发布时间 : 星期五 文章USP-1092-溶出度试验的开发和验证（中英文对照版）更新完毕开始阅读52f71bedfad6195f312ba6f6
Ideally, the standardsolutions should be diluted with the dissolution media at a concentrationwithin the linear range of the method, e.g., 100%, or the selected Q value ofthe dosage strength. However, organic solvent may be used in the preparation ofthe standard, provided that the accuracy criteria can be met during validation.In some cases, the sample may be diluted with mobile phase to improve the peakshape. The standard and sample solutions should both be prepared in the linearconcentration range and measured at the same wavelength.
理想情况下，标准溶液应在线性浓度范围内用溶出介质进行稀释，例如，100％，或者选择制剂剂量Q值。但是，在制备标准溶液时可以使用有机溶剂，在验证过程中要满足准确度标准。在一些情况下，为了改善峰形，样品溶液可以用流动相稀释。应在线性浓度范围内制备标准溶液和样品溶液，并在同一波长处测定。
4. AUTOMATION 4. 自动化
Automateddissolution systems may be configured in variousways and degrees. The elementsof test preparation, initiation, sampling andtiming, and cleaning all can beautomated. Fully automated systems areavailable, as are systems whereindividual steps, such as media preparation orsampling, are automated. Thissection will discuss operational steps that can beautomated. The level ofcomplexity for automation depends on whether theinstrument configuration isopen or closed loop and also whether the analyticaldevice is coupled online oroffline. Online analysis returns the sample aliquotto the test system, as inthe case of spectrophotometry with flow-throughcuvettes. Offline analysisremoves the sample aliquot from the dissolutionmedium for subsequent
analysis,typically by HPLC, where the analysis consumesthe sample. The decision on theconfiguration usually depends on the number ofsamples to be processed and thetime required for their analysis.
自动化的溶出度测定系统有很多方式和层级。由试验准备、开启、定时取样、和清洗构成，均能实现自动化。完全自动化是指每个操作步骤均实现自动化，比如溶出介质的配制或者取样。本章节主要讨论可以实现自动化的操作步骤。自动化的复杂水平取决于溶出仪是开环的还是闭环，同时也取决于分析仪器是脱机还是联机。联机分析是指测试样品能够输送到测定系统中并返还到溶出仪中，例如含有流通比色皿的分光光度计。脱机分析是指从溶出介质中取出等份样品进行后续的分析，通常采用高效液相色谱法，分析样本。仪器配置确定取决于样品处理的量和分析所需要的时间。
Automation may requiredeviations from thepharmacopeial specifications of the instruments, such asincorporation of anintegrated outlet on the bottom of the vessel for cleaningand replacement ofmedium. Operational steps that are not part of thecompendial procedure shouldbe validated. Deviations from the standardprocedure described in <711>,such as use of sampling probes orfiber-optic probes, should be validatedagainst the standard procedure.
自动化操作仪器可能与药典标准有偏差，比如在容器底部的一个集成出口用于清洗和更换介质。药典程序中未提及，应进行验证。在<711>中描述了标准程序的偏差，比如使用取样探针和光导纤维探针，应按照标准程序进行验证。 4.1 Medium Preparation 4.1 介质的配制
Automatedmedia preparation generally is accomplished bydiluting concentrates. Automatedmedia preparation systems typically dispensethe volume of medium into thevessel by monitoring either the weight or volume.Chemical and physicalstability of the concentrates as well as homogeneity ofthe dilutions over theintended period of use are important issues and should beunderstood.Concentrates of buffer solutions and surfactants may have stabilityissues,such as chemical degradation and pH change. Physical instability maymanifestas precipitation, re-crystallization, or phase separation and shouldbeprevented. If deaeration of the medium is required, the level ofdeaerationshould be specified.The concentration of the dissolved oxygen can beused to evaluatethe efficiency of deaeration procedures discussed in section 2.1Deaeration.
自动化溶出介质的制备一般是通过稀释浓溶液来完成的。自动化溶出介质制备系统通常通过监测重量或体积将一定体积的溶出介质分送到溶出杯中。在预期使用过程中浓溶液的物理和化学稳定性和稀释溶液的均一性是重要问题，应深刻理解。缓冲溶液和表面活性剂的浓溶液可能会存在稳定性问题，例如化学降解和pH值的改变。物理稳定性主要是沉淀、重结晶或者相分离，也应防止发生。如果介质要求脱气，脱气水平应该符合规定。介质中氧气的含量可以通过上述章节2.1脱气部分的方法进行评估。 4.2 Sample Introduction and Timing 4.2 定时进样
Samplesshould be inserted in the vessel in a reproducibleway. Automated sampleintroduction and aliquot withdrawal provide an advantageover manual samplingbecause the automated techniques can reduce the variabilityin
thevessel-to-vessel timing of the test intervals. However,
automatedsamplehandling may impose timing limitations that need to be considered.Thepharmacopeial tolerance of ±2% of the specified dissolution test time maybedifficult to meet for early time points.
