溶出度實(shí)驗(yàn)的開發(fā)和驗(yàn)證1092

<1092>THEDISSOLUTIONPROCEDURE:DEVELOPMENTANDVALIDATIONINTRODUCTIONPurpose目的Thedissolutionprocedure:developmentandvalidation<1092>providesacomprehensiveapproachcoveringitemstoconsiderfordevelopingandvalidatingdissolutionproceduresandtheaccompanyinganalyticalprocedures.Itaddressestheuseofautomationthroughoutthetestandprovidesguidanceandcriteriaforvalidation.Italsoaddressesthetreatmentofthedatageneratedandtheinterpretationofacceptancecriteriaforimmediate-andmodified-releasesolidoraldosageforms.溶出度試驗(yàn)的開發(fā)和驗(yàn)證<1092>目的是為溶出度的測定提供了全面的開發(fā)和驗(yàn)證的方法以及相應(yīng)的分析技術(shù)。本指導(dǎo)原則貫穿溶出度測定的全部過程，并對方法驗(yàn)證提供了指導(dǎo)和驗(yàn)證標(biāo)準(zhǔn)。同時(shí)它還涉及對普通制劑和緩釋制劑產(chǎn)生的數(shù)據(jù)和接受標(biāo)準(zhǔn)進(jìn)行說明。Scope范圍Chapter<1092>addressesthedevelopmentandvalidationofdissolutionprocedures,withafocusonsolidoraldosageforms.Manyoftheconceptspresented,however,maybeapplicabletootherdosageformsandroutesofadministration.GeneralrecommendationsaregivenwiththeunderstandingthatmodificaionsoftheapparatusandproceduresasgiveninUSPgeneralchaptersneedtobejustified.<1092>章節(jié)討論了溶出度實(shí)驗(yàn)的開發(fā)和驗(yàn)證，重點(diǎn)是口服固體制劑。所提出的許多概念也可能適用于其他劑型和給藥途徑。關(guān)于設(shè)備和方法的修改部分在USP通則中給出了合理的說明。Theorganizationof<1092>followsthesequenceofactionsoftenperformedinthedevelopmentandvalidationofadissolutiontest.Thesectionsappearinthefollowingsequence.在進(jìn)行溶解度實(shí)驗(yàn)的開發(fā)和驗(yàn)證時(shí)，常遵循指導(dǎo)原則<1092>，具體內(nèi)容如下：1.PRELIMINARYASSESSMENT(FOREARLYSTAGESOFPRODUCTDEVELOPMENT/DISSOLUTIONMETHODDEVELOPMENT)前期評估（對產(chǎn)品開發(fā)以及溶出度方法開發(fā)的前期研究評估）1.1PerformingFilterCompatibility濾膜相容性研究1.2DeterminingSolubilityandStabilityofDrugSubstanceinVariousMedia原料藥在不同溶出介質(zhì)中溶解度測定和穩(wěn)定性研究1.3ChoosingaMediumandVolume溶出介質(zhì)和體積選擇1.4ChoosinganApparatus溶出設(shè)備選擇（槳法和籃法以及其他方法）2.METHODDEVELOPMENT方法開發(fā)2.1Deaeration脫氣2.2Sinkers沉降籃2.3Agitation轉(zhuǎn)速2.4StudyDesign研究設(shè)計(jì)2.4.1TimePoints取樣時(shí)間點(diǎn)2.4.2Observations觀察2.4.3Sampling取樣2.4.4Cleaning清洗2.5DataHandling數(shù)據(jù)處理2.6DissolutionProcedureAssessment溶出方法評估3.ANALYTICALFINISH完成分析3.1SampleProcessing樣品處理3.2Filters過濾3.3Centrifugation離心3.4AnalyticalProcedure分析方法3.5SpectrophotometricAnalysis光譜分析3.6HPLC4.AUTOMATION自動(dòng)化4.1MediumPreparation介質(zhì)的配制4.2SampleIntroductionandTiming定時(shí)進(jìn)樣4.3SamplingandFiltration取樣和過濾4.4Cleaning清洗4.5OperatingSoftwareandComputationofResults操作軟件和計(jì)算的結(jié)果5.VALIDATION驗(yàn)證5.1Specificity/PlaceboInterference專屬性/安慰劑（輔料）干擾5.2LinearityandRange線性和范圍5.3Accuracy/Recovery準(zhǔn)確度/回收率5.4Precision精密度5.4.1REPEATABILITYOFANALYSIS重復(fù)性5.4.2INTERMEDIATEPRECISION/RUGGEDNESS中間精密度/耐用性5.4.3REPRODUCIBILITY重現(xiàn)性5.5Robustness耐用性5.6StabilityofStandardandSampleSolutions樣品溶液和標(biāo)準(zhǔn)溶液的穩(wěn)定性5.7ConsiderationsforAutomation自動(dòng)操作注意事項(xiàng)6.ACCEPTANCECRITERIA可接受標(biāo)準(zhǔn)6.1Immediate-ReleaseDosageForms速釋劑型6.2Delayed-ReleaseDosageForms延遲釋放劑型6.3Extended-ReleaseDosageForms延長釋放劑型6.4MultipleDissolutionTests多個(gè)溶解度試驗(yàn)6.5InterpretationofDissolutionResults溶出結(jié)果說明6.5.1IMMEDIATE-RELEASEDOSAGEFORMS即時(shí)釋放劑型6.5.2DELAYED-RELEASEDOSAGEFORMS延遲釋放劑型6.5.3EXTENDED-RELEASEDOSAGEFORMS延長釋放劑型

