USP溶出度试验开发和验证（中英文对照版）

（1092）溶出度实验的开发和验证【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 recommendations are given with theunderstanding that modifications of the apparatus and procedures as given in USPgeneral 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） 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 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 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

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 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多个溶解度实验

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 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.

为获得准确实验结果，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实验结果出现偏差，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，但在后期实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 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(e.g., micronized or nanoparticles), it can be challenging to find a filterpore size that excludes these small particles.

用于溶出实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M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 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 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.

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.

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。通过实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 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 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 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 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。当需要确定溶出度实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。在溶解度实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。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 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 solubilityinvestigations 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 needed

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

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CMC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β-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β-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 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 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 concentration of 0.5 M in combination with SDS. This can beavoided by using the sodium phosphate salt when preparing 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. Commonly Used Surfactants with Critical Micelle Concentrations

表1 常见表面活性剂的临界胶束浓度

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 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 aqueous–organic solvent mixture as a dissolution mediumis discouraged。 however,with proper justification 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, 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 procedure. Physicalstability may be of concern when precipitation 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37℃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）。稳定性实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 Choosing aMedium and Volume 1.3溶出介质和体积的选择

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 will 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 be justifiedfrom the solubility data and the dissolution profiles.

当开发一个溶出实验方法时，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实验结果进行调整。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 enzymes in the dissolutionmedium is permitted, in accordance 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

inCapsules–Dissolution Testing and Related Quality Attributes<1094>. Validation should be performed with the method using enzymesaccording to section 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>指导原则一致。在“Capsules–Dissolution Testing and RelatedQuality Attributes<1094>”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 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 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 forms, 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 case 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).

另一种选择是使用更贴近于胃和肠道流体组分的介质。这些溶出介质可以含有生理表面活性成分，如牛黄胆酸。这些溶出介质也可能含有乳化剂（卵磷脂）和增加渗透压的组分，比如生理盐水溶液。同时，缓冲液的离子强度或体积摩尔浓度是可以控制的。设计的溶出介质模拟了进食和空腹状态下的胃和肠内状态。这些溶出介质对速释制剂（IR）建立体内溶解行为模型方面是非常有用的，特别是这些速释制剂中含有脂溶性的原料药，可能有助于理解和消化液的生理组成相关的制剂溶出动力学。溶解动力学的模型已成功建立，主要用于速释制剂。对缓释剂型减少药物溶解行为的影响，使用的这些溶出介质需要有区别地进行评估。体外性能测试并不一定需要在空腹和餐后状态建立溶出介质模型。

An acid stage is part 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 basis. Possible resolutions include the addition of surfactant tothe acid stage, or adjustment of the specifications.

对于肠溶制剂，酸中释放度是溶出度的一部分（<711>方法A或者方法B）。针对于药物标签中说明在酸中释放度不得过标示量的10%或者防止酸液中降解而进行抗酸包衣的药物。根据具体情况进行解决，可能的解决方案包括：酸性介质中添加表面活性剂或者调整质量标准）

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 stabilize the drug. There areoccasions where such actions are not sufficient. For compounds that rapidlydegrade to form a stable degradant, monitoring the degradant alone or incombination with a drug substance may be more suitable than analyzing only thedrug substance. In situ spectroscopic techniques tend to be less affected bydegradation when compared with HPLC analysis (including UHPLC and other liquidchromatographic approaches).

在选择溶解介质时，应注意采取措施确保原料药在整个分析过程中的稳定性。在某些情况下抗氧化剂，如抗坏血酸的，可用于在溶出介质中，以保证药物的稳定性。有些时候加入这些抗氧剂是不够的。化合物快速降解形成稳定的降解物，单独监测降解物或与原料药联合监控可能比只分析原料药更适合。与高效液相色谱分析比较（包括超高效液相色谱等液相色谱法），原位光谱分析受降解的影响较小。

For compendial Apparatus 1 (basket) andApparatus 2 (paddle), the volume of the dissolution medium can vary from 500 to1000 mL. Usually, the volume needed for the dissolution test can be determinedin order to maintain sink conditions. In some cases, the volume can be increased tobetween 2 and 4 L, using larger vessels and depending on the concentration andsink conditions of the drug。 justification for this approach is expected. Inpractice, the volume of the dissolution medium is usually maintained within the compendial rangegiven above. Alternatively, it may be preferable to switch to other compendialapparatus, such as a reciprocating cylinder (Apparatus 3), reciprocating holder(Apparatus 7), or flow-through cell (Apparatus 4). Certain applications may require lowvolumes of dissolution media (e.g., 100–200 mL) when the use of a paddle orbasket is preferred. In these cases, an alternative, noncompendial apparatus(e.g., small-volume apparatus) may be used.

