溶出試驗(yàn)的開發(fā)和驗(yàn)證

1、INTRODUCTION前言Purpose目的The Dissolution Procedure: Developmentand Validation <1092> provides a comprehensive approach covering items to considerfor developing and validating dissolution procedures and the accompanyinganalytical procedures. It addresses the use of automation throughout the testa

2、nd provides guidance and criteria for validation. It also addresses thetreatment of the data generated and the interpretation of acceptance 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

3、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 development andvalidation of dissolution procedures, with a focus on solid oral dosage forms.Many of the concepts presented, however, may be applicable to other dosageforms and routes of administration. General recommendations ar

4、e given with theunderstanding that modifications of the apparatus and procedures as given in USPgeneral 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 organization of <1092> follows the sequence of actions often perf

5、ormed inthe development and validation of a dissolution test. The sections appear inthe following sequence.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 OF PRODUCTDEVELOPMENT/DISSOLUTION METHOD DEVELOPMENT)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 C

6、ompatibility1.1 濾膜相容性研究1.2 Determining Solubility and Stability of DrugSubstance in Various 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 Choosing a Medium and Volume1.3 溶出介質(zhì)和體積選擇1.4 Choosing 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)2.1 Deaeration2.1 脫氣2.2 Sinkers2.2 沉降籃2.3 Agitation2.3 轉(zhuǎn)

7、速2.4 Study Design2.4 研究設(shè)計(jì)2.4.1 TimePoints 取樣時(shí)間點(diǎn)2.4.2 Observations 觀察2.4.3 Sampling 取樣2.4.4 Cleaning 清洗2.5 Data Handling2.5 數(shù)據(jù)處理2.6 Dissolution Procedure Assessment2.6 溶出方法評(píng)估1. PRELIMINARYASSESSMENT (FOR EARLY STAGES OF PRODUCT DEVELOPMENT/DISSOLUTION METHODDEVELOPMENT)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）Befor

8、emethod development can begin, it is important to characterize the molecule sothat the filter, medium, volume of medium, and apparatus can be chosen properlyin order to evaluate the performance 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)、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。1.1 Performing Filter Compat

9、ibility1.1 濾膜相容性研究Filtrationis a key sample-preparation step in achieving accurate test results. Thepurpose of filtration is to remove undissolved drug and excipients from thewithdrawn solution. If not removed from the sample solution, particles of thedrug will continue to dissolve and can bias the

10、results. Therefore, filteringthe dissolution samples is usually necessary and should be done immediately ifthe filter is not positioned on the cannula.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器，應(yīng)立即對(duì)溶出度樣品進(jìn)行過濾。Filtration also removes

11、 insolubleexcipients that may otherwise interfere with the analytical finish. Selectionof the proper filter material is important and should be accomplished, andexperimentally justified, early in the development of the dissolutionprocedure. Important characteristics to consider when choosing a filte

12、rmaterial are type, filter size, and pore size. The filter that is selectedbased on evaluation during the early stages of dissolution procedure developmentmay need to be reconsidered at a later time point. Requalification has to beconsidered after a change in composition of the drug product or chang

13、es in thequality of the ingredients (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 of filters used in dissolutiontesting c

14、an be cannula filters, 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 substance particle size is very small(

15、e.g., micronized or nanoparticles), it can be challenging to find a filterpore size that 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：0.2070m，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?。ɡ纾⒎只w?；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。Adsorption of the drug(s) by the filter

16、may occur and needs to be evaluated. Filter materials will interact withdissolution media to affect the recovery of the individual solutes and must beconsidered on a case-by-case basis. Different filter materials exhibitdifferent drug-binding properties. Percentage of drug loss from the filtratedue

17、to binding may be dependent on the drug concentration. Therefore theadsorptive interference should be evaluated on sample solutions at differentconcentrations bracketing the expected concentration range. Where the drugadsorption is saturable, discarding an initial volume of filtrate may allow thecol

18、lection of a subsequent solution that approaches the original solutionconcentration. Alternative filter materials that minimize adsorptiveinterference can usually be found. Prewetting of the filter with the medium maybe necessary. In addition, it is important that leachables from the filter donot in