1.PRELIMINARYASSESSMENT(FOREARLYSTAGESOFPRODUCTDEVELOPMENT/DISSOLUTIONMETHODDEVELOPMENT)1.前期評估（對產(chǎn)品開發(fā)以及溶出度方法開發(fā)的前期研究評估）Beforemethoddevelopmentcanbegin,itisimportanttocharacterizethemoleculesothatthefilter,medium,volumeofmedium,andapparatuscanbechosenproperlyinordertoevaluatetheperformanceofthedosageform.在溶出方法開發(fā)之前，了解顆粒的性質(zhì)是非常重要的，以便對用以評估制劑溶出行為的濾膜、溶出介質(zhì)、溶出介質(zhì)體積和溶出設(shè)備進(jìn)行恰當(dāng)?shù)暮Y選。1.1PerformingFilterCompatibility1.1濾膜相容性研究Filtrationisakeysample-preparationstepinachievingaccuratetestresults.Thepurposeoffiltrationistoremoveundissolveddrugandexcipientsfromthewithdrawnsolution.Ifnotremovedfromthesamplesolution,particlesofthedrugwillcontinuetodissolveandcanbiastheresults.Therefore,filteringthedissolutionsamplesisusuallynecessaryandshouldbedoneimmediatelyifthefilterisnotpositionedonthecannula.為獲得準(zhǔn)確試驗(yàn)結(jié)果，過濾是樣品制備的一個(gè)關(guān)鍵步驟。過濾的目的是為了除去溶出液中未溶解的藥物和輔料。如果不把未溶解的藥物和輔料從樣品溶液中除去，那么未溶解的藥物顆粒將會(huì)繼續(xù)溶解使試驗(yàn)結(jié)果出現(xiàn)偏差。因此，對溶出液進(jìn)行過濾通常是必須的，如果取樣管中沒有過濾器，應(yīng)立即對溶出度樣品進(jìn)行過濾。Filtrationalsoremovesinsolubleexcipientsthatmayotherwiseinterferewiththeanalyticalfinish.Selectionoftheproperfiltermaterialisimportantandshouldbeaccomplished,andexperimentallyjustified,earlyinthedevelopmentofthedissolutionprocedure.Importantcharacteristicstoconsiderwhenchoosingafiltermaterialaretype,size,andporesize.Thefilterthatisselectedbasedonevaluationduringtheearlystagesofdissolutionproceduredevelopmentmayneedtobereconsideredatalatertimepoint.Requalificationhastobeconsideredafterachangeincompositionofthedrugproductorchangesinthequalityoftheingredients(e.g.particlesizeofmicrocrystallinecellulose).過濾也可除去可能會(huì)干擾分析測定的不溶性輔料。選擇適當(dāng)?shù)倪^濾材料是非常重要，應(yīng)該在早期溶出方法開發(fā)的過程中通過實(shí)驗(yàn)確定和完成。在選擇濾膜時(shí)有必要重點(diǎn)考慮濾膜的材料、尺寸和孔徑大小。通常對早期階段溶出方法開發(fā)過程的評價(jià)選擇過濾器，但在后期試驗(yàn)中如果制劑成分改變或組成成分質(zhì)量變化可能需要重新考慮過濾器（例如：微晶纖維素粒徑的改變）。Examplesoffiltersusedindissolutiontestingcanbecannulafilters,filterdisksorfrits,filtertips,orsyringefilters.Thefiltermaterialhastobecompatiblewiththemediaandthedrug.Commonporesizesrangefrom0.20to70μm,however,filtersofotherporesizescanbeusedasneeded.Ifthedrugsubstanceparticlesizeisverysmall(e.g.,micronizedornanoparticles),itcanbechallengingtofindafilterporesizethatexcludesthesesmallparticles.用于溶出試驗(yàn)的過濾器有管路過濾器、過濾盤或玻璃過濾器、濾頭或針頭式過濾器。過濾材料必須與介質(zhì)和藥物相兼容。常見孔徑大小范圍：0.20～70μm，如果需要也可使用其他孔徑大小的過濾器。如果原料藥的粒度很小（例如，微分化顆?；蚣{米顆粒），找到一個(gè)合適的過濾器過濾這些小顆粒至今仍具有挑戰(zhàn)性。Adsorptionofthedrug(s)bythefiltermayoccurandneedstobeevaluated.Filtermaterialswillinteractwithdissolutionmediatoaffecttherecoveryoftheindividualsolutesandmustbeconsideredonacase-by-casebasis.Differentfiltermaterialsexhibitdifferentdrug-bindingproperties.Percentageofdruglossfromthefiltrateduetobindingmaybedependentonthedrugconcentration.Thereforetheadsorptiveinterferenceshouldbeevaluatedonsamplesolutionsatdifferentconcentrationsbracketingtheexpectedconcentrationrange.Wherethedrugadsorptionissaturable,discardinganinitialvolumeoffiltratemayallowthecollectionofasubsequentsolutionthatapproachestheoriginalsolutionconcentration.Alternativefiltermaterialsthatminimizeadsorptiveinterferencecanusuallybefound.Prewettingofthefilterwiththemediummaybenecessary.Inaddition,itisimportantthatleachablesfromthefilterdonotinterferewiththeanalyticalprocedure.Thiscanbeevaluatedbyanalyzingthefiltereddissolutionmediumandcomparingitwiththeunfilteredmedium.