USP-109溶出度試驗的開發(fā)和驗證中英文對照版

（1092）溶出度試驗的開發(fā)和驗證【中英文對照版】INTRODUCTION前言Purpose

目的TheDissolutionProcedure:DevelopmentandValidation<1092>providesacomprehensiveapproachcoveringitemstoconsiderfordevelopingandvalidatingdissolutionproceduresandtheaccompanyinganalyticalprocedures.Itaddressestheuseofautomationthroughoutthetestandprovidesguidanceandcriteriaforvalidation.Italsoaddressesthetreatmentofthedatageneratedandtheinterpretationofacceptancecriteriaforimmediate-andmodified-releasesolidoraldosageforms.溶出實驗:開發(fā)和驗證（1092）指導原則提供了在溶出度方法開發(fā)和驗證過程中以及采用相應分析方法時需要考慮的因素。本指導原則貫穿溶出度實驗的全部過程，并對方法提供了指導和驗證標準。同時它還涉及對普通制劑和緩釋制劑所生成的數(shù)據(jù)和接受標準進行說明。Scope

范圍Chapter<1092>addressesthedevelopmentandvalidationofdissolutionprocedures,withafocusonsolidoraldosageforms.Manyoftheconceptspresented,however,maybeapplicabletootherdosageformsandroutesofadministration.GeneralrecommendationsaregivenwiththeunderstandingthatmodificationsoftheapparatusandproceduresasgiveninUSPgeneralchaptersneedtobejustified.<1092>章節(jié)討論了溶出度實驗的開發(fā)和驗證，重點是口服固體制劑。所提出的許多概念也可能適用于其他劑型和給藥途徑。關于設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.在進行溶解度實驗的開發(fā)和驗證時，常遵循指導原則<1092>,具體內容如下：1.PRELIMINARYASSESSMENT（FOREARLYSTAGESOFPRODUCTDEVELOPMENT/DISSOLUTIONMETHODDEVELOPMENT）.前期評估（對產品開發(fā)以及溶出度方法開發(fā)的前期研究評估）PerformingFilterCompatibility濾膜相容性研究DeterminingSolubilityandStabilityofDrugSubstanceinVariousMedia原料藥在不同溶出介質中溶解度測定和穩(wěn)定性研究ChoosingaMediumandVolume溶出介質和體積選擇ChoosinganApparatus溶出設備選擇（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轉速StudyDesign2.4研究設計TimePoints取樣時間點Observations觀察Sampling取樣Cleaning清洗DataHandling數(shù)據(jù)處理DissolutionProcedureAssessment出方法評估ANALYTICALFINISH.完成分析SampleProcessing樣品處理Filters過濾Centrifugation離心AnalyticalProcedure分析方法SpectrophotometricAnalysis譜分析HPLCPLC法AUTOMATION.自動化MediumPreparation介質的配制SampleIntroductionandTiming定時進樣SamplingandFiltration取樣和過濾Cleaning清洗OperatingSoftwareandComputationofResults作軟件和計算的結果VALIDATION.驗證Specificity/PlaceboInterference專屬性/安慰劑（輔料）干擾LinearityandRange線性和范圍Accuracy/Recovery準確度/回收率Precision5.4精密度REPEATABILITYOFANALYSIS重復性INTERMEDIATEPRECISION/RUGGEDNESS中間精密度/耐用性REPRODUCIBILITY重現(xiàn)性Robustness耐用性StabilityofStandardandSampleSolutions品溶液和標準溶液的穩(wěn)定性ConsiderationsforAutomation動操作注意事項ACCEPTANCECRITERIA.可接受標準Immediate-ReleaseDosageForms速釋劑型Delayed-ReleaseDosageForms延遲釋放劑型Extended-ReleaseDosageForms延長釋放劑型MultipleDissolutionTests多個溶解度試驗InterpretationofDissolutionResults6.5溶出結果說明IMMEDIATE-RELEASEDOSAGEFORMS即時釋放劑型DELAYED-RELEASEDOSAGEFORMS延遲釋放劑型EXTENDED-RELEASEDOSAGEFORMS延長釋放劑型1.PRELIMINARYASSESSMENT(FOREARLYSTAGESOFPRODUCTDEVELOPMENT/DISSOLUTIONMETHODDEVELOPMENT).前期評估(產品開發(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，我們對用以評價制劑溶出行為的濾膜、溶出介質、溶出介質體積和溶出設備進行適當?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.為獲得準確試驗結果，過濾是樣品制備的一個關鍵步驟。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繼續(xù)溶解使試驗結果出現(xiàn)偏差，因此，如果取樣管中沒有過濾器，應立即對溶出度樣品進行過濾。