最新usp1092溶出度試驗(yàn)的開發(fā)和驗(yàn)證(中英文對(duì)照版)資料

1、(1092)溶出度試驗(yàn)的開發(fā)和驗(yàn)證【中英文對(duì)照版】INTRODUCTION.、八、-刖言Purpose目的The Dissoluti on Procedure: Developme ntand Validati on <1092> provides a comprehensive approachcoveringitemsto con siderfor develop ing and validati ng dissoluti on procedures and the accompa nyingan alytical procedures. It addresses the us

2、e of automati on throughout the testa nd providesguidaneeand criteria for validation.It also addressesthetreatme nt of the data gen erated and the in terpretati on of acceptanee criteriafor immediate- and modified-release solid oral dosage forms.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)證過程 中以及采用相應(yīng)分析方法時(shí)需要考慮

3、的因素。 本指導(dǎo)原則貫穿溶出度實(shí)驗(yàn)的全部 過程，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)行說明。Scope范圍Chapter <1092> addresses the developmentandvalidationof dissolution procedures, with a focus on solid oral dosage forms.Ma ny of the con cepts prese nted, however, may be applicable to other dosageforms and routesof

4、 administration.Gen eral recomme ndatio ns are give n with the un dersta nding that modificationsof the apparatus and procedures as givenin USP general chapters need to be justified.<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。The organizationof <109

5、2> follows the sequenee of actionsofte n performed in the developme nt and validati on of a dissoluti ontest. The secti ons appear in the follow ingseque nee.精品文檔在進(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. PRELIMINARY ASSESSMENT （FOR EARLY STAGES OFPRODUCTDEVELOPMENT/DISSOLUTIONMETHOD DEVELOPME

6、NT）1. 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）1.1 Performing Filter Compatibility1.1濾膜相容性研究1.2 Determi ning Solubility and Stability of DrugSubsta nee inVarious Media1.2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1.3 Choos ing a Medium and Volume1.3溶出介質(zhì)和體積選擇1.4 Choos ing an Apparatus1.4溶出設(shè)備選擇（槳法和籃法以及其他方法）2. METHOD DEVELOPMENT2. 方法開發(fā)2

7、.1 Deaerati on2.1脫氣2.2 Si nkers2.2沉降籃2.3 Agitatio n2.3轉(zhuǎn)速2.4 Study Design2.4研究設(shè)計(jì)2.4.1 TimePoi nts2.4.1 取樣時(shí)間點(diǎn)2.4.2 Observatio ns243 Sampli ng243 取樣244 Clea ning244 清洗2.5 Data Ha ndli ng2.5數(shù)據(jù)處理2.6 Dissoluti on Procedure Assessme nt2.6溶出方法評(píng)估3. ANALYTICAL FINISH3. 完成分析3.1 Sample Process ing3.1樣品處理3.2 Fil

8、ters3.2過濾3.3 Ce ntrifugati on3.3 離心3.4 An alytical Procedure3.4分析方法3.5 Spectrophotometric An alysis3.5光譜分析3.6 HPLC3.6HPLC 法4. AUTOMATION4. 自動(dòng)化4.1 Medium Preparati on4.1介質(zhì)的配制4.2 Sample In troduct ion and Timi ng4.3 Sampling and Filtration4.3取樣和過濾4.4 Clea ning4.4清洗4.5 Operati ng Software and Computati

9、o n of Results4.5操作軟件和計(jì)算的結(jié)果5. VALIDATION5. 驗(yàn)證5.1 Specificity/Placebo Interferenee5.1專屬性/安慰劑（輔料）干擾5.2 Lin earity and Range5.2線性和范圍5.3 Accuracy/Recovery5.3準(zhǔn)確度/回收率5.4 Precisi on5.4精密度5.4.1 REPEATABILITY OF ANALYSIS5.4.1 重復(fù)性5.4.2 INTERMEDIATE PRECISION/RUGGEDNESS中間精密度/耐用性5.4.3 REPRODUCIBILITY5.4.3 重現(xiàn)性5.

