USP-1092-溶出度试验的开发和验证(中英文对照版)

1、(1092)溶出度试验的开发和验证【中英文对照版】INTRODUCTION.、八、-刖言Purpose目的The Dissolution Procedure: Developmentand Validation provides a comprehe nsive approach coveri ng items to con siderfor develop ing and validat ing dissoluti on procedures and the accompa nyingan alytical procedures. It addresses the use of automa

2、ti on throughout the testa nd provides guida nee and criteria for validati on. It also addresses thetreatme nt of the data gen erated and the interpretation of acceptance criteriafor immediate- and modified-release solid oral dosage forms.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

3、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标准。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 addresses the developme nt an dvalidati on of dissoluti on 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 routes of admi nistrati

4、on. Gen eral recomme ndatio ns are give n with the un dersta nding that modificati ons of the apparatus and procedures as give n in USPge neral chapters n eed to be justified.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。The orga ni zati on of follows the seque nee

5、 of acti ons ofte n performed in the developme nt and validati on of a dissoluti on test. The secti ons appear in the follow ing seque nee.在进行溶解度实验的开发和验证时，常遵循指导原则,具体内容如下:1. PRELIMINARY ASSESSMENT （FOR EARLY STAGES OFPRODUCTDEVELOPMENT/DISSOLUTION METHOD DEVELOPMENT）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）1.1

6、Performing Filter Compatibility1.1滤膜相容性研究1.2 Determining Solubility and Stability of DrugSubstanee in Various Media1.2原料药在不同溶出介质中溶解度测定和稳定性研究1.3 Choos ing a Medium and Volume1.3溶出介质和体积选择1.4 Choos ing an Apparatus1.4溶出设备选择（桨法和篮法以及其他方法）2. METHOD DEVELOPMENT2. 方法开发2.1 Deaerati on2.1脱气2.2 Si nkers2.2沉降篮2

7、.3 Agitatio n2.3转速2.4 Study Design2.4研究设计2.4.1 TimePoi nts2.4.1取样时间点2.4.2 Observatio ns2.4.2观察2.4.3 Sampli ng2.4.3取样2.4.4 Clea ning2.4.4清洗2.5 Data Ha ndli ng2.5数据处理2.6 Dissoluti on Procedure Assessme nt2.6溶出方法评估3. ANALYTICAL FINISH3. 完成分析3.1 Sample Process ing3.1样品处理3.2 Filters3.2过滤3.3 Ce ntrifugati

8、 on3.3离心3.4 Analytical Procedure3.4分析方法3.5 Spectrophotometric An alysis3.5光谱分析3.6 HPLC3.6HPLC 法4. AUTOMATION4自动化4.1 Medium Preparati on4.1介质的配制4.2 Sample In troduct ion and Timi ng4.2定时进样4.3 Sampling and Filtration4.3取样和过滤4.4 Clea ning4.4清洗4.5 Operati ng Software and Computatio n of Results4.5操作软件和计

9、算的结果5. VALIDATION5验证5.1 Specificity/Placebo Interferenee5.1专属性/安慰剂（辅料）干扰5.2 Lin earity and Range5.2线性和范围5.3 Accuracy/Recovery5.3准确度/回收率5.4 Precisi on5.4精密度5.4.1 REPEATABILITY OF ANALYSIS5.4.1重复性5.4.2 INTERMEDIATE PRECISION/RUGGEDNESS5.4.2中间精密度/耐用性5.4.3 REPRODUCIBILITY5.4.3重现性5.5 Robust ness5.5耐用性5.6

10、 Stability of Sta ndard and Sample Soluti ons5.6样品溶液和标准溶液的稳定性5.7 Con siderati ons for Automati on5.7自动操作注意事项6. ACCEPTANCE CRITERIA6. 可接受标准6.1 Immediate-Release Dosage Forms6.1速释剂型6.2 Delayed-Release Dosage Forms6.2延迟释放剂型6.3 Exte nded-Release Dosage Forms6.3延长释放剂型6.4 Multiple Dissolution Tests6.4多个溶解

