USP_1092_溶出度试验的开发和验证（中英文对照版)

.PAGE/NUMPAGES溶出度试验的开发和验证【中英文对照版】INTRODUCTION前言Purpose目的TheDissolutionProcedure:DevelopmentandValidation<1092>providesacomprehensiveapproachcoveringitemstoconsiderfordevelopingandvalidatingdissolutionproceduresandtheaccompanyinganalyticalprocedures.Itaddressestheuseofautomationthroughoutthetestandprovidesguidanceandcriteriaforvalidation.Italsoaddressesthetreatmentofthedatageneratedandtheinterpretationofacceptancecriteriaforimmediate-andmodified-releasesolidoraldosageforms.溶出实验:开发和验证（1092）指导原则提供了在溶出度方法开发和验证过程中以及采用相应分析方法时需要考虑的因素。本指导原则贯穿溶出度实验的全部过程，并对方法提供了指导和验证。同时它还涉及对普通制剂和缓释制剂所生成的数据和接受标准进行说明。Scope范围Chapter<1092>addressesthedevelopmentandvalidationofdissolutionprocedures,withafocusonsolidoraldosageforms.Manyoftheconceptspresented,however,maybeapplicabletootherdosageformsandroutesofadministration.GeneralrecommendationsaregivenwiththeunderstandingthatmodificationsoftheapparatusandproceduresasgiveninUSPgeneralchaptersneedtobejustified.<1092>章节讨论了溶出度实验的开发和验证，重点是口服固体制剂。所提出的许多概念也可能适用于其他剂型和给药途径。关于设备和方法的修改部分在USP通则中给出了合理的说明。Theorganizationof<1092>followsthesequenceofactionsoftenperformedinthedevelopmentandvalidationofadissolutiontest.Thesectionsappearinthefollowingsequence.在进行溶解度实验的开发和验证时，常遵循指导原则<1092>，具体如下：1.PRELIMINARYASSESSMENT(FOREARLYSTAGESOFPRODUCTDEVELOPMENT/DISSOLUTIONMETHODDEVELOPMENT)1.前期评估（对产品开发以及溶出度方法开发的前期研究评估）1.1PerformingFilterCompatibility1.1滤膜相容性研究1.2DeterminingSolubilityandStabilityofDrugSubstanceinVariousMedia1.2原料药在不同溶出介质中溶解度测定和稳定性研究1.3ChoosingaMediumandVolume1.3溶出介质和体积选择1.4ChoosinganApparatus1.4溶出设备选择（桨法和篮法以及其他方法）2.METHODDEVELOPMENT2.方法开发2.1Deaeration2.1脱气2.2Sinkers2.2沉降篮2.3Agitation2.3转速2.4StudyDesign2.4研究2.4.1TimePoints取样时间点2.4.2Observations观察2.4.3Sampling取样2.4.4Cleaning清洗2.5DataHandling2.5数据处理2.6DissolutionProcedureAssessment2.6溶出方法评估3.ANALYTICALFINISH3.完成分析3.1SampleProcessing3.1样品处理3.2Filters3.2过滤3.3Centrifugation3.3离心3.4AnalyticalProcedure3.4分析方法3.5SpectrophotometricAnalysis3.5光谱分析3.6HPLC3.6HPLC法4.AUTOMATION4.自动化4.1MediumPreparation4.1介质的配制4.2SampleIntroductionandTiming4.2定时进样4.3SamplingandFiltration4.3取样和过滤4.4Cleaning4.4清洗4.5OperatingSoftwareandComputationofResults4.5操作软件和计算的结果5.VALIDATION5.验证5.1Specificity/PlaceboInterference5.1专属性/安慰剂（辅料）干扰5.2LinearityandRange5.2线性和范围5.3Accuracy/Recovery5.3准确度/回收率5.4Precision5.4精密度5.4.1REPEATABILITYOFANALYSIS重复性5.4.2INTERMEDIATEPRECISION/RUGGEDNESS中间精密度/耐用性5.4.3REPRODUCIBILITY重现性5.5Robustness5.5耐用性5.6StabilityofStandardandSampleSolutions5.6样品溶液和标准溶液的稳定性5.7ConsiderationsforAutomation5.7自动操作注意事项6.ACCEPTANCECRITERIA6.