USP1092溶出度试验的开发和验证中英文对照版docx.docx

1、USP1092溶出度试验的开发和验证中英文对照版docxINTRoDUCTloN.、八 、-刖言PurPOSe目的The Dissoluti On Procedure: Developme ntand Validati On PrOVideS aCOmPrehe nsive approach COVeri ng items to con SiderfOr develop ing and VaIidat ing dissoluti on PrOCedUreS and the accompa nyingan alytical procedures. It addresses the USe of

2、automati on throughout the testa nd PrOVideS guida nce and Criteria for VaIidatiO n. It also addresses thetreatme nt of the data gen erated and the in terpretati on of accepta nce 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

3、虑的因素。本指导原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 admin

4、iStration. General recomme ndati ons are give n With the Un dersta nding that modificati ons of the apparatus and PrOCedUreS as give n irUSPge 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 SeqU

5、e nce of acti ons ofte n PerfOrmed in the developme nt and VaIidati on of a dissolutio n test. The SeCt ions appear in the follow ing SeqUe nce.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 OF PRoDUCTDEVELoPMENT/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）

6、1.1PerfOrming FiIter COmPatibiIity1.1滤膜相容性研究1.2Determining Solubility and StabiIity of DrUgSUbStance 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1.3Choos ing a Medium and Volume1.3溶出介质和体积选择1.4Choos 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2.1Deaerati On2.1脱气2.2Si nkers2.2沉降篮2.3Ag

7、itatiO n2.3转速2.4StUdy DeSign2.4研究设计2.4.1TimePOi nts2.4.1取样时间点2.4.2ObSerVatiO ns2.4.2观察2.4.3SamPIi ng2.4.3取样2.4.4Clea ning2.4.4清洗2.5Data Ha ndli ng2.5数据处理2.6Dissoluti On PrOCedUre ASSeSSme nt2.6溶出方法评估3.ANALYTICAL FINISH3.完成分析3.1SamPIe PrOCeSS ing3.1样品处理3.2FiIterS3.2过滤3.3Ce ntrifugati On3.3离心3.4An aly

8、tical PrOCedUre3.4分析方法3.5SPeCtrOphotometric An alysis3.5光谱分析3.6HPLC3.6HPLC 法4.AUToMATloN4自动化4.1Medium PreParati On4.1介质的配制4.2SamPIe In troduct ion and Timi ng4.2定时进样4.3SamPIing and FiItration4.3取样和过滤4.4Clea ning4.4清洗4.5OPerati ng SOftWare and COmPUtatiO n of ReSUItS4.5操作软件和计算的结果5.VALIDATION5验证5.1SPe

9、CifiCity/Placebo In terfere nce5.1专属性/安慰剂（辅料）干扰5.2Lin earity and Range5.2线性和范围5.3ACCUraCy/Recovery5.3准确度/回收率5.4PreCiSi on5.4精密度5.4.1REPEATABILITY OF ANALYSIS5.4.1重复性5.4.2INTERMEDIATE PRECISION/RUGGEDNESS5.4.2中间精密度/耐用性5.4.3REPRODUCIBILITY5.4.3重现性5.5RObUSt ness5.5耐用性5.6StabiIity of Sta ndard and SamPI

10、e Soluti ons5.6样品溶液和标准溶液的稳定性5.7Con Siderati ons for AUtOmati on5.7自动操作注意事项6.ACCEPTANCE CRlTERlA6.可接受标准6.1Immediate-ReleaSe DOSage Forms6.1速释剂型6.2DeIayed-ReIeaSe DOSage Forms6.2延迟释放剂型6.3EXte nded-Release DOSage Forms6.3延长释放剂型6.4MUItiPIe Dissolution TeStS6.4多个溶解度试验6.5Interpretation of Dissolution ReSU

11、ItS6.5溶出结果说明6.5.1IMMEDIATE-RELEASE DOSAGE FoRMS6.5.1即时释放剂型6.5.2DELAYED-RELEASE DOSAGE FORMS6.5.2延迟释放剂型6.5.3EXTENDED-RELEASE DOSAGE FORMS6.5.3延长释放剂型1.PRELlMlNARYASSESSMENT (FoR EARLY STAGES OF PRoDUCT DEVELoPMENT/DISSOLUTION METHODDEVELOPMENT)1.前期评估(产品开发/溶出度方法开发的初期阶段)BefOremethOd developme nt Can beg

12、 in, it is importa nt to CharaCteriZe the molecule SOthat the filter, medium, volume of medium, and apparatus Can be chosen PrOPerIyin order to evaluate the PerfOrma nce 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 PerfOrming FiIter COmPatibility1.1滤膜相容性研究FiItra

13、tiO nis a key SamPIe-PreParati on SteP in achiev ing accurate test results. ThePUrPOSe of filtrati on is to remove Un dissolved drug and excipie nts from thewithdraw n solutio n. If not removed from the SamPIe solution, PartiCIeS of thedrug will continue to dissolve and Can bias the results. Therefo