11、度试验6.5 Interpretation of Dissolution Results6.5溶出结果说明6.5.1 IMMEDIATE-RELEASE DOSAGE FORMS6.5.1即时释放剂型6.5.2 DELAYED-RELEASE DOSAGE FORMS6.5.2延迟释放剂型6.5.3 EXTENDED-RELEASE DOSAGE FORMS6.5.3延长释放剂型1. PRELIMINARYASSESSMENT (FOR EARLY STAGES OF PRODUCTDEVELOPMENT/DISSOLUTION METHODDEVELOPMENT)1. 前期评估（产品开发/溶

12、出度方法开发的初期阶段）Beforemethod developme nt can beg in, it is importa nt to characterize the molecule sothat the filter, medium, volume of medium, and apparatus can be chosen properly in order to evaluate the performa nee of the dosage form.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。1.1 P

13、erforming Filter Compatibility1.1滤膜相容性研究Filtrati on is a key sample-preparati on step in achiev ing accurate test results. Thepurpose of filtrati on is to remove un dissolved drug and excipie nts from thewithdrawn solution. If not removed from the sample solution, particles of thedrug will continue

14、to dissolve and can bias the results. Therefore, filteringthe dissolution samples is usually necessary and should be done immediately ifthe filter is not positi oned on the cannu la.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

15、溶出度样品进行过滤。Filtrati on also removes in solubleexcipie nts that may otherwise in terfere with the analytical finish. Selectionof the proper filter material is important and should be accomplished, andexperimentally justified, early in the development of the dissoluti on procedure. Importa nt character

16、istics to con sider whe n choos ing a filtermaterial are type, filter size, and pore size. The filter that is selectedbased on evaluati on duri ng the early stages of dissolutio n procedure developme ntmay n eed to be rec on sidered at a later time point. Requalificati on has to bec on sidered after

17、 acha nge in compositi on of the drug product or cha nges in thequality of thein gredie nts （e.g. particle size of microcrystalli ne cellulose）.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：

18、微晶纤维素粒径的改变）。Examples of filters used in dissolutiontesting can be cannula filters, filter disks or frits, filter tips, or syringefilters. The filter material has to be compatible with themedia and the drug.Common pore sizes range from 0.20 to 70 mm, however, filters of other poresizes can be used as

19、 n eeded. If the drug substa nee particle size is small(e.g., microni zed or nano particles), it can be challe nging to find a filterporesize that excludes these small particles.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:0.2 0 70 ym,如果原料药的粒度很小（例如，微分如果需要也可使用其他孔径大小的过滤器化颗粒或纳米颗粒），找到一个合

20、适的过滤器过滤这些小颗粒至今仍具有挑战性。Adsorption of the drug(s) by the filtermay occur and needs to be evaluated. Filter materials will in teract withdissoluti on media to affect the recovery of thein dividual solutes and must bec on sidered on a case-by-case basis. Differe nt filter materials exhibitdiffere nt drug

21、-b inding properties. Perce ntage of drug loss from the filtratedue to binding may be depe ndent on the drug concen trati on. Therefore theadsorptive in terfere nee should be evaluated on sample soluti ons at differe ntconcen tratio ns bracket ing the expected concen trati on ran ge. Where thedrugad

22、sorption is saturable, discarding an initial volume of filtrate may allow thecollecti on of a subseque nt soluti on that approaches the orig inal soluti onconcen trati on. Alter native filter materials that mini mizeadsorptive in terfere nee can usually be found. Prewetti ng of the filter with the m

23、edium maybe n ecessary .In additi on, it is importa nt that leachables from the filter donot in terfere with the an alytical procedure. This can be evaluated by analyzingthe filtered dissolution medium and comparing it with the unfiltered medium.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

24、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检测也是非常重要的，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。The filter size should be based on thevolume t

25、o be withdrawn and the amount of particles to be separated. Use of thecorrect filter dime nsions will improve 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 filtrati on through small filter