過濾時(shí)可能會(huì)發(fā)生藥物的吸附，并需要進(jìn)行評估。過濾材料將與溶出介質(zhì)相互作用，影響每個(gè)溶質(zhì)的回收率應(yīng)該根據(jù)具體問題進(jìn)行考慮。不同的過濾材料表現(xiàn)出與藥物結(jié)合的不同特性。由于藥物與濾膜結(jié)合引起藥物從濾液中損失的比例，可能依賴于藥物濃度。因此，應(yīng)采用預(yù)期濃度范圍內(nèi)不同濃度的樣品溶液來評估濾膜吸附干擾。由于藥物吸附是可飽和的，棄去一定體積的初濾液，收集續(xù)濾液，以達(dá)到接近原來的溶液濃度的樣品也是可取的。通常選擇適合的過濾材料，最大限度地減少濾膜吸附干擾，潤濕濾膜對減少吸附也是必要的。此外，從濾膜中濾出物不干擾分析檢測也是非常重要的，一般可以通過溶出介質(zhì)過濾前后進(jìn)行比較得知，濾膜是否干擾樣品的測定。Thefiltersizeshouldbebasedonthevolumetobewithdrawnandtheamountofparticlestobeseparated.Useofthecorrectfilterdimensionswillimprovethroughputandrecovery,andalsoreduceclogging.Useofalargefilterforsmall-volumefiltrationcanleadtolossofsamplethroughhold-upvolume,whereasfiltrationthroughsmallfiltersizesneedshigherpressuresandlongertimes,andthefilterscanclogquickly.根據(jù)要過濾樣品溶液的體積以及要濾除的顆粒量來選擇濾膜尺寸。使用正確的濾膜尺寸將提高溶液的通過率和回收率，并減少濾膜堵塞。使用大尺寸濾膜過濾小體積溶液，將導(dǎo)致樣品溶液損失量過大而收集不到所用樣品量；反正，使用小尺寸濾膜過濾，需要更高的壓力和較長的時(shí)間，并且溶液迅速堵塞濾膜。FiltersusedforUSPapparatus4needspecialattentionbecausetheyareintegratedintheflow-throughprocess.Undissolvedparticlesmaydepositonthefilters,creatingresistancetotheflow.USP儀器4中使用的過濾器需要特別注意，因?yàn)樗鼈冊诹鲃?dòng)過程中使用。不溶顆粒會(huì)沉積在過濾器，產(chǎn)生流動(dòng)阻力。Inthecaseofautomatedsystems,selectionofthefilterwithregardtomaterialandporesizecanbedoneinasimilarmannertomanualfiltration.Flowratethroughthefilterandcloggingmaybecriticalforfiltersusedinautomatedsystems.Experimentalverificationthatafilterisappropriatemaybeaccomplishedbycomparingtheresponsesforfilteredandunfilteredstandardandsamplesolutions.Thisisdonebyfirstpreparingasuitablestandardsolutionandasamplesolution.Forexample,prepareatypicaldissolutionsampleinabeakerandstirvigorouslywithamagneticstirrertodissolvethedrugloadcompletely.Forstandardsolutions,comparetheresultsforfilteredsolutions(afterdiscardingtheappropriatevolume)tothosefortheunfilteredsolutions.Forsamplesolutions,comparetheresultsforfilteredsolutions(afterdiscardingtheappropriatevolume)tothoseforcentrifuged,unfilteredsolutions.在自動(dòng)化系統(tǒng)的情況下，關(guān)于過濾器濾膜材料和孔徑大小可以用類似的方式通過手動(dòng)過濾進(jìn)行選擇。在自動(dòng)化系統(tǒng)中通過過濾器的流量和過濾器的堵塞可能是至關(guān)重要的。通過試驗(yàn)比較過濾和未過濾的標(biāo)準(zhǔn)溶液和樣品溶液的含量差別，驗(yàn)證該過濾器是合適的。首先制備一個(gè)合適的標(biāo)準(zhǔn)溶液和樣品溶液。例如，在燒杯中制備一個(gè)標(biāo)準(zhǔn)溶解樣品，用磁力攪拌器攪拌使藥物完全溶解。對于標(biāo)準(zhǔn)溶液，比較過濾溶液（棄去的適當(dāng)體積后）和未過濾溶液的含量測定結(jié)果；對于樣品溶液，比較過濾（棄去適當(dāng)體積后）、離心、未過濾樣品溶液的含量測定結(jié)果。1.2DeterminingSolubilityandStabilityofDrugSubstanceinVariousMedia1.2原料藥在不同溶出介質(zhì)中的溶解度測定和穩(wěn)定性研究Physicalandchemicalcharacteristicsofthedrugsubstanceneedtobedeterminedaspartoftheprocessofselectingtheproperdissolutionmedium.Whendecidingthecompositionofthemediumfordissolutiontesting,itisimportanttoevaluatetheinfluenceofbuffers,pH,andifneeded,differentsurfactantsonthesolubilityandstabilityofthedrugsubstance.Solubilityofthedrugsubstanceisusuallyevaluatedbydeterminingthesaturationconcentrationofthedrugindifferentmediaat37?usingtheshake-flasksolubilitymethod(equilibriumsolubility).Toleveloutpotentialioneffectsbetweenthedrugandthebuffersusedinthemedia,mixturesofhydrochloricacidandsodiumhydroxideareusedtoperformsolubilityinvestigations;thisisinadditiontothetypicalbuffersolutions.Incertaincases,itmaybenecessarytoevaluatethesolubilityofthedrugattemperatureotherthan37?(i.e.,25?).ThepHoftheclearsupernatantshouldbecheckedtodeterminewhetherthepHchangesduringthesolubilitytest.Alternativeapproachesforsolubilitydeterminationmayalsobeused.