14、re, filteringthe dissolution SamPIeS is usually necessary and should be done immediately ifthe filter is not POSitioned on the CannUla.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，应立即对溶出度样品进行过滤。Filtrati On also removes in SOIubIeeX

15、CiPie nts that may OtherWiSe in terfere With the analytical finish. SeIeCtionof the PrOPer filter material is important and should be accomplished, andexperimentally justified, early in the development of the dissoluti on procedure. ImPOrta nt CharaCteriStiCS to con Sider Whe n choos ing a filtermat

16、erial are type, filter size, and pore size. The filter that is SeIeCtedbaSed on evaluati on duri ng the early StageS of dissoluti on PrOCedUre developme ntmay n eed to be reconSidered at a later time point. ReqUaIifiCation has to beconSidered after a Change in composition of the drug PrOdUCt or Chan

17、ges in thequality of the ingredients (e.g. PartiCIe 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：微晶纤维素粒径的改变)。these small PartiCles.用于溶出试验的过滤器有管路过滤器、 过滤

18、器。过滤材料必须与介质和药物相适合 如果需要也可使用其他孔径大小的过滤器。过滤盘或玻璃过滤器、滤头或针头式 常见孔径大小范围： 0.2 070 m,如果原料药的粒度很小（例如，微分EXamPIeS of filters USed in dissoluti on test ing Can be CannUla filters, filter disks or frits, filter tips, or Syringefilters. The filter material has to be COmPatibIe With the media and the drug.Common pore

19、SiZeS range from 0.20 to 70 mm, however, filters of other POreSiZeS Can be USed as n eeded. If the drug SUbSta nce PartiCIe SiZe is Very small(e.g., microniZed or nanOPartiCles), it Can be challenging to find a filterpore SiZe that excludes化颗粒或纳米颗粒），找到一个合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

20、) by the filtermay occur and needs to be evaluated. FiIter materials will in teract Withdissoluti on media to affect the recovery of the in dividual solutes and must bec on Sidered on a case-by-case basis. Differe nt filter materials exhibitdiffere nt drug-b inding PrOPerties. PerCe ntage of drug lo

21、ss from the filtratedue to binding may be depe ndent on the drug COnCen trati on. TherefOre theadsorptive in terfere nce should be evaluated on SamPIe soluti ons at differe ntconcen trati ons bracket ing the expected COnCen trati on ran ge. Where the drugadsorpti on is saturable, discarding an initi

22、al volume of filtrate may allow thecollection of a SUbSeqUent solution that approaches the origi nal soluti onconcen trati on. Alter native filter materials that mi ni mize adsorptive in terfere nce Can usually be found. PreWetti ng of the filter With the medium maybe necessary. In addition, it is i

23、mportant that IeaChabIeS from the filter donot in terfere With the an alytical procedure. ThiS Can be evaluated by an alyz in gthe 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

24、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 to be WithdraWn and the amount of PartiCI

25、eS to be SeParated. USe of thecorrect filter dime nsions will improve throughput and recovery, and also reduceclogg ing. USe of a large filter for small-volume filtrati on Can lead to loss OfSamPIe through hold-up volume, WhereaS filtration through small filter SiZeSneeds higher PreSSUreS and Ionger

26、 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。FiIterS USed for USP APParatUS 4 needspecial attention because they are integrated in the flow-through PrOCeSs.U ndissol

27、ved PartiCIeS may deposit on the filters, Creat ing resista nce 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 manual filtration. Flow rate through the fi

28、lter and clogg in gmay be CritiCaI for filters USed in automated systems. EXPerime ntal VerifiCati on that a filter isappropriate may be accomplished by COmPari ng the resp on SeS for filtered andunfiltered Standard and SamPIe solutions. ThiS is done by first PreParing asuitable Sta ndard solutio n

29、and a SamPIe soluti on. For example, PrePare atypical dissoluti on SamPIe in a beaker and Stir vigorously With a magn eticstirrer to dissolve the drug load compIetely.For Standard solutions, COmParethe results for filtered solutions (after discardi ng the appropriate volume) tothose for the Un filte

30、red soluti ons. For SamPIe solutions, COmPare the resultsfor filtered solutions (after discarding the appropriate volume) to those forcentrifuged, Unfiltered solutions.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

31、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。1.2Determining Solubility and Stability Of DrUgSUbStanCe 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 the drug SubSta nce n eed to be determ in

32、edas Part of the PrOCeSS of SeIeCt ing the PrOPer diSSolutio n medium. Whe ndecidi ng the CompoSition of the medium for dissolution testing, it is importantto evaluate the in flue nce of buffers, pH, and if n eeded, differe nt SUrfaCta ntson the solubility and StabiIity of the drug SUbSta nce. Solubility of the drugsubsta nce is usually evaluated by determ ining the SatU