26、 sizes needs higher pressures and Ion ger times, and the filters can clog quickly.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。Filters used for USP Apparatus 4 n eedspecial atte nti on because they are in te

27、grated in the flow-through process.U ndissolved particles may deposit on the filters, creati ng resista nee to theflow.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。In the case of automated systems,selection of the filter with regard to material and pore size can be done in asimilar manner to

28、 manual filtration. Flow rate through the filter and cloggingmay be critical for filters used in automated systems. Experime ntalverificati on that a filter isappropriate may be accomplished by compari ng the responses for filtered andunfiltered standard and sample solutions. This is done by first p

29、reparing asuitable standard solution and a sample solution. For example, prepare atypical dissoluti on sample in a beaker and stir vigorously with a mag neticstirrer to dissolve the drug load completely.For sta ndard soluti ons, comparethe results for filtered soluti ons (after discard ing the appro

30、priate volume) tothose for the un filtered solutio ns. For sample soluti ons, compare the resultsfor filtered solutions (after discarding the appropriate volume) to those forcentrifuged, un filtered soluti ons.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

31、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。1.2 Determining Solubility and Stability of DrugSubstanee in Various Media1.2原料药在不同溶出介质中的溶解度测定和稳定性研究Physical and chemical characteristics of t

32、he drug substa nee n eed to be determ in edas part of the process of select ing the proper dissoluti on medium. Whendeciding the composition of the medium for dissolution testing, it is importa ntto evaluate the in flue nce of buffers, pH, and if n eeded, differe nt surfacta ntson the solubility and

33、 stability of the drug substa nce. Solubility of the drugsubsta nce is usually evaluated by determ ining the saturati on concen trati on ofthe drug in differe nt media at 37 using the shake-flask solubility method（equilibrium solubility）. To level out potential ion effects between the druga nd the b

34、uffers used in the media, mixtures of hydrochloric acid and sodiumhydroxide are used to perform solubility inv estigati ons; this is in additi on tothe typical buffer solutions. In certain cases, it may be necessary to evaluatethe solubility of the drug at temperatures other than 37（i.e., 25 ）. Thep

35、Hof the clearsuper nata nt should be checked to determ ine whether the pH cha ngesduri ng the solubility test. Alter native approaches for solubility determ in ati onmay also be used.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37C温度条件下，采用摇瓶溶解法（平衡溶解度

36、）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37C以外条件下（即，25C）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。Typical media for dissoluti on mayin elude the followi ng (not listed in order of prefere nee): diluted hydrochlor

37、icacid, buffers (phosphate or acetate) in the physiologic pH range of 1.2 7.5, simulatedgastric or in test inal fluid (with or 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

38、 acids used can in flue ncethe solubiliz ing effect, and this factor may be evaluated.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1.2-7.5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。Aqueous soluti ons (acidic or buffersoluti ons) may contain a perc

39、e ntage of a surfacta nt e.g., sodium dodecylsulfate (SDS),polysorbate, or lauryldimethylami ne oxide to enhance thesolubility of the drug. 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. Whe n a suitabl

40、e surfacta nt has bee n iden tified,differe nt concen trati ons of that surfacta nt should be in vestigated to iden tifythe lowest concen trati on n eeded to achieve sink conditions. Typically,the surfactant concentration is above its critical micellar concen tratio n( CMC). Table 1 shows a list of

41、some of the surfacta nts used in dissolutio n media. Approximate CMC values are provided with refere nceswhe navailable. The list is not comprehe nsive and is not inten ded to exclude surfacta ntsthat are no t listed. Other substa nces, such ashydroxypropyl b -cyclodextrin,have been used as dissolut

42、ion media additives to enhance dissolution of poorlysoluble compo un ds.The U.S. Food and Drug Admi nistrati on （FDA） maintains adatabase of dissoluti on methods, in cludi ng in formati on on dissoluti on mediathat have bee n used（1）. Typically, the amount of surfacta nt added issufficie nt to achie