19、terfere with the analytical procedure. This can be evaluated by analyzingthe filtered dissolution 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

20、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(rùn)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 be separated. Use of thecorrect filter dimensions will i

21、mprove throughput and recovery, and also reduceclogging. Use of a large filter for small-volume filtration can lead to loss ofsample through hold-up volume, whereas filtration through small filter sizesneeds higher pressures and longer times, and 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

22、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(zhǎng)的時(shí)間，并且溶液迅速堵塞濾膜。Filters used for USP Apparatus 4 needspecial attention because they are integrated in the flow-through process.Undissolved particles may deposit on the filters, creating resistance to thefl

23、ow.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。In the case of automated systems,selection of the filter with regard to material and pore size can be done in asimilar manner to manual filtration. Flow rate through the filter and cloggingmay be critical for filters used in automated systems. E

24、xperimentalverification that a filter isappropriate may be accomplished by comparing the responses for filtered andunfiltered standard and sample solutions. This is done by first preparing asuitable standard solution and a sample solution. For example, prepare atypical dissolution sample in a beaker

25、 and stir vigorously with a magneticstirrer to dissolve the drug load completely.For standard solutions, comparethe results for filtered solutions (after discarding the appropriate volume) tothose for the unfiltered solutions. For sample solutions, compare the resultsfor filtered solutions (after di

26、scarding the appropriate volume) 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（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

27、積后）、離心、未過濾樣品溶液的含量測(cè)定結(jié)果。1.2 Determining Solubility and Stability of DrugSubstance in Various 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 substance need to be determinedas part of the process of selecting the proper dissolution medium. Whendeciding the composition

28、of the medium for dissolution testing, it is importantto evaluate the influence of buffers, pH, and if needed, different surfactantson the solubility and stability of the drug substance. Solubility of the drugsubstance is usually evaluated by determining the saturation concentration ofthe drug in di

29、fferent media at 37° using the shake-flask solubility method(equilibrium solubility). To level out potential ion effects between the drugand the buffers used in the media, mixtures of hydrochloric acid and sodiumhydroxide are used to perform solubility investigations; this is in addition tothe

30、typical buffer solutions. In certain cases, it may be necessary to evaluatethe solubility of the drug at temperatures other than 37° (i.e., 25°). The pHof the clear supernatant should be checked to determine whether the pH changesduring the solubility test. Alternative approaches for solub

31、ility determinationmay 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

32、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 dissolution mayinclude the following (not listed in order of preference): diluted hydrochloricacid, buffers (phosphate or acetate) in the physiologic pH range of 1.27.5, simulatedgastric or intestinal fluid (with or without enzymes),and water. For

33、somedrugs, incompatibility of the drug with certain buffers or salts may influencethe choice of buffer. The molarity of the buffers and acids used can influencethe solubilizing 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

34、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。Aqueous solutions (acidic or buffersolutions) may contain a percentage of a surfactant e.g., sodium dodecylsulfate (SDS),polysorbate, or lauryldimethylamine oxide to enhance thesolubility of the drug. The surfactants selected for the solubilit

35、yinvestigations should cover all common surfactant types, i.e., anionic,nonionic, and cationic. When a suitable surfactant has been identified,different concentrations of that surfactant should be investigated to identifythe lowest concentration neededto achieve sink conditions. Typically,the surfac

36、tant concentration is above its critical micellar concentration(CMC). Table 1 shows a list of some of the surfactants used indissolution media. Approximate CMC values are provided with referenceswhenavailable. The list is not comprehensive and is not intended to exclude surfactantsthat are not liste

37、d. Other substances, such ashydroxypropyl b -cyclodextrin,have been used as dissolution media additives to enhance dissolution of poorlysoluble compounds.The U.S. Food and Drug Administration (FDA) maintains adatabase of dissolution methods, including information on dissolution mediathat have been u

38、sed (1). Typically, the amount of surfactant added issufficient to achieve sink conditions in the desired volume of dissolutionmedium.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

39、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-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(guó)食品藥品管理局（FDA）溶出度數(shù)據(jù)庫(kù)中，已經(jīng)收載含有羥丙基-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。It is important to control thegrade and purity of surfactants becau