Filtrationalsoremovesinsolubleexcipientsthatmayotherwiseinterferewiththeanalyticalfinish.Selectionoftheproperfiltermaterialisimportantandshouldbeaccomplished,andexperimentallyjustified,earlyinthedevelopmentofthedissolutionprocedure.Importantcharacteristicstoconsiderwhenchoosingafiltermaterialaretype,filtersize,andporesize.Thefilterthatisselectedbasedonevaluationduringtheearlystagesofdissolutionproceduredevelopmentmayneedtobereconsideredatalatertimepoint.Requalificationhastobeconsideredafterachangeincompositionofthedrugproductorchangesinthequalityoftheingredients(e.g.particlesizeofmicrocrystallinecellulose).過濾也可除去可能會干擾分析測定的不溶性輔料。選擇適當?shù)倪^濾材料是非常重要，應該在早期溶出方法開發(fā)的過程中通過實驗確定和完成。在選擇濾膜時有必要重點考慮濾膜的材料、型號和孔徑大小。通常對早期階段溶出方法開發(fā)過程的評價選擇過濾器，但在后期試驗中如果制劑成分改變或組成成分質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.Commonporesizesrangefrom0.20to70mm,however,filtersofotherporesizescanbeusedasneeded.Ifthedrugsubstanceparticlesizeisverysmall(e.g.,micronizedornanoparticles),itcanbechallengingtofindafilterporesizethatexcludesthesesmallparticles.用于溶出試驗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.過濾時可能會發(fā)生藥物的吸附，需要進行評估。過濾材料將與溶出介質相互作用，影響每個溶質的回收率應該根據(jù)具體問題進行考慮。不同的過濾材料表現(xiàn)出與藥物結合的不同特性。由于藥物與濾膜結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，應采用預期濃度范圍內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，過濾后的溶出物不干擾分析檢測也是非常重要的，這可以通過過濾后的溶出介質過濾與未過濾的溶出介質進行比較，評估濾膜是否干擾分析測定。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率和回收率，并減少濾膜堵塞。使用大孔徑濾膜過濾小體積溶液，能夠導致樣品溶液損失量過大而收集不到所用樣品量；使用小孔徑濾膜過濾，需要更高的壓力和較長的時間，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，因為它們在流動過程中使用。不溶顆粒會沉積在過濾器，產生流動阻力。Inthecaseofautomatedsystems,selectionofthefilterwithregardtomaterialandporesizecanbedoneinasimilarmannertomanualfiltration.Flowratethroughthefilterandcloggingmaybecriticalforfiltersusedinautomatedsystems.Experimentalverificationthatafilterisappropriatemaybeaccomplishedbycomparingtheresponsesforfilteredandunfilteredstandardandsamplesolutions.Thisisdonebyfirstpreparingasuitablestandardsolutionandasamplesolution.Forexample,prepareatypicaldissolutionsampleinabeakerandstirvigorouslywithamagneticstirrertodissolvethedrugloadcompletely.Forstandardsolutions,comparetheresultsforfilteredsolutions(afterdiscardingtheappropriatevolume)tothosefortheunfilteredsolutions.Forsamplesolutions,comparetheresultsforfilteredsolutions(afterdiscardingtheappropriatevolume)tothoseforcentrifuged,unfilteredsolutions.在自動化系統(tǒng)的情況下，關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過濾進行選擇。在自動化系統(tǒng)中通過過濾器的流量和過濾器的堵塞可能是至關重要的。通過試驗比較過濾和未過濾的標準溶液和樣品溶液的含量差別，驗證該過濾器是合適的。首先制備一個合適的標準溶液和樣品溶液。例如，在燒杯中制備一個標準溶解樣品，用磁力攪拌器攪拌使藥物完全溶解。對于標準溶液，比較過濾溶液（棄去的適當體積后）和未過濾溶液的含量測定結果；對于樣品溶液，比較過濾（棄去適當體積后）、離心、未過濾樣品溶液的含量測定結果。DeterminingSolubilityandStabilityofDrugSubstanceinVariousMedia1.2原料藥在不同溶出介質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,itmaybenecessarytoevaluatethesolubilityofthedrugattemperaturesotherthan37°（i.e.,25°）.ThepHoftheclearsupernatantshouldbecheckedtodeterminewhetherthepHchangesduringthesolubilitytest.Alternativeapproachesforsolubilitydeterminationmayalsobeused.在選擇合適溶出介質的過程中，需要確定原料藥的物理化學特性。當需要確定溶出度試驗中溶出介質的組成時，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中的飽和濃度，來評估藥物的溶解性。為了消除溶出介質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。