10、5 Robust ness5.5耐用性5.6 Stability of Sta ndard and Sample Soluti ons5.6樣品溶液和標(biāo)準(zhǔn)溶液的穩(wěn)定性5.7 Con siderati ons for Automati on6. ACCEPTANCE CRITERIA6. 可接受標(biāo)準(zhǔn)6.1 Immediate-Release Dosage Forms6.1速釋劑型6.2 Delayed-Release Dosage Forms6.2延遲釋放劑型6.3 Exte nded-Release Dosage Forms6.3延長釋放劑型6.4 Multiple Dissolutio n

11、Tests6.4多個(gè)溶解度試驗(yàn)6.5 Interpretation of Dissolution Results6.5溶出結(jié)果說明6.5.1 IMMEDIATE-RELEASE DOSAGE FORMS6.5.1 即時(shí)釋放劑型6.5.2 DELAYED-RELEASE DOSAGE FORMS延遲釋放劑型6.5.3 EXTENDED-RELEASE DOSAGE FORMS6.5.3 延長釋放劑型PRODUCTvolume溶出介質(zhì)、1. PRELIMINARYASSESSMENT (FOR EARLY STAGES OF DEVELOPMENT/DISSOLUTION METHODDEVELO

12、PMENT)1.前期評(píng)估(產(chǎn)品開發(fā)/溶出度方法開發(fā)的初期階段)Beforemethod developme nt can beg in, it is importa nt to characterize the molecule sothat the filter, medium, of medium, and apparatus can be chose n properly in order to evaluate the performa nee of the dosage form.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)體積和溶出設(shè)備進(jìn)行適當(dāng)?shù)暮Y選是非常重

13、要的。1.1 Performing Filter Compatibility1.1濾膜相容性研究精品文檔Filtrati on is a key sample-preparati on step in achiev ing accurate test results. Thepurpose of filtration is to remove un dissolved drug and excipie nts from thewithdraw n soluti on. If not removed from the samplesolution,particles of thedrugwill

14、 continue to dissolve and can bias the results. Therefore, filteringthe dissolution samples is usually necessary and should be doneimmediatelyifthe filter is not positioned onthe cannu la.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，如果取樣管中沒有過濾

15、器，應(yīng)立即對(duì)溶出度樣品進(jìn)行過濾。Filtrati onalso removesin solubleexcipie ntsthat may otherwiseinterferewith the analytical finish. Selectionof the proper filtermaterial is importa nt and should be accomplished, andexperimentallyjustified, early in thedevelopmentof thedissoluti on procedure. Importa nt characteristi

16、cs to con sider when choosinga filtermaterial are type, filter size, and poresize. The filter that is selectedbased on evaluation during the early stages of dissolution procedure developmentmayneedto be rec on sidered at a later time point. Requalificati on has to beconsideredafter a change in compo

17、sitionof the drugproduct or cha nges in thequality of the in gredie nts (e.g.particle size of microcrystalline cellulose).過濾也可除去可能會(huì)干擾分析測(cè)定的不溶性輔料。選擇適當(dāng)?shù)倪^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、型號(hào)和孔徑大小。通常對(duì)早期階段溶出方法開發(fā)過 程的評(píng)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)。Examples o

18、f filters used in dissolutiontestingcan be cannulafilters, filter disks or frits, filter tips, or syringefilters. The filter material has to be compatible with the media and the drug.Common pore sizes range from 0.20 to 70 mm, however, filters of other poresizes can be used as needed. If the drug su

19、bsta nee particle size is very small(e.g., microni zed ornan oparticles),it can be challe nging to find a filterpore sizethat excludes these small particles.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)和藥物相適合。常見孔徑大小范圍：0.2070 ym，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

20、戰(zhàn)性。Adsorptionof the drug(s) by the filtermay occur and needsto be evaluated. Filter materials will in teract withdissoluti on media to affect the recovery of the in dividual solutes and mustbeconsideredon a case-by-casebasis.Differentfiltermaterialsexhibitdiffere ntdrug-b inding properties. Perce nt

21、ageof drug loss from the filtratedue to binding may be dependent on the drug concen trati on. Therefore theadsorptive in terfere nee should be evaluated on sample soluti ons at differentconcentrationsbracketing the expectedconcentrationrange.Where the drugadsorptionis saturable,discardinganinitial v

22、olume of filtrate may allow thecollection of a subseque nt solutio n that approaches the origi nal soluti onconcen trati on. Alter native filter materials that mini mize adsorptive in terfere nee can usually be found.Prewetti ng of the filter with the medium maybe n ecessary. In addition, it is impo

23、rtant that leachables from the filter donot interfere with the analytical procedure. This can be evaluated by an alyz in gthe filtered dissoluti on medium and comparing it with the unfiltered medium.過濾時(shí)可能會(huì)發(fā)生藥物的吸附，需要進(jìn)行評(píng)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

24、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(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(duì)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(cè)也是非常重要的，這可以通過過濾后的溶出介質(zhì)過濾與未過 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。The filter size should be based on thevolume to be withdrawn and the amount of particles to b