在選擇合適溶出介質(zhì)的過程中，需要確定原料藥的物理化學(xué)特性。當(dāng)需要確定溶出度試驗(yàn)中溶出介質(zhì)的組成時(shí)，有必要評估緩沖液、pH值、以及不同的表面活性劑（如果需要）對藥物的溶解度和穩(wěn)定性的影響。在37℃溫度條件下，采用搖瓶溶解法（平衡溶解度）測定原料藥在不同介質(zhì)中的飽和濃度，來評估藥物的溶解性。為了消除溶出介質(zhì)中藥物和緩沖液之間離子的潛在影響，使用鹽酸和氫氧化鈉的混合物對溶解度進(jìn)行研究，這是一種典型的緩沖溶液。在某些情況下，評估藥物在37℃以外條件下（即，25℃）的溶解度可能也是必要的。在溶解度試驗(yàn)過程中應(yīng)檢查上清溶液的pH值，以確定在溶解過程中pH值是否改變。也可使用其他可供選擇的方法進(jìn)行溶解度測定。Typicalmediafordissolutionmayincludethefollowing(notlistedinorderofpreference):dilutedhydrochloricacid;buffers(phosphateoracetate)inthephysiologicpHrangeof1.2–7.5;simulatedgastricorintestinalfluid(withorwithoutenzymes);andwater.Forsomedrugs,incompatibilityofthedrugwithcertainbuffersorsaltsmayinfluencethechoiceofbuffer.Themolarityofthebuffersandacidsusedcaninfluencethesolubilizingeffect,andthisfactormaybeevaluated.溶出的典型介質(zhì)包括（未按照優(yōu)先順序列出）：稀鹽酸、在生理pH值范圍為1.2-7.5緩沖溶液（磷酸鹽或者醋酸鹽）、模擬胃液或腸液（含有或不含有酶）和水。對于一些藥物，與藥物不相容的特定緩沖液或鹽可能會(huì)影響緩沖劑的選擇。所使用的緩沖液和酸的體積摩爾濃度能夠改變藥物的增溶作用，這個(gè)因素也需要評估。Aqueoussolutions(acidicorbuffersolutions)maycontainapercentageofasurfactant[e.g.,sodiumdodecylsulfate(SDS),polysorbate,orlauryldimethylamineoxide]toenhancethesolubilityofthedrug.Thesurfactantsselectedforthesolubilityinvestigationsshouldcoverallcommonsurfactanttypes,i.e.,anionic,nonionic,andcationic.Whenasuitablesurfactanthasbeenidentified,differentconcentrationsofthatsurfactantshouldbeinvestigatedtoidentifythelowestconcentrationneededtoachievesinkconditions.Typically,thesurfactantconcentrationisaboveitscriticalmicellarconcentration(CMC).Table1showsalistofsomeofthesurfactantsusedindissolutionmedia.ApproximateCMCvaluesareprovidedwithreferenceswhenavailable.Thelistisnotcomprehensiveandisnotintendedtoexcludesurfactantsthatarenotlisted.Othersubstances,suchashydroxypropylβ-cyclodextrin,havebeenusedasdissolutionmediaadditivestoenhancedissolutionofpoorlysolublecompounds.TheU.S.FoodandDrugAdministration(FDA)maintainsadatabaseofdissolutionmethods,includinginformationondissolutionmediathathavebeenused(1).Typically,theamountofsurfactantaddedissufficienttoachievesinksonditioninthedesiredvolumeofdissolutionmedium.有時(shí)候水溶性介質(zhì)中（酸性水溶液或緩沖溶液）可能添加一定比例的表面活性劑（如十二烷基硫酸鈉（SDS），聚山梨醇酯，或十二烷基二甲基氧化胺）以提高藥物的溶解度。選擇用于溶解度研究的表面活性劑時(shí)應(yīng)涵蓋所有常用種類的表面活性劑，比如陰離子、非離子型和陽離子，當(dāng)已經(jīng)確定一個(gè)合適的表面活性劑時(shí)，應(yīng)對表面活性劑的不同濃度進(jìn)行研究，以確定達(dá)到漏槽條件所需的最低濃度。一般情況下，表面活性劑的濃度高于它的臨界膠束濃度（CMC）。表1列出了溶出介質(zhì)中常用的表面活性劑，表中提供了CMC的近似臨界值，以便我們參考，此外，表中所列表面活性劑并不全面，不能排除未列出的表面活性劑。其他表面活性劑，如羥丙基β-環(huán)糊精，已被用來作為溶出介質(zhì)添加劑提高難溶性化合物的溶解度，美國食品藥品管理局（FDA）溶出度數(shù)據(jù)庫中，已經(jīng)收載含有羥丙基β-環(huán)糊精的溶出介質(zhì)（1）。通常情況下，表面活性劑的加入量以滿足達(dá)到漏槽條件所需的溶出介質(zhì)體積。Itisimportanttocontrolthegradeandpurityofsurfactantsbecauseuseofdifferentgradescouldaffectthesolubilityofthedrug.Forexample,SDSisavailableinbothatechnicalgradeandahigh-puritygrade.Obtainingpolysorbate80fromdifferentsourcescanaffectitssuitabilitywhenperforminghigh-performanceliquidchromatography(HPLC)analysis.由于使用不同級別的表面活性劑會(huì)影響藥物的溶解度，因此要控制表面活性劑的級別和純度。例如，SDS只有在工業(yè)級和高純度級才可以使用。在使用HPLC方法進(jìn)行分析時(shí)，不同來源的聚山梨酯（吐溫）80會(huì)影響它的適用性。Theremaybeeffectsofcounter-ionsorpHonthesolubilityorsolutionstabilityofthesurfactantsolutions.Forexample,aprecipitateformswhenthepotassiumsaltforthephosphatebufferisusedataconcentrationof0.5MincombinationwithSDS.ThiscanbeavoidedbyusingthesodiumphosphatesaltwhenpreparingmediawithSDS.反離子或pH值可能會(huì)影響表面活性劑溶液的溶解性或穩(wěn)定性。例如，當(dāng)含有SDS的磷酸鹽緩沖液中鉀鹽濃度為0.5mol/L時(shí)，就形成了沉淀析出，但是使用磷酸鈉制備含有SDS的介質(zhì)時(shí)，可以避免這種現(xiàn)象發(fā)生。Table1.CommonlyUsedSurfactantswithCriticalMicelleConcentrations表1常見表面活性劑的臨界膠束濃度Surfactant表面活性劑CMC