对于药典仪器1（篮法）和仪器2（桨法），溶出介质的体积可以从500到1000毫升不同。通常情况下，溶出介质的体积应当满足漏槽条件。在某些情况下，根据药物的浓度和漏槽条件，可使用较大的溶出杯，体积可以增加至2～4升（这种方法必须有充分的理由）。实际上，溶出介质的体积通常在药典规定范围内。可供选择时，选用药典规定的其他仪器也是可取的，如往复式气缸（仪器3），往复架（仪器7），或流通池（仪器4）。当某些仪器需要较少体积的溶出介质（例如，100-200毫升）时，首选桨法或篮法。在这些情况下，非药典仪器仪器（例如，体积小的仪器）也可以选择使用。 1.4 Choosingan Apparatus

1.4溶出设备选择（桨法和篮法以及其他方法）

The choice ofapparatus is based on knowledge of the formulation design and the practicalaspects of dosage form performance in the in vitro test system. In general, acompendial apparatus should be selected.

根据对处方设计的认知和体外实验剂型的实际特点选择仪器。一般来说，首选药典仪器。

For solid oral dosage forms, Apparatus1 and Apparatus 2 are used most frequently. When Apparatus 1 or Apparatus 2 isnot appropriate, another official apparatus may be used. Apparatus 3(reciprocating cylinder) has been found especially useful for chewable tablets,soft gelatin capsules, delayed-release dosage forms, and

nondisintegrating-typeproducts, such as coated beads. Apparatus 4 (flow-through cell) may offeradvantages for modified-release dosage forms and immediate-release dosage formsthat contain active ingredients with limited solubility. In addition, Apparatus4 may have utility for multiple dosage form types such as soft gelatincapsules, beaded products, suppositories, or depot dosage forms, as well assuspension-type extended-release dosage forms. Apparatus 5 (paddle over disk)and Apparatus 6 (rotating cylinder) are useful for evaluating and testingtransdermal dosage forms. Apparatus 7 (reciprocating holder) has application tonon-disintegrating, oral modified-release dosage forms, stents, and implants,as well as transdermal dosage forms. For semisolid dosage forms, the generallyused apparatus include the vertical diffusion cell, immersion cell, andflow-through cell apparatus with the insert for topical dosage forms (seeSemisolid Drug Products—Performance Tests <1724>).

对于口服固体制剂，仪器1和仪器2使用最多。当仪器1或仪器2不适用时，可以使用其他官方仪器。已发现仪器3（往复气缸）适用于咀嚼片、软胶囊、缓释制剂和不崩解型产品（如包衣小球）。仪器4（流通池）对活性成分的溶解度有限的缓释剂型和速释剂型提供了很多优势。此外，仪器4可用于多种剂型类型，如软胶囊，微球制剂，栓剂，或贮库型产品，以及悬浮型缓释剂型。仪器5（桨盘）和仪器6（旋转缸）适用于评价和测试的经皮给药制剂。仪器7（往复架）适用非崩解制剂，口服缓释剂型，支架，和植入物，以及透皮制剂。半固态剂型，常用的仪器包括立式扩散池，浸入细胞，流通单元仪器适用局部制剂（see Semisolid DrugProducts—Performance Tests <1724>）。

Some changes can be made to thecompendial apparatus。 for example, a basket mesh size other than the typical40-mesh basket (e.g., 10-, 20-, or 80-mesh) may be used when the need isclearly documented by supporting data. Care must be taken that baskets areuniform and meet the dimensional requirements specified in <711>.

对药典仪器配件也可以进行一些调整；例如，除了药典仪器40目以外的其他规格的溶出篮（例如：10，20或者80目），通过充足的数据进行详细的阐明

后也可以使用。必须注意的是篮网孔径必须是均匀的并且满足<711>规定的尺寸要求。

A noncompendial apparatus may have someutility with proper justification, qualification, and documentation ofsuperiority over the standard equipment. For example, a small-volume apparatuswith mini paddles and baskets may be considered for low-dosage strengthproducts. A rotating bottle or dialysis tubes may have utility for microspheresand implants, peak vessels, and modified flow-through cells for special dosageforms including powders and stents.

非药典溶出仪器具有优于药典标准仪器的合适设备、资质和文件。例如，一个小体积的溶出仪器配有小桨或者小篮可以用于低剂量制剂。旋转瓶或透析管可能适用于微球、植入制剂，改进的流通池适用于特殊剂型包括粉末和支架。 2. METHODDEVELOPMENT 2. 方法的开发

A properly designed test should yielddata that are not highly variable, and should be free of significant stabilityproblems.High variability in the results can make it difficult to identifytrends or effects of formulation changes. Sample size can affect the observedvariability. One guidance defines dissolution results as highly variable if therelative standard deviation (RSD) is more than 20% at time points of 10 min orless and more than 10% at later time points for a sample size of 12 (14).However,during method development, smaller sample sizes may be used, and theanalyst will need to make a judgment accordingly.Most dissolution results,however, exhibit less variability. In the development of a dissolutionprocedure the source of the variability should be investigated, and attemptsshould be made to reduce variability whenever possible. The two most likelycauses are the formulation itself (e.g., drug substance, excipients, ormanufacturing process) or artifacts associated with the test procedure (e.g.,coning, tablets sticking to the vessel wall or basket screen). Visualobservations are often helpful for understanding the source of the variabilityand whether the dissolution test itself is contributing to the variability. Anytime the dosagecontents do not disperse freely throughout the vessel in auniform fashion, aberrant results can occur. Depending on the problem, theusual remedies include changing any of the following factors: the apparatustype, speed of agitation, level of deaeration,sinker type, or composition ofthe medium.

