USP-109溶出度試驗(yàn)的開發(fā)和驗(yàn)證中英文對(duì)照版

（1092）溶出度試驗(yàn)的開發(fā)和驗(yàn)證【中英文對(duì)照版】INTRODUCTION前言Purpose

目的TheDissolutionProcedure:DevelopmentandValidation<1092>providesacomprehensiveapproachcoveringitemstoconsiderfordevelopingandvalidatingdissolutionproceduresandtheaccompanyinganalyticalprocedures.Itaddressestheuseofautomationthroughoutthetestandprovidesguidanceandcriteriaforvalidation.Italsoaddressesthetreatmentofthedatageneratedandtheinterpretationofacceptancecriteriaforimmediate-andmodified-releasesolidoraldosageforms.溶出實(shí)驗(yàn):開發(fā)和驗(yàn)證（1092）指導(dǎo)原則提供了在溶出度方法開發(fā)和驗(yàn)證過(guò)程中以及采用相應(yīng)分析方法時(shí)需要考慮的因素。本指導(dǎo)原則貫穿溶出度實(shí)驗(yàn)的全部過(guò)程，并對(duì)方法提供了指導(dǎo)和驗(yàn)證標(biāo)準(zhǔn)。同時(shí)它還涉及對(duì)普通制劑和緩釋制劑所生成的數(shù)據(jù)和接受標(biāo)準(zhǔn)進(jìn)行說(shuō)明。Scope

范圍Chapter<1092>addressesthedevelopmentandvalidationofdissolutionprocedures,withafocusonsolidoraldosageforms.Manyoftheconceptspresented,however,maybeapplicabletootherdosageformsandroutesofadministration.GeneralrecommendationsaregivenwiththeunderstandingthatmodificationsoftheapparatusandproceduresasgiveninUSPgeneralchaptersneedtobejustified.<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(shuō)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(píng)估（對(duì)產(chǎn)品開發(fā)以及溶出度方法開發(fā)的前期研究評(píng)估）PerformingFilterCompatibility濾膜相容性研究DeterminingSolubilityandStabilityofDrugSubstanceinVariousMedia原料藥在不同溶出介質(zhì)中溶解度測(cè)定和穩(wěn)定性研究ChoosingaMediumandVolume溶出介質(zhì)和體積選擇ChoosinganApparatus溶出設(shè)備選擇（槳法和籃法以及其他方法）METHODDEVELOPMENT.方法開發(fā)Deaeration脫氣Sinkers沉降籃Agitation轉(zhuǎn)速StudyDesign2.4研究設(shè)計(jì)TimePoints取樣時(shí)間點(diǎn)Observations觀察Sampling取樣Cleaning清洗DataHandling數(shù)據(jù)處理DissolutionProcedureAssessment出方法評(píng)估ANALYTICALFINISH.完成分析SampleProcessing樣品處理Filters過(guò)濾Centrifugation離心AnalyticalProcedure分析方法SpectrophotometricAnalysis譜分析HPLCPLC法AUTOMATION.自動(dòng)化MediumPreparation介質(zhì)的配制SampleIntroductionandTiming定時(shí)進(jìn)樣SamplingandFiltration取樣和過(guò)濾Cleaning清洗OperatingSoftwareandComputationofResults作軟件和計(jì)算的結(jié)果VALIDATION.驗(yàn)證Specificity/PlaceboInterference專屬性/安慰劑（輔料）干擾LinearityandRange線性和范圍Accuracy/Recovery準(zhǔn)確度/回收率Precision5.4精密度REPEATABILITYOFANALYSIS重復(fù)性INTERMEDIATEPRECISION/RUGGEDNESS中間精密度/耐用性REPRODUCIBILITY重現(xiàn)性Robustness耐用性StabilityofStandardandSampleSolutions品溶液和標(biāo)準(zhǔn)溶液的穩(wěn)定性ConsiderationsforAutomation動(dòng)操作注意事項(xiàng)ACCEPTANCECRITERIA.可接受標(biāo)準(zhǔn)Immediate-ReleaseDosageForms速釋劑型Delayed-ReleaseDosageForms延遲釋放劑型Extended-ReleaseDosageForms延長(zhǎng)釋放劑型MultipleDissolutionTests多個(gè)溶解度試驗(yàn)InterpretationofDissolutionResults6.5溶出結(jié)果說(shuō)明IMMEDIATE-RELEASEDOSAGEFORMS即時(shí)釋放劑型DELAYED-RELEASEDOSAGEFORMS延遲釋放劑型EXTENDED-RELEASEDOSAGEFORMS延長(zhǎng)釋放劑型1.PRELIMINARYASSESSMENT(FOREARLYSTAGESOFPRODUCTDEVELOPMENT/DISSOLUTIONMETHODDEVELOPMENT).前期評(píng)估(產(chǎn)品開發(fā)/溶出度方法開發(fā)的初期階段)Beforemethoddevelopmentcanbegin,itisimportanttocharacterizethemoleculesothatthefilter,medium,volumeofmedium,andapparatuscanbechosenproperlyinordertoevaluatetheperformanceofthedosageform.在開始溶出方法開發(fā)之前，我們對(duì)用以評(píng)價(jià)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)行適當(dāng)?shù)暮Y選是非常重要的。PerformingFilterCompatibility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(guò)濾是樣品制備的一個(gè)關(guān)鍵步驟。