在溶解度試驗過程中應檢查上清溶液的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,suchashydroxypropylb-cyclodextrin,havebeenusedasdissolutionmediaadditivestoenhancedissolutionofpoorlysolublecompounds.TheU.S.FoodandDrugAdministration(FDA)maintainsadatabaseofdissolutionmethods,includinginformationondissolutionmediathathavebeenused(1).Typically,theamountofsurfactantaddedissufficienttoachievesinkconditionsinthedesiredvolumeofdissolutionmedium.有時候水溶性介質中（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應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，當已經確定一個合適的表面活性劑時，應對表面活性劑的不同濃度進行研究，以確定達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，已被用來作為溶出介質添加劑提高難溶性化合物的溶解度，美國食品藥品管理局（1口人）溶出度數(shù)據(jù)庫中，已經收載含有羥丙基B-環(huán)糊精的溶出介質（1）。通常情況下，表面活性劑的加入量以滿足達到漏槽條件所需的溶出介質體積。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方法進行分析時，不同來源的聚山梨酯（吐溫）80會影響它的適用性。Theremaybeeffectsofcounter-ionsorpHonthesolubilityorsolutionstabilityofthesurfactantsolutions.Forexample,aprecipitateformswhenthepotassiumsaltforthephosphatebufferisusedataconcentrationof0.5MincombinationwithSDS.ThiscanbeavoidedbyusingthesodiumphosphatesaltwhenpreparingmediawithSDS.反離子或pH值可能會影響表面活性劑溶液的溶解性或穩(wěn)定性。例如，當含有SDS的磷酸鹽緩沖液中鉀鹽濃度為0.5mol/L時，就形成了沉淀析出，但是使用磷酸鈉制備含有SDS的介質時，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5和軍袤篁蕓［季蕓生力G2平 1不駕于Q、要小夷,豳況《吐遇as產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.0強般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。不推薦使用純化水作為溶出介質的原因：水的質量變化取決于它的來源，而水的pH值不像緩沖溶液能夠嚴格控制；此外，若藥物和輔料的溶出對pH值敏感時需要考慮使用緩沖液。另外使用水一有機溶劑混合物作為溶出介質也是不推薦的，但是，特殊情況下（有充分適當?shù)睦碛桑?，也是可以接受的。Investigationsofthestabilityofthedrugsubstanceshouldbecarriedout,whenneeded,intheselecteddissolutionmediumwithexcipientspresent,at37°.Thiselevatedtemperaturehasthepotentialtodecreasesolutionstability（degradation）.Stabilityshouldallowforsufficienttimetocompleteorrepeattheanalyticalprocedure.Physicalstabilitymaybeofconcernwhenprecipitationoccursbecauseoflowersolubilityatroomorrefrigeratedtemperature.必要時，應該對原料藥的穩(wěn)定性進行考察，在所選擇的溶出介質中加入輔料，在37℃條件下進行考察。這種升高的溫度會潛在的降低溶液的穩(wěn)定性（降解）。穩(wěn)定性試驗應考慮到有足夠的時間來完成或重復分析過程。當因室溫或冷藏貯存時降低藥物的溶解度而發(fā)生沉淀時，物理穩(wěn)定性也需要關注。ChoosingaMediumandVolume溶出介質和體積的選擇Whendevelopingadissolutionprocedure,onegoalistohavesinkconditions,whicharedefinedashavingavolumeofmediumatleastthreetimesthevolumerequiredtoformasaturatedsolutionofdrugsubstance.Whensinkconditionsarepresent,itismorelikelythatdissolutionresultswillreflectthepropertiesofthedosageform.Amediumthatfailstoprovidesinkconditionsmaybeacceptableifitisappropriatelyjustified.Thecompositionandvolumeofdissolutionmediumareguidedbythesolubilityinvestigations.Forexample,thechoiceandconcentrationofasurfactantneedtobejustifiedfromthesolubilitydataandthedissolutionprofiles.當開發(fā)一個溶出試驗方法時，首先要滿足漏槽條件，漏槽條件定義為溶出介質體積至少為藥物達到飽和溶液所需體積的三倍。當滿足漏槽條件后，溶出度結果能夠更好的反映藥物制劑的質量。在適當條件下，介質不滿足漏槽條件也是可以接受的。溶解介質的組成和體積應根據(jù)溶解度的試驗結果進行調整。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)和溶出曲線進行調整。Theuseofenzymesinthedissolutionmediumispermitted,inaccordancewithDissolution<711>,whendissolutionfailuresoccurasaresultofcross-linkingwithgelatincapsulesorgelatin-coatedproducts.AdiscussionofthephenomenonofcrosslinkingandmethoddevelopmentusingenzymescanbefoundinCapsules-DissolutionTestingandRelatedQualityAttributes<1094>.Validationshouldbeperformedwiththemethodusingenzymesaccordingtosection5.Validation當交聯(lián)明膠膠囊或明膠包衣的制劑溶出失敗時，在溶出介質中允許加入酶，這同溶出度<711>指導原則一致。