合理设计一个实验保证数据稳定性（即较低的变异性），并且能够明显反映出样品稳定性问题。结果的高变异难以确定处方变化的趋势和处方变化对溶出度结果的影响。样本大小影响所观察到的变异性。如果在10分钟 12个样本的相对标准偏差（RSD）不得过20%或者后续取样点的RSD值大于10%。，指导原则对溶出度实验结果定义为高变异性。然而，在方法开发过程中，可以使用较小的样

本量，需要对分析作出相应的判断。大多数溶出结果，表现出较少的变异性。在溶出度实验开发过程中应对产生变异的原因进行研究，只要有可能，应尝试减少变异性。引起变异性的两个最可能的原因是制剂本身（例如，原料药，辅料，或制剂工艺）和与检测过程相关的处理过程（例如，溶出漩涡，片粘在溶出杯壁或篮网上）。实验过程的观察往往有助于查找产生变异的原因或者溶出度测定方法本身是否会产生变异性。任何时间内剂量含量不能均匀地分散在整个容器中，异常结果就可能发生。根据不同的问题，通常的调节方法包括下列任何一个因素的改变：仪器，转速，脱气程度，沉降篮类型，或者溶出介质的组成。

Many causesof variability can be found in the formulation and manufacturing process. Forexample, poor content uniformity,process inconsistencies, excipientinteractions or interference, film coating, capsule shell aging, and hardeningor softeningof the dosage form on stability may be sources of variability andinterferences.

在处方开发和制剂工艺中，可以找到产生变异的许多原因。例如，含量均匀度的差异，工艺的不一致，辅料的相互作用或干扰，包衣，胶囊壳老化，制剂稳定性考查中出现的硬化或软化是产生和干扰变异的原因。 2.1 Deaeration 2.1脱气

Thesignificance of deaeration of the dissolution medium should be determinedbecause air bubbles can act as a barrier to the dissolution process if presenton the dosage unit or basket mesh and can adversely affect the reliability ofthe test results. Furthermore, bubbles can cause particles to cling to theapparatus and vessel walls. Bubbles on the dosage unit may increasebuoyancy,leading to an increase in the dissolution rate, or may decrease the availablesurface area, leading to a decrease in the dissolution rate. Poorly solubledrugs are most sensitive to interference from air bubbles。 therefore,deaeration may be needed when testing these types of products. A deaerationmethod is described as a footnote in the Procedure section of <711>.Typicalsteps include heating the medium, filtering, and drawing a vacuum for a shortperiod of time. Other methods of deaeration are available and are in routineuse throughout the industry. Once a suitable deaeration process is identified,it should be documented as part of the dissolution procedure. The extent ofdeaeration can be evaluated by measuring the total dissolved gas pressure or bymeasuring the concentration of dissolved oxygen in water. For example, anoxygen concentration below 6 mg/L has been found effective as a marker foradequate deaeration of water for the Performance Verification Test with USPPrednisone Tablets RS.

应明确溶出介质脱气的目的，因为在溶解过程中如果在剂量单位或篮网出现气泡，会起到一个屏障作用，影响实验结果的可靠性。此外，气泡会使颗粒粘在设备和容器壁上。剂量单位上的气泡可能会增加浮力，导致溶解速率增加，或者

也有可能会减少可接触的表面积导致溶出率下降。气泡对难溶性药物的干扰最敏感；因此检验这些类型的产品时需要脱气。在<711>部分附录中描述了脱气方法。典型的脱气方法：加热、过滤和在短时间内抽真空。其他脱气方法和常规使用的脱气方法也是可用的。一旦确定一个合适的脱气方法，应该作为溶出方法的一部分记录下来。通过测量总溶解气体压力或通过测量水中溶解的气体浓度来评估脱气的程度。例如，使用USP的性能验证测试泼尼松龙片校正片发现水中氧浓度低于6毫克/升时，表明水已充分脱气。

Media containing surfactants usuallyare not deaerated because the process results in excessive foaming, and usuallythe effect of dissolved air on the dissolution process is mitigated by thereduced surface tension of the medium. Sometimes, deaerating the medium beforeadding surfactants can be effective.