可接受标准6.1Immediate-ReleaseDosageForms6.1速释剂型6.2Delayed-ReleaseDosageForms6.2延迟释放剂型6.3Extended-ReleaseDosageForms6.3延长释放剂型6.4MultipleDissolutionTests6.4多个溶解度试验6.5InterpretationofDissolutionResults6.5溶出结果说明6.5.1IMMEDIATE-RELEASEDOSAGEFORMS即时释放剂型6.5.2DELAYED-RELEASEDOSAGEFORMS延迟释放剂型6.5.3EXTENDED-RELEASEDOSAGEFORMS延长释放剂型1.PRELIMINARYASSESSMENT(FOREARLYSTAGESOFPRODUCTDEVELOPMENT/DISSOLUTIONMETHODDEVELOPMENT)1.前期评估（产品开发/溶出度方法开发的初期阶段）Beforemethoddevelopmentcanbegin,itisimportanttocharacterizethemoleculesothatthefilter,medium,volumeofmedium,andapparatuscanbechosenproperlyinordertoevaluatetheperformanceofthedosageform.在开始溶出方法开发之前，我们对用以评价制剂溶出行为的滤膜、溶出介质、溶出介质体积和溶出设备进行适当的筛选是非常重要的。1.1PerformingFilterCompatibility1.1滤膜相容性研究Filtrationisakeysample-preparationstepinachievingaccuratetestresults.Thepurposeoffiltrationistoremoveundissolveddrugandexcipientsfromthewithdrawnsolution.Ifnotremovedfromthesamplesolution,particlesofthedrugwillcontinuetodissolveandcanbiastheresults.Therefore,filteringthedissolutionsamplesisusuallynecessaryandshouldbedoneimmediatelyifthefilterisnotpositionedonthecannula.为获得准确试验结果，过滤是样品制备的一个关键步骤。过滤的目的是为了除去溶出液中未溶解的药物和辅料。如果不把未溶解的药物和辅料从样品溶液中除去，那么未溶解的药物颗粒将会继续溶解使试验结果出现偏差，因此，如果取样管中没有过滤器，应立即对溶出度样品进行过滤。Filtrationalsoremovesinsolubleexcipientsthatmayotherwiseinterferewiththeanalyticalfinish.Selectionoftheproperfiltermaterialisimportantandshouldbeaccomplished,andexperimentallyjustified,earlyinthedevelopmentofthedissolutionprocedure.Importantcharacteristicstoconsiderwhenchoosingafiltermaterialaretype,filtersize,andporesize.Thefilterthatisselectedbasedonevaluationduringtheearlystagesofdissolutionproceduredevelopmentmayneedtobereconsideredatalatertimepoint.Requalificationhastobeconsideredafterachangeincompositionofthedrugproductorchangesinthequalityoftheingredients(e.g.particlesizeofmicrocrystallinecellulose).过滤也可除去可能会干扰分析测定的不溶性辅料。选择适当的过滤材料是非常重要，应该在早期溶出方法开发的过程中通过实验确定和完成。在选择滤膜时有必要重点考虑滤膜的材料、型号和孔径大小。通常对早期阶段溶出方法开发过程的评价选择过滤器，但在后期试验中如果制剂成分改变或组成成分质量变化可能需要重新考虑过滤器，（例如：微晶纤维素粒径的改变）。