過(guò)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，如果取樣管中沒有過(guò)濾器，應(yīng)立即對(duì)溶出度樣品進(jìn)行過(guò)濾。Filtrationalsoremovesinsolubleexcipientsthatmayotherwiseinterferewiththeanalyticalfinish.Selectionoftheproperfiltermaterialisimportantandshouldbeaccomplished,andexperimentallyjustified,earlyinthedevelopmentofthedissolutionprocedure.Importantcharacteristicstoconsiderwhenchoosingafiltermaterialaretype,filtersize,andporesize.Thefilterthatisselectedbasedonevaluationduringtheearlystagesofdissolutionproceduredevelopmentmayneedtobereconsideredatalatertimepoint.Requalificationhastobeconsideredafterachangeincompositionofthedrugproductorchangesinthequalityoftheingredients(e.g.particlesizeofmicrocrystallinecellulose).過(guò)濾也可除去可能會(huì)干擾分析測(cè)定的不溶性輔料。選擇適當(dāng)?shù)倪^(guò)濾材料是非常重要，應(yīng)該在早期溶出方法開發(fā)的過(guò)程中通過(guò)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、型號(hào)和孔徑大小。通常對(duì)早期階段溶出方法開發(fā)過(guò)程的評(píng)價(jià)選擇過(guò)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(guò)濾器，(例如：微晶纖維素粒徑的改變)。Examplesoffiltersusedindissolutiontestingcanbecannulafilters,filterdisksorfrits,filtertips,orsyringefilters.Thefiltermaterialhastobecompatiblewiththemediaandthedrug.Commonporesizesrangefrom0.20to70mm,however,filtersofotherporesizescanbeusedasneeded.Ifthedrugsubstanceparticlesizeisverysmall(e.g.,micronizedornanoparticles),itcanbechallengingtofindafilterporesizethatexcludesthesesmallparticles.用于溶出試驗(yàn)的過(guò)濾器有管路過(guò)濾器、過(guò)濾盤或玻璃過(guò)濾器、濾頭或針頭式過(guò)濾器。過(guò)濾材料必須與介質(zhì)和藥物相適合。常見孔徑大小范圍：0.20?70pm,如果需要也可使用其他孔徑大小的過(guò)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(guò)濾器過(guò)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(guò)濾時(shí)可能會(huì)發(fā)生藥物的吸附，需要進(jìn)行評(píng)估。過(guò)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(guò)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(lái)評(píng)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(lái)的溶液濃度的樣品也是可取的。通常選擇適合的過(guò)濾材料，最大限度地減少濾膜吸附干擾，潤(rùn)濕濾膜對(duì)減少吸附也是必要的。此外，過(guò)濾后的溶出物不干擾分析檢測(cè)也是非常重要的，這可以通過(guò)過(guò)濾后的溶出介質(zhì)過(guò)濾與未過(guò)濾的溶出介質(zhì)進(jìn)行比較，評(píng)估濾膜是否干擾分析測(cè)定。Thefiltersizeshouldbebasedonthevolumetobewithdrawnandtheamountofparticlestobeseparated.Useofthecorrectfilterdimensionswillimprovethroughputandrecovery,andalsoreduceclogging.Useofalargefilterforsmall-volumefiltrationcanleadtolossofsamplethroughhold-upvolume,whereasfiltrationthroughsmallfiltersizesneedshigherpressuresandlongertimes,andthefilterscanclogquickly.根據(jù)要過(guò)濾樣品溶液的體積以及樣品溶液中顆粒的量選擇濾膜孔徑。使用正確的濾膜孔徑將提高溶液的通過(guò)率和回收率，并減少濾膜堵塞。使用大孔徑濾膜過(guò)濾小體積溶液，能夠?qū)е聵悠啡芤簱p失量過(guò)大而收集不到所用樣品量；使用小孔徑濾膜過(guò)濾，需要更高的壓力和較長(zhǎng)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(guò)濾器需要特別注意，因?yàn)樗鼈冊(cè)诹鲃?dòng)過(guò)程中使用。不溶顆粒會(huì)沉積在過(guò)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(guò)濾器濾膜材料和孔徑大小可以用類似的方式通過(guò)手動(dòng)過(guò)濾進(jìn)行選擇。在自動(dòng)化系統(tǒng)中通過(guò)過(guò)濾器的流量和過(guò)濾器的堵塞可能是至關(guān)重要的。通過(guò)試驗(yàn)比較過(guò)濾和未過(guò)濾的標(biāo)準(zhǔn)溶液和樣品溶液的含量差別，驗(yàn)證該過(guò)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(duì)于標(biāo)準(zhǔn)溶液，比較過(guò)濾溶液（棄去的適當(dāng)體積后）和未過(guò)濾溶液的含量測(cè)定結(jié)果；對(duì)于樣品溶液，比較過(guò)濾（棄去適當(dāng)體積后）、離心、未過(guò)濾樣品溶液的含量測(cè)定結(jié)果。