含有表面活性剂的溶出介质由于脱气过程会产生过多气泡通常不容易脱气，通常采用减少溶出介质中的表面张力，来减轻溶解的空气对溶解过程产生的影响，有时，在加入表面活性剂之前对溶出介质进行脱气是有效的。

To determine whetherdeaeration of the medium is necessary, compare results from dissolution samplesrun in non-deaeratedmedium and medium deaerated using a compendial technique,as described above. If no effect of deaeration is detected, this experiment could serve asjustification that deaeration is not required in the future. If there is aneffect, however, then it isnecessary to carefully control this parameter, andit is prudent to characterize the robustness of the deaeration process.

Thedissolvedgas content of deaerated media under atmospheric pressure is unstable and willtend toward saturation. Manipulationsof the deaerated medium such as stirringor pouring can increase the rate at which atmospheric gases are redissolved. 确定溶出介质是否需要脱气是必要的，如上面所描述的，使用药典技术中的脱气方法，比较样品在脱气和未脱气的溶出介质中的溶出实验结果。如果检测结果表明脱气对溶出结果没有影响，该实验就可以作为不需要进行脱气的理由进行说明。如果脱气对实验结果有影响，那么有必要准确控制这个参数，详细描述脱气过程中耐受性特点。在大气压强下，脱气介质中溶解的气体量是不稳定的，会趋向饱和。比如搅拌或倾倒已脱气的介质可以增加气体的再溶解速率。 2.2 Sinkers 2.2沉降篮

Sinkersare often used to adjust the buoyancy of dosage forms that would otherwisefloat during testing with Apparatus 2. When sinkers are used, a detaileddescription of the sinker must be provided in the written procedure. It may beuseful to evaluate different sinker types, recognizing that sinkers cansignificantly influence the dissolution profile of a dosage unit. Whentransferring the procedure, the same sinkers should be used, or if a differentdesign is used, it should be shown to produce equivalent results. There

areseveral types of commercially available sinkers. In <711>, a harmonizedsinker is described in Figure 2a.

在使用仪器2进行测试时，沉降篮通常用于调节易于漂浮的剂型。当使用沉降蓝时，必须对沉降篮仪器进行详细描述。评估沉降篮的不同类型，同时要认识到沉降篮能够显著影响溶出曲线。当转移这个方法时，应使用相同的沉降篮，或者如果使用不同设计的沉降篮，应当证明两种不同的沉降篮产生的结果相同。有几种可用的商业类型的沉降篮。在<711>中图2a中统一对沉降篮进行了详细的描述。

A standard sinker can be made by using theappropriate length of wire and coiling it around a cylinder. For materials,use316 stainless steel wire, typically 0.032 inch/20 gauge, or other inertmaterial and wind the wire around cylinders of appropriatediameter (e.g., corkborers) for an appropriate number of turns to fit the capsule shell type. Sizesare shown in Table 2. Theends of the coil can be curved to retain thecapsule within the sinker when they are immersed. Because the ends of thewiremay be rough, they may need to be filed. If the sinker is handmade, thesinker material and construction procedure instructionsshould be documented(e.g., dimension, design, number of coils)。 if a commercial sinker is used, thevendor part numbershould be reported if available.

一个标准的沉降篮可以通过使用合适长度的金属丝围绕圆柱体卷绕制成。使用316不锈钢丝为材料，通常0.032英寸/20号，或其它惰性材料和缠绕适当直径的圆柱体（如，木塞穿孔器）和缸丝匝数量以适合胶囊壳的类型。表2中列出了尺寸。线圈的端部可以是弯曲的，以保持胶囊在沉降篮内浸润。因为金属丝的端部是粗糙的，他们可能需要修整。如果沉降篮是手工制作，应记录沉降篮的材料和结构（例如，尺寸，设计，线圈数）。如果用的是商业沉降篮，应当提供供应商零件号。

Table 2. WireSinkers Used With Common Capsule Shell Sizes

表2普通胶囊壳规格使用的沉降篮金属线尺寸

Although sinkers are typically used to keep thedosage form at the bottom of the vessel, they can also be used to keep dosageforms from sticking to the vessel (e.g., film-coated tablets). The sinkershould be appropriate to the dosage form。 therefore,the same sinker size maynot be suitable for all dosage-form sizes. The sinker should not be too tightaround the dosage form because this may restrict interaction with the

medium.Conversely, if wrapped too loosely, the dosage form may escape soon after the testbegins. The sinker should be small enough that the capsule does not change itsorientation within the sinker.Care should be taken when testing capsules thathave some cross-linking present, to keep the sticky shell from attaching to thevessel bottom. In this case, the harmonized sinker design provided in Figure2a of <711>will be advantageous.