25、e separated.Use of thecorrectfilter dime nsions will improve throughput andrecovery, andalso reduceclogging. Use of a large filter for small-volume filtration can lead to loss ofsample through hold-up volume, whereas filtrati on through small filter sizes needs higher pressures and Ion gertimes, and

26、 the filters can clog quickly.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?qū)е聵悠啡芤簱p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(shí)間，并且溶液迅速堵塞濾膜。Filters used for USP Apparatus 4 n eedspecial atte nti onbecause they are in tegrated in the flow-through process.Undissolved partic

27、les may deposit on the filters, creati ng resista nee to theflow.USP儀器4中使用的過濾器需要特別注意，因?yàn)樗鼈冊(cè)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of the filter withIn the case of automatedsystems,selectionregard to material and pore size can be done in asimilar manner to manualfiltration.Flow rate through the filter andcloggingm

28、aybe critical for filters used in automated systems.Experime ntalverificationthat a filter isappropriate may be accomplishedby comparingthe responsesfor filteredandunfilteredstandardand samplesolutions.This is done by firstpreparingasuitablestandardsolutionand a samplesolution.For example, prepare a

29、typical dissoluti on sample in a beaker and stir vigorouslywith a magneticstirrer to dissolve the drug load completely.For sta ndardsoluti ons,comparethe results for filteredsoluti ons(after discardi ng the appropriate volume) tothose for the unfiltered solutions. For sample solutions, compare the r

30、esultsfor filteredsoluti ons(after discardi ng the appropriatevolume) to those forcentrifuged, unfiltered solutions.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(duì)于標(biāo)準(zhǔn)溶液，比較過濾溶液

31、（棄去的適當(dāng)體積后）和未過濾溶液的含量測(cè)定結(jié)果； 對(duì)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(cè)定結(jié)果。1.2 Determi ningSolubility and Stability of DrugSubsta nee inVarious Media1.2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Physical and chemical characteristics of the drug substanee need to be determ inedas part of the process of selectingthe proper dissolu

32、tion medium.Whendecidingthe compositionof the medium for dissolution testing, it is importantto evaluate the in flue nee of buffers, pH, and if n eeded,differe ntsurfactantsonthe solubility and stability of the drug substanee.Solubility of the drugsubsta nee is usually evaluated by determ ining the

33、saturatio n concen tratio n ofthe drug indiffere nt media at 37° using the shake-flask solubilitymethod(equilibriumsolubility). To level out potentialion effectsbetween thedrugand the buffers usedin themedia, mixturesof hydrochloric acidand sodiumhydroxide areusedto performsolubilityinvestigati

34、ons;this is in additiontothe typical bufferto evaluatetheo (i.e., be checked to solubility test.solutions.In certaincases, it may be necessarysolubility of the drug at temperatures other than 37 250). The pHof the clearsupernatant shoulddeterm ine whether the pH cha ngesduri ngtheAlter native approa

35、ches for solubility determ in ati onmay also be used.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(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 C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 C以外條件下（即，25 C）的溶解度可能也是必要的

36、。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(cè)定。Typical media for dissoluti on mayin elude the followi ng (notlisted in order of preferenee):diluted hydrochloricacid, buffers(phosphate or acetate) in the physiologic pH range of 1.2 - 7.5, simulatedgastric or in test inal fluid (with or

37、 without en zymes),a nd water. For somedrugs, in compatibility of the drug with certa in buffers or salts may in flue ncethe choice of buffer. The molarity of the buffers and acids used can in flue ncethe solubiliz ing effect, and this factor may be evaluated.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.

38、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(acidic or buffersolutions) may contain aperce ntage of a surfacta nt e.g., sodium dodecylsulfate(SDS),polysorbate, or lauryldimethylamineoxide to enhancethesolubility of the dr

39、ug. The surfacta nts selected for the solubility inv estigati ons should cover all com mon surfacta nt types, i.e., anionic,nonionic, and cati onic. When a suitable surfactanthas been identified,differentconcentrationsof thatsurfacta nt should be inv estigated to ide ntifythe lowest concen trati on

40、n eededto achieve sink con diti ons. Typically,the surfacta ntconcentrationis above its critical micellarconcentration(CMC).Table 1 shows a list of some of the surfacta nts usedin dissoluti on media. Approximate CMC values are provided with refere nceswhe navailable. The list is not comprehe nsive a

41、nd is not intendedto exclude surfactantsthat are not listed.Other substances, such ashydroxypropyl b -cyclodextrin,have bee n used as dissoluti on media additives to enhance dissoluti on of poorlysoluble compo un ds.The U.S. Food andDrug Administration(FDA) maintainsadatabase of dissolutionmethods,i