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行方法開發(fā)的研究。根據(jù)第5節(jié)驗證，使用酶方法按照溶出度方法學驗證的要求進行驗證。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。這些溶出介質可以含有生理表面活性成分，如牛黃膽酸。這些溶出介質也可能含有乳化劑（卵磷脂）和增加滲透壓的組分，比如生理鹽水溶液。同時，緩沖液的離子強度或體積摩爾濃度是可以控制的。設計的溶出介質模擬了進食和空腹狀態(tài)下的胃和腸內狀態(tài)。這些溶出介質對速釋制劑（IR）建立體內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的制劑溶出動力學。溶解動力學的模型已成功建立，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需要有區(qū)別地進行評估。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）。針對于藥物標簽中說明在酸中釋放度不得過標示量的10%或者防止酸液中降解而進行抗酸包衣的藥物。根據(jù)具體情況進行解決，可能的解決方案包括：酸性介質中添加表面活性劑或者調整質量標準）Duringselectionofthedissolutionmedium,careshouldbetakentoensurethatthedrugsubstanceissuitablystablethroughouttheanalysis.Insomecases,antioxidantssuchasascorbicacidmaybeusedinthedissolutionmediumtostabilizethedrug.Thereareoccasionswheresuchactionsarenotsufficient.Forcompoundsthatrapidlydegradetoformastabledegradant,monitoringthedegradantaloneorincombinationwithadrugsubstancemaybemoresuitablethananalyzingonlythedrugsubstance.InsituspectroscopictechniquestendtobelessaffectedbydegradationwhencomparedwithHPLCanalysis（includingUHPLCandotherliquidchromatographicapproaches）.在選擇溶解介質時，應注意采取措施確保原料藥在整個分析過程中的穩(wěn)定性。在某些情況下抗氧化劑，如抗壞血酸的，可用于在溶出介質中，以保證藥物的穩(wěn)定性。有些時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)，溶出介質的體積可以從500到1000毫升不同。通常情況下，溶出介質的體積應當滿足漏槽條件。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)。實際上，溶出介質的體積通常在藥典規(guī)定范圍內。可供選擇時，選用藥典規(guī)定的其他儀器也是可取的，如往復式氣缸(儀器3),往復架(儀器7),或流通池(儀器4)。當某些儀器需要較少體積的溶出介質（例如，100-200毫升）時，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溶出設備選擇（槳法和籃法以及其他方法）Thechoiceofapparatusisbasedonknowledgeoftheformulationdesignandthepracticalaspectsofdosageformperformanceintheinvitrotestsystem.Ingeneral,acompendialapparatusshouldbeselected.根據(jù)對處方設計的認知和體外試驗劑型的實際特點選擇儀器。一般來說，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>).對于口服固體制劑，儀器1和儀器2使用最多。當儀器1或儀器2不適用時，可以使用其他官方儀器。已發(fā)現(xiàn)儀器3(往復氣缸)適用于咀嚼片、軟膠囊、緩釋制劑和不崩解型產品（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，或貯庫型產品，以及懸浮型緩釋劑型。儀器5（槳盤）和儀器6（旋轉缸）適用于評價和測試的經皮給藥制劑。儀器7（往復架）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散池，浸入細胞，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>.對藥典儀器配件也可以進行一些調整；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)進行詳細的闡明后也可以使用。必須注意的是籃網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)于藥典標準儀器的合適設備、資質和文件。例如，一個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。旋轉瓶或透析管可能適用于微球、植入制劑，改進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.合理設計一個試驗保證數(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個樣本的相對標準偏差(RSD)不得過20%或者后續(xù)取樣點的RSD值大于10%。，指導原則對溶出度試驗結果定義為高變異性。然而，在方法開發(fā)過程中，可以使用較小的樣本量，需要對分析作出相應的判斷。大多數(shù)溶出結果，表現(xiàn)出較少的變異性。在溶出度試驗開發(fā)過程中應對產生變異的原因進行研究，只要有可能，應嘗試減少變異性。引起變異性的兩個最可能的原因是制劑本身(例如，原料藥，輔料，或制劑工藝)和與檢測過程相關的處理過程(例如，溶出漩渦，片粘在溶出杯壁或籃網上)。試驗過程的觀察往往有助于查找產生變異的原因或者溶出度測定方法本身是否會產生變異性。任何時間內劑量含量不能均勻地分散在整個容器中，異常結果就可能發(fā)生。根據(jù)不同的問題，通常的調節(jié)方法包括下列任何一個因素的改變：儀器，轉速，脫氣程度，沉降籃類型，或者溶出介質的組成。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