(%Wt/Volume)Ref.Anionic陰離子Sodiumdodecylsulfate(SDS),Sodiumlaurylsulfate(SLS)十二烷基硫酸鈉0.18–0.23%(2–4)Taurocholicacidsodiumsalt牛黃膽酸鈉0.2%(3)Cholicacidsodiumsalt膽酸鈉0.16%(3)Desoxycholicacidsodiumsalt脫氧膽酸鈉0.12%(3)Cationic陽離子Cetyltrimethylammoniumbromide(CTAB,Hexadecyltrimethylammoniumbromide)十六烷基三甲基溴化銨0.033%–0.036%

(0.92–1.0mM)(5,6)Benzethoniumchloride(Hyamine1622)芐索氯銨0.18%(4mM)(2)Nonionic非離子Polysorbate20(Polyoxyethylene(20)sorbitanmonolaurate,Tween20)聚山梨酯20（吐溫20）0.07%–0.09%(3,7)Polysorbate80(Polyoxyethylene(80)sorbitanmonooleate,Tween80)聚山梨酯80（吐溫80）0.02%–0.08%(3,7)Caprylocaproylpolyoxyl-8glycerides(Labrasol)辛酸癸酸聚乙二醇甘油酯0.01%(4)Polyoxyl35castoroil(CremophorEL)聚氧乙烯蓖麻油350.02%(8)Polyoxyethylene23laurylether(Brij35)聚氧乙烯月桂醇醚0.013%(9)Octoxinol(TritonX-100)辛苯聚醇0.01%–0.03%(3,10)Zwitterion兩性離子LauryldimethylamineN-oxide(LDAO)月桂基二甲基胺N-氧化物0.023%(11)Routinely,thedissolutionmediumisbuffered;however,theuseofpurifiedwaterasthedissolutionmediumissuitableforproductswithadissolutionbehaviorindependentofthepHofthemedium.Thereareseveralreasonswhypurifiedwatermaynotbepreferred.Thewaterqualitycanvarydependingonitssource,andthepHofthewaterisnotasstrictlycontrolledasthepHofbuffersolutions.Additionally,thepHcanvaryfromdaytodayandcanalsochangeduringtherun,dependingonthedrugsubstanceandexcipients.Useofanaqueous–organicsolventmixtureasadissolutionmediumisdiscouraged;however,withproperjustificationthistypeofmediummaybeacceptable.通常，溶出介質(zhì)為緩沖鹽溶液，但是，對于非pH值依賴性的制劑可以使用純化水作為溶出介質(zhì)。不推薦使用純化水作為溶出介質(zhì)的原因：水的質(zhì)量變化取決于它的來源，而水的pH值不像緩沖溶液能夠嚴(yán)格控制；此外，若藥物和輔料的溶出對pH值敏感時(shí)需要考慮使用緩沖液。另外使用水-有機(jī)溶劑混合物作為溶出介質(zhì)也是不推薦的，但是，特殊情況下（有充分適當(dāng)?shù)睦碛桑彩强梢越邮艿?。Investigationsofthestabilityofthedrugsubstanceshouldbecarriedout,whenneeded,intheselecteddissolutionmediumwithexcipientspresent,at37°.Thiselevatedtemperaturehasthepotentialtodecreasesolutionstability(degradation).Stabilityshouldallowforsufficienttimetocompleteorrepeattheanalyticalprocedure.Physicalstabilitymaybeofconcernwhenprecipitationoccursbecauseoflowersolubilityatroomorrefrigeratedtemperature.必要時(shí)，應(yīng)該對原料藥的穩(wěn)定性進(jìn)行考察，在所選擇的溶出介質(zhì)中加入輔料，在37℃條件下進(jìn)行考察。這種升高的溫度會(huì)潛在的降低溶液的穩(wěn)定性（降解）。穩(wěn)定性試驗(yàn)應(yīng)考慮到有足夠的時(shí)間來完成或重復(fù)分析過程。當(dāng)因室溫或冷藏貯存時(shí)降低藥物的溶解度而發(fā)生沉淀時(shí)，物理穩(wěn)定性也需要關(guān)注。1.3ChoosingaMediumandVolume1.3溶出介質(zhì)和體積的選擇Whendevelopingadissolutionprocedure,onegoalistohavesinkconditions,whicharedefinedashavingavolumeofmediumatleastthreetimesthevolumerequiredtoformasaturatedsolutionofdrugsubstance.Whensinkconditionsarepresent,itismorelikelythatdissolutionresultswillreflectthepropertiesofthedosageform.Amediumthatfailstoprovidesinkconditionsmaybeacceptableifitisappropriatelyjustified.Thecompositionandvolumeofdissolutionmediumareguidedbythesolubilityinvestigations.Forexample,thechoiceandconcentrationofasurfactantneedtobejustifiedfromthesolubilitydataandthedissolutionprofiles.