Examplesoffiltersusedindissolutiontestingcanbecannulafilters,filterdisksorfrits,filtertips,orsyringefilters.Thefiltermaterialhastobecompatiblewiththemediaandthedrug.Commonporesizesrangefrom0.20to70mm,however,filtersofotherporesizescanbeusedasneeded.Ifthedrugsubstanceparticlesizeisverysmall(e.g.,micronizedornanoparticles),itcanbechallengingtofindafilterporesizethatexcludesthesesmallparticles.用于溶出试验的过滤器有管路过滤器、过滤盘或玻璃过滤器、滤头或针头式过滤器。过滤材料必须与介质和药物相适合。常见孔径大小范围：0.20～70μm，如果需要也可使用其他孔径大小的过滤器。如果原料药的粒度很小（例如，微分化颗粒或纳米颗粒），找到一个合适的过滤器过滤这些小颗粒至今仍具有挑战性。Adsorptionofthedrug(s)bythefiltermayoccurandneedstobeevaluated.Filtermaterialswillinteractwithdissolutionmediatoaffecttherecoveryoftheindividualsolutesandmustbeconsideredonacase-by-casebasis.Differentfiltermaterialsexhibitdifferentdrug-bindingproperties.Percentageofdruglossfromthefiltrateduetobindingmaybedependentonthedrugconcentration.Thereforetheadsorptiveinterferenceshouldbeevaluatedonsamplesolutionsatdifferentconcentrationsbracketingtheexpectedconcentrationrange.Wherethedrugadsorptionissaturable,discardinganinitialvolumeoffiltratemayallowthecollectionofasubsequentsolutionthatapproachestheoriginalsolutionconcentration.Alternativefiltermaterialsthatminimizeadsorptiveinterferencecanusuallybefound.Prewettingofthefilterwiththemediummaybenecessary.Inaddition,itisimportantthatleachablesfromthefilterdonotinterferewiththeanalyticalprocedure.Thiscanbeevaluatedbyanalyzingthefiltereddissolutionmediumandcomparingitwiththeunfilteredmedium.过滤时可能会发生药物的吸附，需要进行评估。过滤材料将与溶出介质相互作用，影响每个溶质的回收率应该根据具体问题进行考虑。不同的过滤材料表现出与药物结合的不同特性。由于药物与滤膜结合引起药物从滤液中损失的比例，可能依赖于药物浓度。因此，应采用预期浓度范围内不同浓度的样品溶液来评估滤膜吸附干扰。由于药物吸附是可饱和的，弃去一定体积的初滤液，收集续滤液，以达到接近原来的溶液浓度的样品也是可取的。通常选择适合的过滤材料，最大限度地减少滤膜吸附干扰，润湿滤膜对减少吸附也是必要的。此外，过滤后的溶出物不干扰分析也是非常重要的，这可以通过过滤后的溶出介质过滤与未过滤的溶出介质进行比较，评估滤膜是否干扰分析测定。Thefiltersizeshouldbebasedonthevolumetobewithdrawnandtheamountofparticlestobeseparated.Useofthecorrectfilterdimensionswillimprovethroughputandrecovery,andalsoreduceclogging.Useofalargefilterforsmall-volumefiltrationcanleadtolossofsamplethroughhold-upvolume,whereasfiltrationthroughsmallfiltersizesneedshigherpressuresandlongertimes,andthefilterscanclogquickly.根据要过滤样品溶液的体积以及样品溶液中颗粒的量选择滤膜孔径。使用正确的滤膜孔径将提高溶液的通过率和回收率，并减少滤膜堵塞。使用大孔径滤膜过滤小体积溶液，能够导致样品溶液损失量过大而收集不到所用样品量；使用小孔径滤膜过滤，需要更高的压力和较长的时间，并且溶液迅速堵塞滤膜。FiltersusedforUSPApparatus4needspecialattentionbecausetheyareintegratedintheflow-throughprocess.Undissolvedparticlesmaydepositonthefilters,creatingresistancetotheflow.USP仪器4中使用的过滤器需要特别注意，因为它们在流动过程中使用。不溶颗粒会沉积在过滤器，产生流动阻力。