40、se use of different grades could affectthe solubility of the drug. For example, SDS is available in both a technicalgrade and a high-purity grade. Obtaining polysorbate 80 from different sourcescan affect its suitability when performing high-performance liquidchromatography (HPLC) analysis.由于使用不同級(jí)別的

41、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 surfactant solutions. Forexample, a precipitate forms when the potassium salt for the phosphate bufferis used at a co

42、ncentration of 0.5 M in combination 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)，可以避免這種現(xiàn)象發(fā)生。Table 1. Commonly Used Surfactants with Critical Micelle Concentrations

43、表1 常見表面活性劑的臨界膠束濃度Routinely, the dissolution medium is buffered; however, the useof purified water as the dissolution medium is suitable for products with adissolution behavior independent of the pH of the medium. There are severalreasons why purified water may not be preferred. The water quality can

44、 varydepending on its source, and the pH of the water is not as strictly controlledas the pH of buffer solutions. Additionally, the pH can vary from day to dayand can also change during the run, depending on the drug substance andexcipients. Use of an aqueousorganic solvent mixture as a dissolution

45、mediumis discouraged; however,with proper justification 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。Investigations of the stability

46、 of thedrug substance should be carried out, when needed, in the selected dissolutionmedium with excipients present, at 37°. This elevated temperature has thepotential to decrease solution stability (degradation). Stability should allowfor sufficient time to complete or repeat the analytical pr

47、ocedure. Physicalstability may be of concern when precipitation occurs because 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。1.3 Choosing aMedium and Volume1.3

48、溶出介質(zhì)和體積的選擇When developing a dissolution procedure, one goal is to have sinkconditions, which are defined as having a volume of medium at least three timesthe volume required to form a saturated solution of drug substance. When sinkconditions are present, it is more likely that dissolution results wi

49、ll 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 dissolution medium are guided by the solubility investigations.For example, the choice and concentration of a surfactant need to

50、 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，需要根據(jù)藥物溶解度數(shù)據(jù)和溶出曲線進(jìn)行調(diào)整。The use of enzymes in the dissolutionmedium is permitted, in a

51、ccordance with Dissolution <711>, when dissolution failures occur as a result of cross-linkingwith gelatin capsules or gelatin-coated products. A discussion of thephenomenon of crosslinking and method development using enzymes can be found inCapsulesDissolution Testing and Related Quality Attr

52、ibutes<1094>. Validation should be performed with the method using enzymesaccording to section 5. 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“CapsulesDissolution Testing and RelatedQuality Attributes<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)

53、證。Another option is to use media thatfollow more closely the composition of fluids in the stomach and intestinaltract. These media may contain physiological surface-active ingredients, suchas taurocholates. The media also may contain emulsifiers (lecithin) andcomponents such as saline solution that

54、increase osmolality. Also, the ionicstrength or molarity of the buffer solutions may be manipulated. The media aredesigned to represent the fed and fasted state in the stomach and smallintestine.These media may be very useful in modeling in vivo dissolutionbehavior of immediate-release (IR) dosage f

55、orms, in particular those containinglipophilic drug substances, and may help in understanding the dissolutionkinetics of the product related to the physiological make-up of the digestivefluids. Results of successful modeling of dissolution kinetics have beenpublished,mainly for IR products. In the c

56、ase of extended-release dosage formswith reduced effect of the drug substance on dissolution behavior, the use ofsuch media needs to be evaluated differently. In vitro performance testing doesnot necessarily require media modeling the fasted and postprandial states (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

57、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。An acid stage is p

58、art of the testing ofdelayed-release products by Method A or Method B in <711>. For drugs with acid solubility less than 10% of the labelclaim or drugs that degrade in acid the usefulness of the acid stage indetecting a coating failure is compromised. This would be handled on acase-by-case bas

59、is. Possible resolutions include the addition of surfactant tothe acid stage, or adjustment of the specifications.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)）During selection of the dissolutionmedium, care should be taken to ensure that the drug substance is suitablystable throughout the analysis. In some cases, antioxidants such as ascorbicacid may be used in the dissolution medium to