當(dāng)開發(fā)一個(gè)溶出試驗(yàn)方法時(shí)，首先要滿足漏槽條件，漏槽條件定義為溶出介質(zhì)體積至少為藥物達(dá)到飽和溶液所需體積的三倍。當(dāng)滿足漏槽條件后，溶出度結(jié)果能夠更好的反映藥物制劑的質(zhì)量。在適當(dāng)條件下，介質(zhì)不滿足漏槽條件也是可以接受的。溶解介質(zhì)的組成和體積應(yīng)根據(jù)溶解度的試驗(yàn)結(jié)果進(jìn)行調(diào)整。例如，表面活性劑種類和濃度選擇，需要根據(jù)藥物溶解度數(shù)據(jù)和溶出曲線進(jìn)行調(diào)整。Theuseofenzymesinthedissolutionmediumispermitted,inaccordancewithDissolution<711>,whendissolutionfailuresoccurasaresultofcross-linkingwithgelatincapsulesorgelatin-coatedproducts.AdiscussionofthephenomenonofcrosslinkingandmethoddevelopmentusingenzymescanbefoundinCapsules–DissolutionTestingandRelatedQualityAttributes<1094>.Validationshouldbeperformedwiththemethodusingenzymesaccordingtosection5.Validation.當(dāng)交聯(lián)明膠膠囊或明膠包衣的制劑溶出失敗時(shí)，在溶出介質(zhì)中允許加入酶，這同溶出度<711>指導(dǎo)原則一致。在“Capsules–DissolutionTestingandRelatedQualityAttributes<1094>”中可以找到發(fā)生交聯(lián)現(xiàn)象的討論和采用酶進(jìn)行方法開發(fā)的研究。根據(jù)第5節(jié)驗(yàn)證，使用酶方法按照溶出度方法學(xué)驗(yàn)證的要求進(jìn)行驗(yàn)證。Anotheroptionistousemediathatfollowmorecloselythecompositionoffluidsinthestomachandintestinaltract.Thesemediamaycontainphysiologicalsurface-activeingredients,suchastaurocholates.Themediaalsomaycontainemulsifiers(lecithin)andcomponentssuchassalinesolutionthatincreaseosmolality.Also,theionicstrengthormolarityofthebuffersolutionsmaybemanipulated.Themediaaredesignedtorepresentthefedandfastedstateinthestomachandsmallintestine.Thesemediamaybeveryusefulinmodelinginvivodissolutionbehaviorofimmediate-release(IR)dosageforms,inparticularthosecontaininglipophilicdrugsubstances,andmayhelpinunderstandingthedissolutionkineticsoftheproductrelatedtothephysiologicalmake-upofthedigestivefluids.Resultsofsuccessfulmodelingofdissolutionkineticshavebeenpublished,mainlyforIRproducts.Inthecaseofextended-releasedosageformswithreducedeffectofthedrugsubstanceondissolutionbehavior,theuseofsuchmedianeedstobeevaluateddifferently.Invitroperformancetestingdoesnotnecessarilyrequiremediamodelingthefastedandpostprandialstates(12,13).另一種選擇是使用更貼近于胃和腸道流體組分的介質(zhì)。這些溶出介質(zhì)可以含有生理表面活性成分，如牛黃膽酸。這些溶出介質(zhì)也可能含有乳化劑（卵磷脂）和增加滲透壓的組分，比如生理鹽水溶液。同時(shí)，緩沖液的離子強(qiáng)度或體積摩爾濃度是可以控制的。設(shè)計(jì)的溶出介質(zhì)模擬了進(jìn)食和空腹?fàn)顟B(tài)下的胃和腸內(nèi)狀態(tài)。這些溶出介質(zhì)對速釋制劑（IR）建立體內(nèi)溶解行為模型方面是非常有用的，特別是這些速釋制劑中含有脂溶性的原料藥，可能有助于理解和消化液的生理組成相關(guān)的制劑溶出動(dòng)力學(xué)。溶解動(dòng)力學(xué)的模型已成功建立，主要用于速釋制劑。對緩釋劑型減少藥物溶解行為的影響，使用的這些溶出介質(zhì)需要有區(qū)別地進(jìn)行評估。體外性能測試并不一定需要在空腹和餐后狀態(tài)建立溶出介質(zhì)模型。Anacidstageispartofthetestingofdelayed-releaseproductsbyMethodAorMethodBin<711>Fordrugswithacidsolubilitylessthan10%ofthelabelclaimordrugsthatdegradeinacidtheusefulnessoftheacidstageindetectingacoatingfailureiscompromised.Thiswouldbehandledonacase-by-casebasis.Possibleresolutionsincludetheadditionofsurfactanttotheacidstage,oradjustmentofthespecifications.對于腸溶制劑，酸中釋放度是溶出度的一部分（<711>方法A或者方法B）。針對于藥物標(biāo)簽中說明在酸中釋放度不得過標(biāo)示量的10%或者防止酸液中降解而進(jìn)行抗酸包衣的藥物。根據(jù)具體情況進(jìn)行解決，可能的解決方案包括：酸性介質(zhì)中添加表面活性劑或者調(diào)整質(zhì)量標(biāo)準(zhǔn)）。Duringselectionofthedissolutionmedium,careshouldbetakentoensurethatthedrugsubstanceissuitablystablethroughouttheanalysis.Insomecases,antioxidantssuchasascorbicacidmaybeusedinthedissolutionmediumtostabilizethedrug.Thereareoccasionswheresuchactionsarenotsufficient.Forcompoundsthatrapidlydegradetoformastabledegradant,monitoringthedegradantaloneorincombinationwithadrugsubstancemaybemoresuitablethananalyzingonlythedrugsubstance.InsituspectroscopictechniquestendtobelessaffectedbydegradationwhencomparedwithHPLCanalysis(includingUHPLCandotherliquidchromatographicapproaches).