虽然通常使用的沉降篮是为了保持剂型在容器底部，它们也能够使剂型不粘附在容器壁中（例如：薄膜包衣片）。沉降篮应适合于剂型。因此，相同大小的沉降篮可能不适合所有的剂型型号。沉降篮不应围绕剂型太紧或太松，太紧可能会限制剂型与介质的相互作用，太松剂型可能会逃脱。在测试开始后不久。沉降篮应该足够小使得胶囊在沉降篮内不能改变方向。胶囊存在交联时，实验时应小心，以保持胶囊壳不粘附在容器底部。在这种情况下，在<711>图2a中统一提供的沉降篮设计将是有利的。 2.3 Agitation 2.3转速

Forimmediate-release capsule or tablet formulations, Apparatus 1 (baskets) at 50–100 rpm or Apparatus 2 (paddles) at 50or 75rpm are used commonly. Other agitation speeds are acceptable with appropriatejustification. Rates outside 25–150 rpmfor both the paddle and the basket are usually not appropriatebecause of mixing inconsistencies that can be generated bystirring too slow ortoo fast. Agitation rates between 25 and 50 rpm are generally acceptable forsuspensions.

对于速释胶囊或片剂，一般采用仪器1（篮法）50～100 rpm，或者仪器2（桨法）50或75rpm。如果有合适的理由选择其他转速也是可以接受的。考虑到转速太慢或太快产生混合不一致，无论是篮法或者桨法，低于25 rpm或高于150 rpm的转速，均是不能接受的。对于混悬剂一般推荐转速25rpm～50rpm。 For dosage forms that exhibit coning(mounding) under the paddle at 50 rpm, the coning can be reduced by increasingthe paddle speed to 75 rpm, thus reducing the artifact and improving the data.If justified, 100 rpm may be used with Apparatus 2, especially forextended-release products. Decreasing or increasing the apparatus rotationspeed may be justified if to achieve an in-vitro–in-vivo correlation (IVIVC)the resulting profiles better reflect in vivo performance, or if the methodresults in better discrimination without adversely affecting method variability.

桨转速50rpm时，剂型在浆下存在圆锥（丘）状，将转速增加至75 rpm可以减少圆锥状，从而提高溶出数据。尤其是对于缓释制剂制剂，如果经过证明，也可以采用桨法100rpm转速。如果能够实现体内外相关性（IVIVC），使体外溶出曲线更好的反应体内溶出特性，或者在不影响方法差异性的情况下溶出结果具有更好的区分力，增加或减小仪器转速均是合理的。

Apparatus 3 (reciprocating cylinder)can be used at dip rates ranging from 5 to 30 dips/min. The hydrodynamics areinfluenced by the cylinder's reciprocating motion and the resulting movement ofthe sample in the medium. The reciprocating motion of the cylinder and screenmay cause foaming if the medium contains surfactants. Addition of ananti-foaming agent such as simethicone or n-octanol may be useful foravoiding foaming from surfactants.

仪器3（往复缸）可用于浸率范围5～30 dips/分钟。气缸的往复运动影响流体力学和样品在介质中溶出结果。如果溶出介质中含有表面活性剂，在气缸和监视器的往复运动会引起起泡。加入消泡剂，如硅油或正辛醇，可避免表面活性剂产生的泡沫。

Apparatus 4(flow-through cell) is described in <711> with standard flow rates of 4, 8,and 16 mL/min. Other flow rates for Apparatus 4 can be used if justified and ifwithin the capacity of the pump to conform with the requirements in á711?. Agitationin Apparatus 4 is not only related to the pump speed but can also be affectedby cell diameter. At a set flow rate, as measured by volume, the 12-mm cellwill develop a greater linear fluid velocity than is achieved in the 22.6-mmcell. Apparatus 4 can be configured with the addition of glass beads in theentry cone of the flow-through cell (packed column) or without glass beads(open column).

仪器4 (流通池)在<711>中描述了标准流速4、8、16ml/min。如果经过验证并且在该泵的承受的能力范围内符合<711>的要求，仪器4也可以使用其他流速。在仪器4中搅动不仅影响泵的速度也影响孔直径。通过测定体积设定流速，12mm孔径比22.6mm孔径产生的线性流速要大。仪器4在流体单元的入口通过加入玻璃珠（填充柱）或者去掉玻璃珠（开放柱）进行配置。 2.4 Study Design 2.4 研究设计

Selectionof the agitation rate and other study design elements for the dosage form,whether immediate release or modified release, should conform to therequirements and specifications (i.e., apparatus, procedures, andinterpretation) given in <711>.