Inthecaseofautomatedsystems,selectionofthefilterwithregardtomaterialandporesizecanbedoneinasimilarmannertomanualfiltration.Flowratethroughthefilterandcloggingmaybecriticalforfiltersusedinautomatedsystems.Experimentalverificationthatafilterisappropriatemaybeaccomplishedbycomparingtheresponsesforfilteredandunfilteredstandardandsamplesolutions.Thisisdonebyfirstpreparingasuitablestandardsolutionandasamplesolution.Forexample,prepareatypicaldissolutionsampleinabeakerandstirvigorouslywithamagneticstirrertodissolvethedrugloadcompletely.Forstandardsolutions,comparetheresultsforfilteredsolutions(afterdiscardingtheappropriatevolume)tothosefortheunfilteredsolutions.Forsamplesolutions,comparetheresultsforfilteredsolutions(afterdiscardingtheappropriatevolume)tothoseforcentrifuged,unfilteredsolutions.在自动化系统的情况下，关于过滤器滤膜材料和孔径大小可以用类似的方式通过手动过滤进行选择。在自动化系统中通过过滤器的流量和过滤器的堵塞可能是至关重要的。通过试验比较过滤和未过滤的标准溶液和样品溶液的含量差别，验证该过滤器是合适的。首先制备一个合适的标准溶液和样品溶液。例如，在烧杯中制备一个标准溶解样品，用磁力搅拌器搅拌使药物完全溶解。对于标准溶液，比较过滤溶液（弃去的适当体积后）和未过滤溶液的含量测定结果；对于样品溶液，比较过滤（弃去适当体积后）、离心、未过滤样品溶液的含量测定结果。1.2DeterminingSolubilityandStabilityofDrugSubstanceinVariousMedia1.2原料药在不同溶出介质中的溶解度测定和稳定性研究Physicalandchemicalcharacteristicsofthedrugsubstanceneedtobedeterminedaspartoftheprocessofselectingtheproperdissolutionmedium.Whendecidingthecompositionofthemediumfordissolutiontesting,itisimportanttoevaluatetheinfluenceofbuffers,pH,andifneeded,differentsurfactantsonthesolubilityandstabilityofthedrugsubstance.Solubilityofthedrugsubstanceisusuallyevaluatedbydeterminingthesaturationconcentrationofthedrugindifferentmediaat37°usingtheshake-flasksolubilitymethod(equilibriumsolubility).Toleveloutpotentialioneffectsbetweenthedrugandthebuffersusedinthemedia,mixturesofhydrochloricacidandsodiumhydroxideareusedtoperformsolubilityinvestigations;thisisinadditiontothetypicalbuffersolutions.Incertaincases,itmaybenecessarytoevaluatethesolubilityofthedrugattemperaturesotherthan37°(i.e.,25°).ThepHoftheclearsupernatantshouldbecheckedtodeterminewhetherthepHchangesduringthesolubilitytest.Alternativeapproachesforsolubilitydeterminationmayalsobeused.在选择合适溶出介质的过程中，需要确定原料药的物理化学特性。当需要确定溶出度试验中溶出介质的组成时，有必要评估缓冲液、pH值、以及不同的表面活性剂（如果需要）对药物的溶解度和稳定性的影响。在37℃温度条件下，采用摇瓶溶解法（平衡溶解度）测定原料药在不同介质中的饱和浓度，来评估药物的溶解性。为了消除溶出介质中药物和缓冲液之间离子的潜在影响，使用盐酸和氢氧化钠的混合物对溶解度进行研究，这是一种典型的缓冲溶液。在某些情况下，评估药物在37℃以外条件下（即，25℃）的溶解度可能也是必要的。在溶解度试验过程中应检查上清溶液的pH值，以确定在溶解过程中pH值是否改变。也可使用其他可供选择的方法进行溶解度测定。