在選擇溶解介質(zhì)時(shí)，應(yīng)注意采取措施確保原料藥在整個(gè)分析過程中的穩(wěn)定性。在某些情況下抗氧化劑，如抗壞血酸的，可用于在溶出介質(zhì)中，以保證藥物的穩(wěn)定性。有些時(shí)候加入這些抗氧劑是不夠的?；衔锟焖俳到庑纬煞€(wěn)定的降解物，單獨(dú)監(jiān)測降解物或與原料藥聯(lián)合監(jiān)控可能比只分析原料藥更適合。與高效液相色譜分析比較（包括超高效液相色譜等液相色譜法），原位光譜分析受降解的影響較小。ForcompendialApparatus1(basket)andApparatus2(paddle),thevolumeofthedissolutionmediumcanvaryfrom500to1000mL.Usually,thevolumeneededforthedissolutiontestcanbedeterminedinordertomaintainsinkconditions.Insomecases,thevolumecanbeincreasedtobetween2and4L,usinglargervesselsanddependingontheconcentrationandsinkconditionsofthedrug;justificationforthisapproachisexpected.Inpractice,thevolumeofthedissolutionmediumisusuallymaintainedwithinthecompendialrangegivenabove.Alternatively,itmaybepreferabletoswitchtoothercompendialapparatus,suchasareciprocatingcylinder(Apparatus3),reciprocatingholder(Apparatus7),orflow-throughcell(Apparatus4).Certainapplicationsmayrequirelowvolumesofdissolutionmedia(e.g.,100–200mL)whentheuseofapaddleorbasketispreferred.Inthesecases,analternative,noncompendialapparatus(e.g.,small-volumeapparatus)maybeused.對于藥典儀器1（籃法）和儀器2（槳法），溶出介質(zhì)的體積可以從500到1000毫升不同。通常情況下，溶出介質(zhì)的體積應(yīng)當(dāng)滿足漏槽條件。在某些情況下，根據(jù)藥物的濃度和漏槽條件，可使用較大的溶出杯，體積可以增加至2～4升（這種方法必須有充分的理由）。實(shí)際上，溶出介質(zhì)的體積通常在藥典規(guī)定范圍內(nèi)?？晒┻x擇時(shí)，選用藥典規(guī)定的其他儀器也是可取的，如往復(fù)式氣缸（儀器3），往復(fù)架（儀器7），或流通池（儀器4）。當(dāng)某些儀器需要較少體積的溶出介質(zhì)（例如，100-200毫升）時(shí)，首選槳法或籃法。在這些情況下，非藥典儀器儀器（例如，體積小的儀器）也可以選擇使用。1.4ChoosinganApparatus1.4溶出設(shè)備選擇（槳法和籃法以及其他方法）Thechoiceofapparatusisbasedonknowledgeoftheformulationdesignandthepracticalaspectsofdosageformperformanceintheinvitrotestsystem.Ingeneral,acompendialapparatusshouldbeselected.根據(jù)對處方設(shè)計(jì)的認(rèn)知和體外試驗(yàn)劑型的實(shí)際特點(diǎn)選擇儀器。一般來說，首選藥典儀器。Forsolidoraldosageforms,Apparatus1andApparatus2areusedmostfrequently.WhenApparatus1orApparatus2isnotappropriate,anotherofficialapparatusmaybeused.Apparatus3(reciprocatingcylinder)hasbeenfoundespeciallyusefulforchewabletablets,softgelatincapsules,delayed-releasedosageforms,andnondisintegrating-typeproducts,suchascoatedbeads.Apparatus4(flow-throughcell)mayofferadvantagesformodified-releasedosageformsandimmediate-releasedosageformsthatcontainactiveingredientswithlimitedsolubility.Inaddition,Apparatus4mayhaveutilityformultipledosageformtypessuchassoftgelatincapsules,beadedproducts,suppositories,ordepotdosageforms,aswellassuspension-typeextended-releasedosageforms.Apparatus5(paddleoverdisk)andApparatus6(rotatingcylinder)areusefulforevaluatingandtestingtransdermaldosageforms.Apparatus7(reciprocatingholder)hasapplicationtonon-disintegrating,oralmodified-releasedosageforms,stents,andimplants,aswellastransdermaldosageforms.Forsemisoliddosageforms,thegenerallyusedapparatusincludetheverticaldiffusioncell,immersioncell,andflow-throughcellapparatuswiththeinsertfortopicaldosageforms(seeSemisolidDrugProducts—PerformanceTests<1724>.對于口服固體制劑，儀器1和儀器2使用最多。當(dāng)儀器1或儀器2不適用時(shí)，可以使用其他官方儀器。已發(fā)現(xiàn)儀器3（往復(fù)氣缸）適用于咀嚼片、軟膠囊、緩釋制劑和不崩解型產(chǎn)品（如包衣小球）。儀器4（流通池）對活性成分的溶解度有限的緩釋劑型和速釋劑型提供了很多優(yōu)勢。此外，儀器4可用于多種劑型類型，如軟膠囊，微球制劑，栓劑，或貯庫型產(chǎn)品，以及懸浮型緩釋劑型。