不管是速释制剂或者是缓控释制剂，对转速选择和剂型的其他研究设计，均应符合<711>规范要求（即仪器，方法和说明）。 2.4.1 TIME POINTS 2.4.1 取样时间点

For immediate-release dosage forms, theduration of the dissolution procedure is typically 30–60 min。 in most cases, asingle time point specification is adequate for pharmacopeial purposes. Formethod development, however, a sufficient number of time points should beselected to adequately characterize the ascending and plateau

phases of thedissolution curve. Industrial and regulatory concepts of product comparabilityand performance may require additional time points, which may also be requiredfor product registration or approval. According to the

BiopharmaceuticsClassification System referred to in severalFDA Guidances, highly soluble,highly permeable drugs formulated into very rapidly dissolving products neednot be subjected to a profile comparison if they can be shown to release 85% ormore of the drug substance within 15 min. For these types of products, aone-point test or disintegration will suffice. However, most products do notfall into this category. Dissolution profiles of immediate-release productstypically show a gradual increase reaching 85%–100% at about 30–45 min. Thus,sufficient dissolution time points are chosen to characterize the performancefor most immediate-release products. For some products,including suspensions,useful information may be obtained from earlier points, e.g., 5–10 min. Forslower-dissolving products, time points later than 60 min may be useful.Dissolution test times for compendial tests are usually established on thebasis of an evaluation of the dissolution profile data.

对于速释制剂，溶出度测定时间通常为30～60 min；在大多数情况下，单点取样设计足够满足药典的控制要求。但是，对于方法的开发阶段，应选择足够多的时间点来充分表征溶出量增加和达到溶出平台的趋势。工业和法规概念对产品的相似性和产品性能进行研究需要增加取样时间点，产品的注册或批准同样需要。根据FDA指导原则中生物药剂学分类系统，高溶解性高渗透性药物（快速溶出药物），如果在15分钟内溶出度达到85%以上，可不再进行曲线考察，单点实验就足够了。然而，大多数产品不属于这一分类。速释制剂的溶出度通常呈逐渐增加趋势，一般在30～45分钟溶出达到85%～100%。因此，大多数速释制剂会选择充足的时间点来表征产品的溶出特性。对于一些产品，包括悬浮液，早期取样时间点获得的信息比较有用，例如，5，10分钟。对于溶出速度较慢的产品，60分钟后的时间点可能是有用的。药典中规定溶解度实验时间的确定通常是建立在对溶出曲线数据评估的基础之上。

The f2 similarityfactor may not be useful when more than 85% is dissolved at 15 min. If the f2similarity factor is to be used,multiple time points for the dissolution testare required, with at least two time points with mean percent dissolved(typically for n = 12) below 85% dissolved and only one point above 85% forboth products (16). Therefore, the addition of early time points may be useful.

f2相似因子不适用于15分钟溶出量大于85%的制剂。如果使用f2相似因子进行比较，需要进行多个时间点溶出度测定，至少两个取样时间点平均溶出值低于85%（一般是n=12）并且两组产品的溶出度值只有一个时间点大于85%。因此，在早期增加时间点检查是有必要的。

For testing anextended-release dosage form, at least three time points are chosen, to guardagainst dose dumping, to define the in vitro release profile, and to show thatessentially complete release (>80%) of the drug is achieved. Additionalsampling times may be useful. Certain IVIVC criteria, such as level Bcorrelation (according to In Vitro and In Vivo Evaluation of DosageForms<1088>), require the experimental determination of the timeto dissolve 100% of the label claim. Selection of the final time points isreflective of the data from the drug release profile that are generated duringdevelopment. For products containing more than a single active ingredient,determine the drug release for each active ingredient.

对于缓释剂型溶出实验，至少选择三个时间点确定体外释放曲线，以防止剂量释放不完全，并要求药物释放完全（>80%）。增加取样时间点可能是有用的。根据体内外相关标准，如B级相关（根据“In Vitro and In Vivo Evaluation of Dosage Forms <1088>”）需要根据实验确定药物释放100%的时间点。在开发过程中，最后时间点的选择是为了反映药物释放曲线。对于含有多个活性成分的产品，需要确定每种活性成分的药物释放。

Delayed-release dosage formsusually require specifications for at least two time points。 therefore, it isimportant during development to evaluate the entire dissolution profile. In thecase of enteric-coated dosage forms, the functionality of the coating isusually proven by challenge in an acid medium, followed by a demonstration ofdissolution in a higher-pH medium. Chapter <711> gives a standard buffer medium for that stage of testing but other mediamay be used if justified. The timing of the acid stage is typically 2 h, andrelease in the buffer is similar to the timing

forimmediate-release forms. Fordelayed-release dosage forms that are not enteric coated, setting of specificationsis different. Unlike delayed release, the onset of release is not determined by theexperimental design, which is the pH change。 multivariatespecifications,therefore, may be needed to definetime ranges and corresponding percentageranges

延迟释放剂型通常需要至少设计2个时间点，因此，在开发过程中对整个溶出曲线进行评估是非常重要的。至于肠溶包衣制剂，通常用在酸介质中的抗酸能力来证明包衣作用，然后证明在一个较高的pH值介质中的溶出度，在<711>章节给出了标准的缓冲介质中的溶解行为（如果经过验证其他溶出介质也是可以使用的）。酸中释放时间通常是2小时，与速释制剂在缓冲液中释放时间类似。对于没有进行肠溶包衣的缓释剂型，规格设定是不同的。不像延迟释放，不能通过实验设计、pH值变化来确定初始释放,因此，多种规格的制剂可能需要确定时间范围和相应的百分比范围。

So-called infinity points canbe useful during development studies. To obtain an infinity point, the paddleor basket speed is increased at the end of the run (after the last time

point)for a sustained period (typically, 15–60 min), after which time an

additionalsample is taken. Although there is no requirement for 100% dissolution in theprofile, the infinity point can be compared to content uniformity data and mayprovide useful information about formulation characteristics during initialdevelopment or about method bias.