Typicalmediafordissolutionmayincludethefollowing(notlistedinorderofpreference):dilutedhydrochloricacid,buffers(phosphateoracetate)inthephysiologicpHrangeof1.2–7.5,simulatedgastricorintestinalfluid(withorwithoutenzymes),andwater.Forsomedrugs,incompatibilityofthedrugwithcertainbuffersorsaltsmayinfluencethechoiceofbuffer.Themolarityofthebuffersandacidsusedcaninfluencethesolubilizingeffect,andthisfactormaybeevaluated.溶出的典型介质包括（未按照优先顺序列出）：稀盐酸、在生理pH值范围为缓冲溶液（磷酸盐或者醋酸盐）、模拟胃液或肠液（含有或不含有酶）和水。对于一些药物，与药物不相容的特定缓冲液或盐可能会影响缓冲剂的选择。所使用的缓冲液和酸的体积摩尔浓度能够改变药物的增溶作用，这个因素也需要评估。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,suchashydroxypropylb-cyclodextrin,havebeenusedasdissolutionmediaadditivestoenhancedissolutionofpoorlysolublecompounds.TheU.S.FoodandDrugAdministration(FDA)maintainsadatabaseofdissolutionmethods,includinginformationondissolutionmediathathavebeenused(1).Typically,theamountofsurfactantaddedissufficienttoachievesinkconditionsinthedesiredvolumeofdissolutionmedium.有时候水溶性介质中（酸性水溶液或缓冲溶液）可能添加一定比例的表面活性剂（如十二烷基硫酸钠（SDS），聚山梨醇酯，或十二烷基二甲基氧化胺）以提高药物的溶解度。选择用于溶解度研究的表面活性剂时应涵盖所有常用种类的表面活性剂，比如阴离子、非离子型和阳离子，当已经确定一个合适的表面活性剂时，应对表面活性剂的不同浓度进行研究，以确定达到漏槽条件所需的最低浓度。一般情况下，表面活性剂的浓度高于它的临界胶束浓度（CMC）。表1列出了溶出介质中常用的表面活性剂，表中提供了CMC的近似临界值，以便我们参考，此外，表中所列表面活性剂并不全面，不能排除未列出的表面活性剂。其他表面活性剂，如羟丙基β-环糊精，已被用来作为溶出介质添加剂提高难溶性化合物的溶解度，美国食品药品管理局（FDA）溶出度数据库中，已经收载含有羟丙基β-环糊精的溶出介质（1）。通常情况下，表面活性剂的加入量以满足达到漏槽条件所需的溶出介质体积。Itisimportanttocontrolthegradeandpurityofsurfactantsbecauseuseofdifferentgradescouldaffectthesolubilityofthedrug.Forexample,SDSisavailableinbothatechnicalgradeandahigh-puritygrade.Obtainingpolysorbate80fromdifferentsourcescanaffectitssuitabilitywhenperforminghigh-performanceliquidchromatography(HPLC)analysis.由于使用不同级别的表面活性剂会影响药物的溶解度，因此要控制表面活性剂的级别和纯度。例如，SDS只有在工业级和高纯度级才可以使用。在使用HPLC方法进行分析时，不同来源的聚山梨酯（吐温）80会影响它的适用性。Theremaybeeffectsofcounter-ionsorpHonthesolubilityorsolutionstabilityofthesurfactantsolutions.Forexample,aprecipitateformswhenthepotassiumsaltforthephosphatebufferisusedataconcentrationof0.5MincombinationwithSDS.ThiscanbeavoidedbyusingthesodiumphosphatesaltwhenpreparingmediawithSDS.反离子或pH值可能会影响表面活性剂溶液的溶解性或稳定性。例如，当含有SDS的磷酸盐缓冲液中钾盐浓度为0.5mol/L时，就形成了沉淀析出，但是使用磷酸钠制备含有SDS的介质时，可以避免这种现象发生。