DeterminingSolubilityandStabilityofDrugSubstanceinVariousMedia1.2原料藥在不同溶出介質(zhì)中的溶解度測(cè)定和穩(wěn)定性研究Physicalandchemicalcharacteristicsofthedrugsubstanceneedtobedeterminedaspartoftheprocessofselectingtheproperdissolutionmedium.Whendecidingthecompositionofthemediumfordissolutiontesting,itisimportanttoevaluatetheinfluenceofbuffers,pH,andifneeded,differentsurfactantsonthesolubilityandstabilityofthedrugsubstance.Solubilityofthedrugsubstanceisusuallyevaluatedbydeterminingthesaturationconcentrationofthedrugindifferentmediaat37°usingtheshake-flasksolubilitymethod（equilibriumsolubility）.Toleveloutpotentialioneffectsbetweenthedrugandthebuffersusedinthemedia,mixturesofhydrochloricacidandsodiumhydroxideareusedtoperformsolubilityinvestigations;thisisinadditiontothetypicalbuffersolutions.Incertaincases,itmaybenecessarytoevaluatethesolubilityofthedrugattemperaturesotherthan37°（i.e.,25°）.ThepHoftheclearsupernatantshouldbecheckedtodeterminewhetherthepHchangesduringthesolubilitytest.Alternativeapproachesforsolubilitydeterminationmayalsobeused.在選擇合適溶出介質(zhì)的過(guò)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(píng)估緩沖液、pH值、以及不同的表面活性劑（如果需要）對(duì)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(cè)定原料藥在不同介質(zhì)中的飽和濃度，來(lái)評(píng)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(duì)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(píng)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(guò)程中應(yīng)檢查上清溶液的pH值，以確定在溶解過(guò)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(cè)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(duì)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(píng)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(yáng)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(duì)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B-環(huán)糊精，已被用來(lái)作為溶出介質(zhì)添加劑提高難溶性化合物的溶解度，美國(guó)食品藥品管理局（1口人）溶出度數(shù)據(jù)庫(kù)中，已經(jīng)收載含有羥丙基B-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(jí)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(jí)別和純度。例如，SDS只有在工業(yè)級(jí)和高純度級(jí)才可以使用。在使用HPLC方法進(jìn)行分析時(shí)，不同來(lái)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麥宜晶■愴刻二CMC1%重量，依積〕七參■李文聿M陽(yáng)離子戶-二二燒在流曦就CSDSrSLS3p0.18%-0.23^p牛磅韭醛鉆?0.2%^立，至整納戶CM5%啟" 女 '兢量悲鼓鼾卡 ,, 0.12^ '_?:陰離子戶十六烷基三甲桂魂化受CCTAB）中a3吠止。兆%CO.92-L.OmM）產(chǎn)5和軍袤篁蕓［季蕓生力G2平 1不駕于Q、要小夷,豳?zèng)r《吐遇as產(chǎn)0.07%-0.09%^3g受」賽旗80（吐浪的〕爐0.0?%-0.08%^3一*李童壹藪娶乙二郎吩通番CLabraso：）p0.01^ -: 4卡 ,衰受Z.管莖同注35CCronophorEL^^口02M鼾襄量己礴丹崔醒嬰CBrij353q’ 0.013%^李態(tài)案穿CTntonX-lOOj點(diǎn).0強(qiáng)般9福晞V3；史需性離孑Q出槌在二甲甚詼N-邕化物CLDAODQ口一曜甥B11QRoutinely,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(duì)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(lái)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(duì)pH值敏感時(shí)需要考慮使用緩沖液。另外使用水一有機(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?，也是可以接受的。Investigationsofthestabilityofthedrugsubstanceshouldbecarriedout,whenneeded,intheselecteddissolutionmediumwithexcipientspresent,at37°.Thiselevatedtemperaturehasthepotentialtodecreasesolutionstability（degradation）.Stabilityshouldallowforsufficienttimetocompleteorrepeattheanalyticalprocedure.Physicalstabilitymaybeofconcernwhenprecipitationoccursbecauseoflowersolubilityatroomorrefrigeratedtemperature.