所谓的无穷点在开发研究中是有用的。为了获得一个无穷大点，在运行结束后（一般是最后一个取样时间点）增加桨或篮的转速，并维持一段时间（通常是15～60分钟），在这段时间后，取样测定。虽然在溶出曲线中不要求100%的溶出，但是无限点可以比较药物的均一性，并可以提供有用的信息，用于评估初始开发过程中的制剂特性或方法偏差。 2.4.2 OBSERVATIONS 2.4.2 观察

Visual observations and recordings ofproduct dissolution and disintegration behavior are useful because dissolutionand disintegrationpatterns can be indicative of variables in the formulation ormanufacturing process. For visual observation, proper lighting (with appropriateconsideration of photo-degradation) of the vessel contents and clear visibilityin the bath are essential.Documenting observations by drawing sketches andtaking photographs or videos can be instructive and helpful for thosewho arenot able to observe the real-time dissolution test. Observations are especiallyuseful during method development andformulation optimization. It is importantto record observations of all six vessels to determine if the observation isseen in all six vessels, or just a few. If the test isperformed to assist with formulation development, provide any uniqueobservations to theformulator. Examples of typical observations include, butare not limited to, the following:

观察并记录产品的崩解和溶出行为是有用的，因为崩解和溶出方式可以为处方和工艺提供详细的信息。观察过程中，为清晰观察溶出杯中内容物，提供适当程度的光（适当考虑光降解）是必不可少的。绘制草图、拍摄照片或录像记录观测结果，对那些不能够实时观察溶出度实验的人来说是有用的。观察溶出过程变化对方法开发和配方优化特别有用。重要的是要记录所有六个溶出杯的观察结果，以确定是否在六个容器中观察到该结果，或者仅仅是几个溶出杯观察到该结果。如果测试的目的是为了协助处方开发，为处方设计提供任何观察到的独特现象。通常观察到的现象包括，但不限于以下内容：

1.Uneven distribution of particles throughout the vessel. This can occur when particlescling to the sides of the vessel, when there is coning or mounding directlyunder the apparatus (e.g., below the basket or paddle), when particles float atthe surface of the medium, when film-coated tablets stick to the vessel, and/orwhen off-center mounds are formed.

2.Air bubbles on the inside of the vessel or on the apparatus or dosage unit.Sheen on the apparatus is also a sign of air bubbles. This observation wouldtypically be made when assessing the need to deaerate the medium.

3.Dancing or spinning of the dosage unit, or the dosage unit being hit by thepaddle. 4.Adhesion of particles to the paddle or the inside of the basket, which may beobserved upon removal of the stirring deviceat the end of the run.

5.Pellicles or analogous formations, such as transparent sacs or rubbery, swollenmasses surrounding the capsule contents.

6.Presence of large floating particles or chunks of the dosage unit, especiallyat the surface of the media.

7.Observation of the disintegration rate (e.g., percentage reduction in size ofthe dosage unit within a certain time frame).

8.Complex disintegration of the coating of modified or enteric-coated products,[e.g., the partial opening and splittingapart (similar to a clamshell) orincomplete opening of the shell], accompanied by the release of air bubbles andexcipients.

9.Whether the dosage form lands in the vessel center or off-center, and ifoff-center, whether it sticks there.

10.Time required for the complete dissolution of the capsule shell or for tabletdisintegration.

1.颗粒在整个容器内分布不均。这可以发生在颗粒附着到容器的两侧，篮下或者桨下有锥型堆积物，当物品浮在介质表面，当薄膜衣片粘在杯壁，和/或当偏离中心的堆状物形成。

2.气泡在容器内或仪器上或单片制剂上。仪器上的光泽也是气泡的标志。在评估是否需要进行溶出介质脱气时会进行这些观察。 3.单位制剂摇晃或者旋转，或溶出桨击中单位制剂。 4.实验结束后，颗粒粘附于桨或篮内。

5.薄膜或类似的结构，如透明囊或橡皮囊，围绕胶囊内容物的膨胀部分。 6.尤其在溶出介质表面，存在大量的漂浮颗粒或块状物。

7.观察的崩解速度（例如，在一定的时间范围内，在剂量单位大小的百分比减少）。 8.包衣修饰或肠溶性产品的复杂崩解[例如，部分开放和分裂（类似于翻盖）或不完整的外壳开口]，伴随气泡和辅料的释放。

9.剂型是否位于中心还是偏离中心，如果偏离中心，是否粘附。 10.胶囊壳完全溶解或片剂崩解所需的时间。

Observationsalso help to document that the proper procedure has been followed, or more importantly,that a deviation has occurred. Examples include the confirmation that a dosageform is actually in the vessel during the test or that more than one dosageform

are inadvertently in the same vessel, or that a filter from theautosampler has dropped into the vessel.