Table1.CommonlyUsedSurfactantswithCriticalMicelleConcentrations表1常见表面活性剂的临界胶束浓度Routinely,thedissolutionmediumisbuffered;however,theuseofpurifiedwaterasthedissolutionmediumissuitableforproductswithadissolutionbehaviorindependentofthepHofthemedium.Thereareseveralreasonswhypurifiedwatermaynotbepreferred.Thewaterqualitycanvarydependingonitssource,andthepHofthewaterisnotasstrictlycontrolledasthepHofbuffersolutions.Additionally,thepHcanvaryfromdaytodayandcanalsochangeduringtherun,dependingonthedrugsubstanceandexcipients.Useofanaqueous–organicsolventmixtureasadissolutionmediumisdiscouraged;however,withproperjustificationthistypeofmediummaybeacceptable.通常，溶出介质为缓冲盐溶液，但是，对于非pH值依赖性的制剂可以使用纯化水作为溶出介质。不推荐使用纯化水作为溶出介质的原因：水的质量变化取决于它的来源，而水的pH值不像缓冲溶液能够严格控制；此外，若药物和辅料的溶出对pH值敏感时需要考虑使用缓冲液。另外使用水-有机溶剂混合物作为溶出介质也是不推荐的，但是，特殊情况下（有充分适当的理由），也是可以接受的。Investigationsofthestabilityofthedrugsubstanceshouldbecarriedout,whenneeded,intheselecteddissolutionmediumwithexcipientspresent,at37°.Thiselevatedtemperaturehasthepotentialtodecreasesolutionstability(degradation).Stabilityshouldallowforsufficienttimetocompleteorrepeattheanalyticalprocedure.Physicalstabilitymaybeofconcernwhenprecipitationoccursbecauseoflowersolubilityatroomorrefrigeratedtemperature.必要时，应该对原料药的稳定性进行考察，在所选择的溶出介质中加入辅料，在37℃条件下进行考察。这种升高的温度会潜在的降低溶液的稳定性（降解）。稳定性试验应考虑到有足够的时间来完成或重复分析过程。当因室温或冷藏贮存时降低药物的溶解度而发生沉淀时，物理稳定性也需要关注。1.3ChoosingaMediumandVolume1.3溶出介质和体积的选择Whendevelopingadissolutionprocedure,onegoalistohavesinkconditions,whicharedefinedashavingavolumeofmediumatleastthreetimesthevolumerequiredtoformasaturatedsolutionofdrugsubstance.Whensinkconditionsarepresent,itismorelikelythatdissolutionresultswillreflectthepropertiesofthedosageform.Amediumthatfailstoprovidesinkconditionsmaybeacceptableifitisappropriatelyjustified.Thecompositionandvolumeofdissolutionmediumareguidedbythesolubilityinvestigations.Forexample,thechoiceandconcentrationofasurfactantneedtobejustifiedfromthesolubilitydataandthedissolutionprofiles.当开发一个溶出试验方法时，首先要满足漏槽条件，漏槽条件定义为溶出介质体积至少为药物达到饱和溶液所需体积的三倍。当满足漏槽条件后，溶出度结果能够更好的反映药物制剂的质量。在适当条件下，介质不满足漏槽条件也是可以接受的。溶解介质的组成和体积应根据溶解度的试验结果进行调整。例如，表面活性剂种类和浓度选择，需要根据药物溶解度数据和溶出曲线进行调整。Theuseofenzymesinthedissolutionmediumispermitted,inaccordancewithDissolution<711>,whendissolutionfailuresoccurasaresultofcross-linkingwithgelatincapsulesorgelatin-coatedproducts.AdiscussionofthephenomenonofcrosslinkingandmethoddevelopmentusingenzymescanbefoundinCapsules–DissolutionTestingandRelatedQualityAttributes<1094>.Validationshouldbeperformedwiththemethodusingenzymesaccordingtosection5.Validation.当交联明胶胶囊或明胶包衣的制剂溶出失败时，在溶出介质中允许加入酶，这同溶出度<711>指导原则一致。