureto±0.1°,unlessotherwisespecifiedintheindividualmono-VISCOMETERMETHODSgraph.MaintaintheviscometerinaverticalpositionforatimeperiodofNLT30mintoallowthesampletempera-Thefollowingproceduresareusedtodeterminetheviscosityofturetoreachequilibrium.Closetube(M),andraisetheaNewtonianfluid,i.e.afluidhavingaviscositythatisinde-leveloftheliquidintube(N)toalevelabout8mmabovependentoftheshearingstressrateorrateofshear.Unlessmark(E≡h1).Keeptheliquidatthislevelbyclosingtubeotherwisedirectedintheindividualmonograph,useMethod(N)andopeningtube(M).Opentube(N),andmeasureI.thetimerequiredfortheleveloftheliquidtodropfrom•METHODI.UBBELOHDE-TYPECAPILLARYVISCOMETERmark(E≡h1)to(F≡h2),usinganappropriateaccurateApparatus:Thedeterminationmaybecarriedoutwithantimingdevice.[NOTE—InTable1,theminimumflowtimeUbbelohde-typecapillaryviscometer(Figure1)thathastheshouldbe350sforsizeno.1,and200sforallothersizes.specificationsdescribedinTable1orTable2.InTable2,theminimumflowtimeshouldbe300sforsizeno.0,and200sforallothersizes.]Calibration:Calibrateeachviscometeratthetesttempera-turebyusingfluidsofknownviscositiesofappropriatevis-cositystandardstodeterminetheviscometerconstant,k.Theviscosityvaluesofthecalibrationstandardsshouldbrackettheexpectedviscosityvalueofthesampleliquid.Determinetheviscometerconstantatthesametempera-tureasthesampleliquidundertest.Calculatetheviscometerconstant,k,inmm2/s2,fromtheequation:k=η/(ρ×t)η=knownviscosityoftheliquid(mPa·s)ρ=densityoftheliquid(g/mL)t=flowtimefortheliquidtopassfromtheuppermarktothelowermark(s)CalculationofkinematicandNewtonianviscositiesofsamplefluid:Acapillaryviscometerischosensothattheflowtime,t,rangesbetween200and1000s,andthekinematicenergycorrectionistypicallylessthan1%.Iftheviscosityconstant,k,isknown,usethefollowingequationtocalculatethekinematicviscosity,v,inmm2/s,fromtheflowtime,t,ins.v=k×tIfthedensityofthefluidisknownatthetemperatureoftheviscositymeasurement,thentheNewtonianviscosity,η,inmPa·s,iscalculatedbythefollowingequation:η=v×ρρ=densityofthefluid(g/mL)Figure1.Ubbelohde-TypeCapillaryViscometerTheflowtimeofthefluidunderexaminationisthemeanofNLTthreeconsecutivedeterminations.TheresultisvalidifProcedure:Filltheviscometerthroughtube(L)withasuf-thepercentageoftherelativestandarddeviation(%RSD)ficientquantityofthesampleliquidthatisappropriateforforthethreereadingsisNMT2.0%.theviscometerbeingusedorbyfollowingthemanufactur-•METHODII.OSTWALD-TYPECAPILLARYVISCOMETERer’sinstructions.CarryouttheexperimentwiththetubeinApparatus:Thedeterminationmaybecarriedoutwithanaverticalposition.Fillbulb(A)withtheliquid,andalsoOstwald-typecapillaryviscometer(Figure2).ensurethatthelevelofliquidinbulb(B)isbelowtheexittotheventilationtube(M).ImmersetheviscometerinaTable1NominalMeasurableInternalInternalConstantKinematicDiameterVolumeDiameterSizeofViscometerViscosityRangeofTube,ofBulb,ofTube,Number(mm2/s2)(mm2/s)R(mm)(±2%)C(mL)(±5%)N(mm)10.013.5–100.645.62.8–3.21A0.036–300.845.62.8–3.220.120–1001.155.62.8–3.22A0.360–3001.515.62.8–3.231.0200–1,0002.065.63.7–4.33A3.0600–3,0002.745.64.6–5.44102,000–10,0003.705.64.6–5.44A306,000–30,0004.075.65.6–6.4510020,000–100,0006.765.66.8–7.5OfficialfromAugust1,2013Copyright(c)2013TheUnitedStatesPharmacopeialConvention.Allrightsreserved.