必要時(shí)，應(yīng)該對(duì)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(lái)完成或重復(fù)分析過(guò)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。ChoosingaMediumandVolume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(duì)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(duì)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(píng)估。體外性能測(cè)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(duì)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(duì)于藥物標(biāo)簽中說(shuō)明在酸中釋放度不得過(guò)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(guò)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。化合物快速降解形成穩(wěn)定的降解物，單獨(dú)監(jiān)測(cè)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(duì)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。ChoosinganApparatus1.4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(duì)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(lái)說(shuō)，首選藥典儀器。Forsolidoraldosageforms,Apparatus]andApparatus2areusedmostfrequently.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(duì)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(duì)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(shì)。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(kù)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(píng)價(jià)和測(cè)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（seeSemisolidDrugProduct—PerformanceTests<1724>）。Somechangescanbemadetothecompendialapparatus;forexample,abasketmeshsizeotherthanthetypical40-meshbasket（e.g.,10-,20-,or80-mesh）maybeusedwhentheneedisclearlydocumentedbysupportingdata.Caremustbetakenthatbasketsareuniformandmeetthedimensionalrequirementsspecifiedin<711>.對(duì)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(guò)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(shì)和處方變化對(duì)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(duì)標(biāo)準(zhǔn)偏差(RSD)不得過(guò)20%或者后續(xù)取樣點(diǎn)的RSD值大于10%。，指導(dǎo)原則對(duì)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(guò)程中，可以使用較小的樣本量，需要對(duì)分析作出相應(yīng)的判斷。大多數(shù)溶出結(jié)果，表現(xiàn)出較少的變異性。在溶出度試驗(yàn)開發(fā)過(guò)程中應(yīng)對(duì)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(cè)過(guò)程相關(guān)的處理過(guò)程(例如，溶出漩渦，片粘在溶出杯壁或籃網(wǎng)上)。試驗(yàn)過(guò)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(cè)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。Manycausesofvariabilitycanbefoundintheformulationandmanufacturingprocess.Forexample,poorcontentuniformity,processinconsistencies,excipientinteractionsorinterference,filmcoating,capsuleshellaging,andhardeningorsofteningofthedosageformonstabilitymaybesourcesofvariabilityandinterferences.在處方開發(fā)和制劑工藝中，可以找到產(chǎn)生變異的許多原因。例如，含量均勻度的差異，工藝的不一致，輔料的相互作用或干擾，包衣，膠囊殼老化，制劑穩(wěn)定性考查中出現(xiàn)的硬化或軟化是產(chǎn)生和干擾變異的原因。2.1Deaeration2.1脫氣Thesignificanceofdeaerationofthedissolutionmediumshouldbedeterminedbecauseairbubblescanactasabarriertothedissolutionprocessifpresentonthedosageunitorbasketmeshandcanadverselyaffectthereliabilityofthetestresults.Furthermore,bubblescancauseparticlestoclingtotheapparatusandvesselwalls.Bubblesonthedosageunitmayincreasebuoyancy,leadingtoanincreaseinthedissolutionrate,ormaydecreasetheavailablesurfacearea,leadingtoadecreaseinthedissolutionrate.Poorlysolubledrugsaremostsensitivetointerferencefromairbubbles;therefore,deaerationmaybeneededwhentestingthesetypesofproducts.Adeaera