在“Capsules–DissolutionTestingandRelatedQualityAttributes<1094>”中可以找到发生交联现象的讨论和采用酶进行方法开发的研究。根据第5节验证，使用酶方法按照溶出度方法学验证的要求进行验证。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).另一种选择是使用更贴近于胃和肠道流体组分的介质。这些溶出介质可以含有生理表面活性成分，如牛黄胆酸。这些溶出介质也可能含有乳化剂（卵磷脂）和增加渗透压的组分，比如生理盐水溶液。同时，缓冲液的离子强度或体积摩尔浓度是可以控制的。设计的溶出介质模拟了进食和空腹状态下的胃和肠内状态。这些溶出介质对速释制剂（IR）建立体内溶解行为模型方面是非常有用的，特别是这些速释制剂中含有脂溶性的原料药，可能有助于理解和消化液的生理组成相关的制剂溶出动力学。溶解动力学的模型已成功建立，主要用于速释制剂。对缓释剂型减少药物溶解行为的影响，使用的这些溶出介质需要有区别地进行评估。体外性能测试并不一定需要在空腹和餐后状态建立溶出介质模型。Anacidstageispartofthetestingofdelayed-releaseproductsbyMethodAorMethodBin<711>.Fordrugswithacidsolubilitylessthan10%ofthelabelclaimordrugsthatdegradeinacidtheusefulnessoftheacidstageindetectingacoatingfailureiscompromised.Thiswouldbehandledonacase-by-casebasis.Possibleresolutionsincludetheadditionofsurfactanttotheacidstage,oradjustmentofthespecifications.对于肠溶制剂，酸中释放度是溶出度的一部分（<711>方法A或者方法B）。针对于药物标签中说明在酸中释放度不得过标示量的10%或者防止酸液中降解而进行抗酸包衣的药物。根据具体情况进行解决，可能的解决包括：酸性介质中添加表面活性剂或者调整质量标准）Duringselectionofthedissolutionmedium,careshouldbetakentoensurethatthedrugsubstanceissuitablystablethroughouttheanalysis.Insomecases,antioxidantssuchasascorbicacidmaybeusedinthedissolutionmediumtostabilizethedrug.Thereareoccasionswheresuchactionsarenotsufficient.Forcompoundsthatrapidlydegradetoformastabledegradant,monitoringthedegradantaloneorincombinationwithadrugsubstancemaybemoresuitablethananalyzingonlythedrugsubstance.InsituspectroscopictechniquestendtobelessaffectedbydegradationwhencomparedwithHPLCanalysis(includingUHPLCandotherliquidchromatographicapproaches).在选择溶解介质时，应注意采取措施确保原料药在整个分析过程中的稳定性。在某些情况下抗氧化剂，如抗坏血酸的，可用于在溶出介质中，以保证药物的稳定性。有些时候加入这些抗氧剂是不够的。化合物快速降解形成稳定的降解物，单独监测降解物或与原料药联合监控可能比只分析原料药更适合。与高效液相色谱分析比较（包括超高效液相色谱等液相色谱法），原位光谱分析受降解的影响较小。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.对于药典仪器1（篮法）和仪器2（桨法），溶出介质的体积可以从500到1000毫升不同。通常情况下，溶出介质的体积应当满足漏槽条件。在某些情况下，根据药物的浓度和漏槽条件，可使用较大的溶出杯，体积可以增加至2～4升（这种方法必须有充分的理由）。实际上，溶出介质的体积通常在药典规定范围内。可供选择时，选用药典规定的其他仪器也是可取的，如往复式气缸（仪器3），往复架（仪器7），或流通池（仪器4）。当某些仪器需要较少体积的溶出介质（例如，100-200毫升）时，首选桨法或篮法。在这些情况下，非药典仪器仪器（例如，体积小的仪器）也可以选择使用。1.4ChoosinganApparatus1.4溶出设备选择（桨法和篮法以及其他方法）Thechoiceofapparatusisbasedonknowledgeoftheformulationdesignandthepracticalaspectsofdosageformperformanceintheinvitrotestsystem.Ingeneral,acompendialapparatusshouldbeselected.根据对处方设计的认知和体外试验剂型的实际特点选择仪器。一般来说，首选药典仪器。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