43、ve sink con diti ons in the desired volume of dissoluti onm edium.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C

44、MC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 禺环糊精，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&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。It is important to control thegrade and purity of surfactants because use of different grades could affectthe solubility of th

45、e drug. For example, SDS is available in both a tech ni calgrade and a high-purity grade. Obtai ning polysorbate 80 from differe nt sourcesca n affect its suitability whe n perform ing high-performa nee liquidchromatography （HPLC） an alysis.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

46、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。There may be effects of coun ter-i ons orpH on the solubility or soluti on stability of the surfacta nt soluti ons. Forexample, a precipitate forms whe n the potassium salt for the phosphate bufferis used at a concen tratio n of 0.5 M in comb in atio n wi

47、th SDS. This can beavoided by using the sodium phosphate salt whe n prepari ng media with SDS.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。Table 1. Commo nly Used Surfacta nts with Critical Micelle Concen trati ons表1常见表面活性剂的临界胶束浓度CMC (%養董憬科)*二

48、堤逢云魏骑(SDS.SLS) Q0.lS%-0.23%2十Q.2嫁0 16畑0.12%-六烷基三甲基溟化铁(CIAB) p0033%-0.036%0.92*l.OmMJ a0.18%(4r)iM)药0.07%-0.09%0.02%-0.083.7左最癸取奏二爲mm奇 Labrasol ?0.01?W和寰兰二 吟亘融淳35 CremophorEL?门0.025轰遥二坪弓哇嚣上:Bnj35)户ClOUh合云畫薛CTriton X-100)户0沉洛g护r:临W密基二玄羞就N負化柚(LDAO)0.023UpRoutinely, the dissolution medium is buffered; h

49、owever, the useof purified water as the dissolution medium is suitable for products with adissolution behavior in depe ndent of the pH of the medium. There are severalreas ons why purified water may not be preferred. The water quality can varydepe nding on its source, and thepH of the water is not a

50、s strictly controlledas the pH of buffer solutions.Additi on ally, the pH can vary from day to daya nd can also cha nge duri ng the run, depe nding on the drug substa nee an dexcipie nts. Use of an aqueous-orga nic solve nt mixture as a dissoluti on mediumis discouraged; however,with proper justific

51、ati on this type of medium may beacceptable.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。Investigations of the stability of thedrug substance should be carried out, w

52、henneeded, in the selected dissolutionmedium with excipients present, at 37 . Thiselevated temperature has thepote ntial to decrease soluti on stability （degradati on）.Stability should allowfor sufficient time to complete or repeat the analytical procedure. Physicalstability may be of concern whe n

53、precipitati on occurs because of lowersolubility at room or refrigerated temperature.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37C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。1.3 Choos ing aMedium and Volume 1.3溶出介质和体积的选择 Whe n develop ing a dissolutio n p

54、rocedure, one goal is to have sinkcon diti ons, which are defined as having a volume of medium at least three timesthe volume required to form a saturated soluti on of drug substa nee. Whe n sinkcon diti ons are present, it is more likely that dissolution results will reflectthe properties of the do

55、sage form. A medium that fails to provide sinkconditions may be acceptable if it is appropriately justified. The compositi onand volume of dissoluti on medium are guided by the solubility investigations.For example, the choice and concentration of a surfactant need to be justifiedfrom the solubility

56、 data and the dissolution profiles.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。The use of en zymes in the dissoluti onm edium is permitted, in accorda nee with Dissolutio

57、n , when dissolution failures occur as a result of cross-linkingwith gelati n capsules or gelati n-coated products. A discussi on of thephe nomenon of crossli nking and method developme nt using en zymes can be found in Capsules-Dissolutio n Testi ng and Related Quality Attributes . Validatio n shou

58、ld be performed with the method using en zymesaccord ing to sect ion 5. 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才旨导原则一致。在 Capsules-Dissolutio n Testi ng andRelatedQuality Attributes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。Another option is to use media thatfollow more closely the composition of