儀器5（槳盤）和儀器6（旋轉(zhuǎn)缸）適用于評價(jià)和測試的經(jīng)皮給藥制劑。儀器7（往復(fù)架）適用非崩解制劑，口服緩釋劑型，支架，和植入物，以及透皮制劑。半固態(tài)劑型，常用的儀器包括立式擴(kuò)散池，浸入細(xì)胞，流通單元儀器適用局部制劑（seeSemisolidDrugProducts—PerformanceTests<1724>）。Somechangescanbemadetothecompendialapparatus;forexample,abasketmeshsizeotherthanthetypical40-meshbasket(e.g.,10-,20-,or80-mesh)maybeusedwhentheneedisclearlydocumentedbysupportingdata.Caremustbetakenthatbasketsareuniformandmeetthedimensionalrequirementsspecifiedin<711>.對藥典儀器配件也可以進(jìn)行一些調(diào)整；例如，除了藥典儀器40目以外的其他規(guī)格的溶出籃（例如：10，20或者80目），通過充足的數(shù)據(jù)進(jìn)行詳細(xì)的闡明后也可以使用。必須注意的是籃網(wǎng)孔徑必須是均勻的并且滿足<711>規(guī)定的尺寸要求。Anoncompendialapparatusmayhavesomeutilitywithproperjustification,qualification,anddocumentationofsuperiorityoverthestandardequipment.Forexample,asmall-volumeapparatuswithminipaddlesandbasketsmaybeconsideredforlow-dosagestrengthproducts.Arotatingbottleordialysistubesmayhaveutilityformicrospheresandimplants,peakvessels,andmodifiedflow-throughcellsforspecialdosageformsincludingpowdersandstents.非藥典溶出儀器具有優(yōu)于藥典標(biāo)準(zhǔn)儀器的合適設(shè)備、資質(zhì)和文件。例如，一個(gè)小體積的溶出儀器配有小槳或者小籃可以用于低劑量制劑。旋轉(zhuǎn)瓶或透析管可能適用于微球、植入制劑，改進(jìn)的流通池適用于特殊劑型包括粉末和支架。2.METHODDEVELOPMENT2.方法的開發(fā)Aproperlydesignedtestshouldyielddatathatarenothighlyvariable,andshouldbefreeofsignificantstabilityproblems.Highvariabilityintheresultscanmakeitdifficulttoidentifytrendsoreffectsofformulationchanges.Samplesizecanaffecttheobservedvariability.Oneguidancedefinesdissolutionresultsashighlyvariableiftherelativestandarddeviation(RSD)ismorethan20%attimepointsof10minorlessandmorethan10%atlatertimepointsforasamplesizeof12(14).However,duringmethoddevelopment,smallersamplesizesmaybeused,andtheanalystwillneedtomakeajudgmentaccordingly.Mostdissolutionresults,however,exhibitlessvariability.Inthedevelopmentofadissolutionprocedurethesourceofthevariabilityshouldbeinvestigated,andattemptsshouldbemadetoreducevariabilitywheneverpossible.Thetwomostlikelycausesaretheformulationitself(e.g.,drugsubstance,excipients,ormanufacturingprocess)orartifactsassociatedwiththetestprocedure(e.g.,coning,tabletsstickingtothevesselwallorbasketscreen).Visualobservationsareoftenhelpfulforunderstandingthesourceofthevariabilityandwhetherthedissolutiontestitselfiscontributingtothevariability.Anytimethedosagecontentsdonotdispersefreelythroughoutthevesselinauniformfashion,aberrantresultscanoccur.Dependingontheproblem,theusualremediesincludechanginganyofthefollowingfactors:theapparatustype,speedofagitation,levelofdeaeration,sinkertype,orcompositionofthemedium.合理設(shè)計(jì)一個(gè)試驗(yàn)保證數(shù)據(jù)穩(wěn)定性（即較低的變異性），并且能夠明顯反映出樣品穩(wěn)定性問題。結(jié)果的高變異難以確定處方變化的趨勢和處方變化對溶出度結(jié)果的影響。樣本大小影響所觀察到的變異性。如果在10分鐘12個(gè)樣本的相對標(biāo)準(zhǔn)偏差（RSD）超過20%或者后續(xù)取樣點(diǎn)的RSD值大于10%，指導(dǎo)原則對溶出度試驗(yàn)結(jié)果定義為高變異性。然而，在方法開發(fā)過程中，可以使用較小的樣本量，分析者需要作出相應(yīng)的判斷。然而，大多數(shù)溶出結(jié)果都表現(xiàn)出較少的變異性。在溶出度試驗(yàn)開發(fā)過程中應(yīng)對產(chǎn)生變異的原因進(jìn)行研究，只要有可能，應(yīng)嘗試減少變異性。引起變異性的兩個(gè)最可能的原因是制劑本身（例如，原料藥，輔料，或制劑工藝）和與檢測過程相關(guān)的處理過程（例如，溶出漩渦，片粘在溶出杯壁或籃網(wǎng)上）。試驗(yàn)過程的觀察往往有助于查找產(chǎn)生變異的原因或者溶出度測定方法本身是否會(huì)產(chǎn)生變異性。任何時(shí)間內(nèi)劑量含量不能均勻地分散在整個(gè)容器中，異常結(jié)果就可能發(fā)生。根據(jù)不同的問題，通常的調(diào)節(jié)方法包括下列任何一個(gè)因素的改變：儀器，轉(zhuǎn)速，脫氣程度，沉降籃類型，或者溶出介質(zhì)的組成。Manycausesofvariabilitycanbefoundintheformulationand