42、ncludinginformation on dissolution mediathat havebeen used(1) . Typically, the amount of surfactant addedissufficientto achieve sink conditionsin the desired volumeof dissoluti onm edium.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

43、，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(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

44、。It is important to controlthegrade and purity of surfactantsbecause use of differentgrades could affectthe solubility ofthe drug. For example, SDS is available in both a technicalgrade and a high-purity grade. Obtaining polysorbate 80 from differe nt sourcesca n affect its suitability whe n perform

45、 ing high-performa nee liquidchromatography （HPLC） an alysis.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)，不同來源的聚山梨酯（吐溫） 80會(huì)影響它的適用性。 There may be effects of counter-ions orpH on the solubility or solution stability of the surfactantsolutions.Forexample,a precipitat

46、e forms when the potassium salt for the phosphate bufferis used at a concen trati on of 0.5 M in comb in ati on with SDS. This can beavoided by using the sodium phosphate salt when preparing media with SDS.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

47、種現(xiàn)象發(fā)生。Table 1. CommonlyUsed Surfactantswith Critical MicelleConcen trati ons表1常見表面活性劑的臨界膠束濃度CMC (%釜董桂科-二堤遷云駁騎(SDS.SLS)心0.18%-0.23%2斗0.2嫁01曲0.12%-六烷基三甲基溟化鐵(CIAB)羊0.033°c-0 036%(092-LOmW Q節(jié)索螯冬(季齧超邁X應(yīng)0一 1即曲4也1)心CLO 了 強(qiáng)-0 09% 心菱襄酹加£吐型80)護(hù)0.02%-0.0843.7去藪.矣敦鷲己二醇m沖葩 Labrasol ?0.01*4扣梵走二吟乏氏掃35 &l

48、t;Cretnophor EL? “裴喘工坪弓咗露花:Bnj35)盧幸三發(fā)薛CTriton X-100)戶W密基二卓墓譽(yù)W復(fù)化勵(lì)(LDAO) P0.023UpRout in ely, the dissoluti on mediumis buffered; however, theuseof purified water as the dissolution medium is suitable for products with adissoluti on behavior in depe ndent of thepH of the medium. There are severalreaso

49、nswhy purified watermay not be preferred.The water qualitycan varydependingon its source, and the pH of the water is not as strictlycon trolledasthe pH of buffersoluti ons.Additi on ally,the pHcan vary from day to daya nd can also cha nge duri ng therun, dependingon the drugsubstaneeandexcipients. U

50、se ofan aqueous - orga nic solve nt mixture as a dissoluti onmediumis discouraged; however,with proper justificatio n this type of medium may beacceptable.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-有機(jī)溶劑混合物作為 溶出

51、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?受的。Inv estigatio ns of the stability of thedrug substa nee shouldbe carried out, whe n n eeded, in the selecteddissolutio nm edium with excipie nts prese nt, at 37°. Thiselevated temperature has thepote ntial to decrease solutio nstability（degradatio n）.Stabili

52、ty should allowfor sufficie nt timeto complete or repeat the an alytical procedure.Physicalstability may be of concern when precipitationoccursbecause of lowersolubility at room or refrigerated temperature.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 C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

53、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。1.3 Choos ing aMedium and Volume1.3溶出介質(zhì)和體積的選擇When developinga dissolution procedure, one goal is to havesinkconditions, which are defined as having a volume ofmedium at least three timesthe volume required to form a saturated soluti on of drug substa nee. When

54、sinkcon diti ons are present, it is more likely that dissolution results will reflectthe properties of the dosage form. A medium that fails to provide sinkconditions may be acceptable if it is appropriately justified. The compositionand volume of dissoluti on medium are guided by the solubility in v

55、estigati on s.Forexample, the choice and concen trati onofa surfactant need to be justifiedfrom the solubility data and the dissolution profiles.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

56、據(jù)藥物溶解度數(shù)據(jù)和溶出曲線進(jìn)行調(diào)整。The use ofenzymesin the dissolutionmediumis permitted,in accorda nee withDissoluti on<711>, whe n dissoluti ongelat incapsulesfailures occur as a result of cross-linkingwithor gelatin-coatedproducts. A discussionof thephenomenonof crosslinking and method development using enz

57、ymes can be found in Capsules Dissoluti onTesti ng and Related QualityAttributes <1094>. Validati on should be performed with themethod using en zymesaccord ing to sect ion5. Validati on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 - Dissolutio n Testi ng中可以找到發(fā)生交聯(lián)現(xiàn)象的and RelatedQuality Attributes<1094>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。Ano ther opti on is to use media tha