USP-1092-溶出度试验的开发和验证(中英文对照版)

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（1092）溶出度试验的开发和验证【中英文对照版】

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 testand 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 <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

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recommendations are given with theunderstanding that modifications of the apparatus and procedures as given in

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USP general chapters need to be justified.

<1092>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 organization of <1092> follows the sequence of actions often performed inthe development and validation of a dissolution test. The sections appear inthe following sequence.

在进行溶解度实验的开发和验证时，常遵循指导原则<1092>，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）

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1.1 Performing Filter Compatibility

1.1滤膜相容性研究

1.2 Determining Solubility and Stability of DrugSubstance in Various Media 1.2原料药在不同溶出介质中溶解度测定和稳定性研究

1.3 Choosing a Medium and Volume

1.3溶出介质和体积选择

1.4 Choosing an Apparatus

1.4溶出设备选择（桨法和篮法以及其他方法）

2. METHOD DEVELOPMENT

2.方法开发

2.1 Deaeration

2.1脱气

2.2 Sinkers

2.2沉降篮

2.3 Agitation

2.3转速

2.4 Study Design

2.4研究设计

2.4.1 TimePoints

2.4.1取样时间点

2.4.2 Observations

2.4.2观察

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2.4.3 Sampling

2.4.3取样

2.4.4 Cleaning

2.4.4清洗

2.5 Data Handling

2.5数据处理

2.6 Dissolution Procedure Assessment

2.6溶出方法评估

3. ANALYTICAL FINISH

3.完成分析

3.1 Sample Processing

3.1 样品处理

3.2 Filters

3.2 过滤

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3.3 Centrifugation

3.3 离心

3.4 Analytical Procedure

3.4 分析方法

3.5 Spectrophotometric Analysis

3.5 光谱分析

3.6 HPLC

3.6HPLC法

4. AUTOMATION

4.自动化

4.1 Medium Preparation

4.1介质的配制

4.2 Sample Introduction and Timing

4.2定时进样

4.3 Sampling and Filtration

4.3取样和过滤

4.4 Cleaning

4.4 清洗

4.5 Operating Software and Computation of Results

4.5操作软件和计算的结果

5. VALIDATION

5.验证

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5.1 Specificity/Placebo Interference

5.1专属性/安慰剂（辅料）干扰

5.2 Linearity and Range

5.2线性和范围

5.3 Accuracy/Recovery

5.3准确度/回收率

5.4 Precision

5.4精密度

5.4.1 REPEATABILITY OF ANALYSIS

5.4.1重复性

5.4.2 INTERMEDIATE PRECISION/RUGGEDNESS 5.4.2中间精密度/耐用性

5.4.3 REPRODUCIBILITY

5.4.3重现性

5.5 Robustness

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5.5耐用性

5.6 Stability of Standard and Sample Solutions

5.6样品溶液和标准溶液的稳定性

5.7 Considerations for Automation

5.7自动操作注意事项

6. ACCEPTANCE CRITERIA

6.可接受标准

6.1 Immediate-Release Dosage Forms

6.1速释剂型

6.2 Delayed-Release Dosage Forms

6.2延迟释放剂型

6.3 Extended-Release Dosage Forms

6.3延长释放剂型

6.4 Multiple Dissolution Tests

6.4多个溶解度试验

6.5 Interpretation of Dissolution Results

6.5溶出结果说明

6.5.1 IMMEDIATE-RELEASE DOSAGE FORMS 6.5.1即时释放剂型

6.5.2 DELAYED-RELEASE DOSAGE FORMS 6.5.2延迟释放剂型

6.5.3 EXTENDED-RELEASE DOSAGE FORMS

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6.5.3延长释放剂型

1. PRELIMINARYASSESSMENT (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 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 Filter Compatibility

1.1滤膜相容性研究

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 results. Therefore, filteringthe dissolution samples is usually necessary and should be done immediately ifthe filter is not positioned on the cannula.

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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。

Filtration also removes 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 filtermaterial 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 changes in thequality of the ingredients (e.g. particle size of microcrystalline 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）。

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 the media and the 91ab623eac51f01dc281e53a580216fc710a53e5mon 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(e.g.,

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micronized or nanoparticles), it can be challenging to find a filterpore size that excludes these small particles.

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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：0.20～70μm，如果需要也可使用其他孔径大小的过滤器。如果原料药的粒度很小（例如，微分化颗粒或纳米颗粒），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) by the filtermay occur and needs to be evaluated. Filter materials will interact withdissolution media to affect the recovery of the inpidual solutes and must beconsidered on a case-by-case basis. Different filter materials exhibitdifferent drug-binding properties. Percentage of drug loss from the filtratedue 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 thecollection 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 interfere with the analytical procedure. This can be evaluated by analyzingthe filtered dissolution medium and comparing it with the unfiltered medium.

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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 particles to be separated. Use of thecorrect filter dimensions 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 filtration through small filter sizesneeds higher pressures and longer 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 needspecial attention because they are integrated in the flow-through process.Undissolved particles may deposit on the filters, creating resistance to theflow.

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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 filter and cloggingmay be critical for filters used in automated systems. Experimental verification 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 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 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 DrugSubstance in Various Media

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1.2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 substance need to be determinedas part of the process of selecting the proper dissolution medium. Whendeciding the composition 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 different media a t 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 typical buffer solutions. In certain cases, it may be necessary to evaluatethe solubility of the drug at temperatures other than 37

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° (i.e., 25°). The pHof the clear supernatant should be checked to determine whether the pH changesduring the solubility test. Alternative approaches for solubility determinationmay 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37℃温度条件下，采用摇瓶溶解法（平衡溶解度）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37℃以外条件下（即，25℃）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 dissolution mayinclude the following (not listed in order of preference): diluted hydrochloricacid, buffers (phosphate or acetate) in the physiologic pH range of 1.2–7.5, simulatedgastric or intestinal fluid (with or without enzymes),and water. For 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。

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