溶出杯中应有一个循环的取样管路。自动进样和定量取样优于手动取样，因为它减少了在容器-容器测试时间间隔中引起的变量。但是，自动取样可能需要考虑时间的限制。在早期取样点手动取样很难满足药典对取样时间的要求，即相对标准偏差在±2%以内。 4.3 Sampling and Filtration 4.3 取样和过滤
Autosamplingis a useful alternative to manual sampling,especially if the test includesseveral time points. The transfer and filtrationof sample solutions from thedissolution instrument to the analytical unit maybe undertaken via tube connectionsor via robotic devices operated in a stepwiseprocedure. Sample volumes may beremoved from the dissolution medium and notreturned (consumptive sampling), orthe sample volume may be returned to thedissolution medium (recirculatedsampling).
自动取样是替代手动取样的一种有用方法，尤其是对于多个取样点的试验。样品溶液从溶出仪到分析单元的转移和过滤通过弯管接头或自动装置逐步操作完成。样品溶液从溶出仪中取出后，可以不回收至溶出仪中（消耗取样）或者返回至溶出仪中（循环取样）。
There are many brands ofautosamplers, includingsemi-automated and fully automated systems. Routineperformance checks,cleaning, and maintenance, as described in the pertinentstandard operatingprocedures or metrology documents,help to ensure reliableoperation of thesedevices.
目前自动溶出仪有多种品牌，有半自动的也有全自动的。仪器应当按照相应标准操作规程进行日常的性能检查、清洗和维护，以满足仪器正常运行。 Sampling probes may or may notremain in the vesselthroughout the entire run. Sampling probes or fiber-opticprobes can disturb thehydrodynamics of the vessel; therefore, adequatevalidation should be performedto ensure that the probes are not causing asignificant change in thedissolution rate. If filters are used that aredifferent from those used formanual sampling,then these different filtersshould also be evaluatedseparately. The position of the pharmacopeial samplingzone for Apparatus 1 andApparatus 2 is midway from the top of the stirringelement to the medium surfaceand depends on the medium
volume.Sampling probesshould pull the sample from thesampling zone. Instruments for which thesampling occurs through the hollowshaft should be designed with a means toadjust the depth of the inlet apertureto allow conformance with thisrequirement. The programmed sampling volumedepends on the dead volume of thetubing, cuvettes, and other devices and has tobe adjusted accordingly.
在整个运行过程中取样针可以放在或者不放在溶出杯中。取样针或者光纤取样针可能会影响管路中溶出介质的流体力学，因此需要进行充足的验证以保证不对药物的溶出速率造成重大的影响。如果使用的滤膜与手动操作的不同，同样需要对滤膜进行考察。药典装置1和装置2采样区的位置在搅拌元件顶部到介质表面，取决于介质的体积，取样针应能从取样区进行取样。使用空心轴进行取样的仪器，应采用一种方法来调整入口孔的深度使其符合要求。取样量根据管路、比色皿和其他设备的死体积，进行相应的调整。
A recirculated samplingalignment can be operated eitherby discharging the tubing contents into thevessel after each sampling or byallowing the tubing to remain filled withsolution in the intervals betweensampling points. In the latter case, the deadvolume and carryover effects areimportant considerations.
通过管路进行循环采样校准操作，在每次取样后将管中的溶液排入溶出杯中或者在两个取样点中间取样管充满溶液。在后者的情况下，死体积和浓度效应的影响是需要重点考虑的因素。
The need for sample volumereplacementshould be considered. In consumptive sampling with multiplesampling timepoints, the withdrawn volume may be replaced with an equal volumeof freshmedium. The sampling volume may be critical if, in total, it exceeds1% of thestated volume of dissolution medium required by the procedure. If itcan beshown that replacement of the medium is not necessary, the volume changemust bepart of the calculation of results. See section 2.5 Data Handling.
需要考虑更换样品体积。在多个采样时间点的试验中，补液是需要考虑的。当取样量的总体积超过溶出介质总体积的1%时，影响是很大的。如果能够表明介质的替换不是必须的，那么体积变化作为计算结果的一部分需要考虑，具体参见2.5节数据处理。
Carryover may occur whensubsequent samplesare affected by residues or conditions of previous samples; theeffect of thefirst sample or condition “carries over” to the second. In liquidhandling,residues of liquids previously in the sample solution may contaminatesubsequentsample solutions. Dissolution