发生偏差时，观察也有助于证明所进行操作方法的正确性或哪些操作方法是重要的。实例包括在实验期间确认在容器中实际存在的是一种剂型，或同一容器无意中存在多种剂型，或自动进样器的过滤器掉进容器中。 2.4 Study Design 2.4 研究设计

Selectionof the agitation rate and other study design elements for the dosage form,whether immediate release or modified release, should conform to therequirements and specifications (i.e., apparatus, procedures, andinterpretation) given in <711>.

不管是速释制剂或者是缓控释制剂，对转速选择和剂型的其他研究设计，均应符合<711>规范要求（即仪器，方法和说明）。 2.4.1 TIME POINTS 2.4.1 取样时间点

For immediate-release dosage forms, theduration of the dissolution procedure is typically 30–60 min。 in most cases, asingle time point specification is adequate for pharmacopeial purposes. Formethod development, however, a sufficient number of time points should beselected to adequately characterize the ascending and plateau phases of thedissolution curve. Industrial and regulatory concepts of product comparabilityand performance may require additional time points, which may also be requiredfor product registration or approval. According to the

BiopharmaceuticsClassification System referred to in severalFDA Guidances, highly soluble,highly permeable drugs formulated into very rapidly dissolving products neednot be subjected to a profile comparison if they can be shown to release 85% ormore of the drug substance within 15 min. For these types of products, aone-point test or disintegration will suffice. However, most products do notfall into this category. Dissolution profiles of immediate-release productstypically show a gradual increase reaching 85%–100% at about 30–45 min. Thus,sufficient dissolution time points are chosen to characterize the performancefor most immediate-release products. For some products,including suspensions,useful information may be obtained from earlier points, e.g., 5–10 min. Forslower-dissolving products, time points later than 60 min may be useful.Dissolution test times for compendial tests are usually established on thebasis of an evaluation of the dissolution profile data.

对于速释制剂，溶出度测定时间通常为30～60 min；在大多数情况下，单点取样设计足够满足药典的控制要求。但是，对于方法的开发阶段，应选择足够多的时间点来充分表征溶出量增加和达到溶出平台的趋势。工业和法规概念对产

品的相似性和产品性能进行研究需要增加取样时间点，产品的注册或批准同样需要。根据FDA指导原则中生物药剂学分类系统，高溶解性高渗透性药物（快速溶出药物），如果在15分钟内溶出度达到85%以上，可不再进行曲线考察，单点实验就足够了。然而，大多数产品不属于这一分类。速释制剂的溶出度通常呈逐渐增加趋势，一般在30～45分钟溶出达到85%～100%。因此，大多数速释制剂会选择充足的时间点来表征产品的溶出特性。对于一些产品，包括悬浮液，早期取样时间点获得的信息比较有用，例如，5，10分钟。对于溶出速度较慢的产品，60分钟后的时间点可能是有用的。药典中规定溶解度实验时间的确定通常是建立在对溶出曲线数据评估的基础之上。

The f2 similarityfactor may not be useful when more than 85% is dissolved at 15 min. If the f2similarity factor is to be used,multiple time points for the dissolution testare required, with at least two time points with mean percent dissolved(typically for n = 12) below 85% dissolved and only one point above 85% forboth products (16). Therefore, the addition of early time points may be useful.

f2相似因子不适用于15分钟溶出量大于85%的制剂。如果使用f2相似因子进行比较，需要进行多个时间点溶出度测定，至少两个取样时间点平均溶出值低于85%（一般是n=12）并且两组产品的溶出度值只有一个时间点大于85%。因此，在早期增加时间点检查是有必要的。

For testing anextended-release dosage form, at least three time points are chosen, to guardagainst dose dumping, to define the in vitro release profile, and to show thatessentially complete release (>80%) of the drug is achieved. Additionalsampling times may be useful. Certain IVIVC criteria, such as level Bcorrelation (according to In Vitro and In Vivo Evaluation of DosageForms<1088>), require the experimental determination of the timeto dissolve 100% of the label claim. Selection of the final time points isreflective of the data from the drug release profile that are generated duringdevelopment. For products containing more than a single active ingredient,determine the drug release for each active ingredient.

对于缓释剂型溶出实验，至少选择三个时间点确定体外释放曲线，以防止剂量释放不完全，并要求药物释放完全（>80%）。增加取样时间点可能是有用的。根据体内外相关标准，如B级相关（根据“In Vitro and In Vivo Evaluation of Dosage Forms <1088>”）需要根据实验确定药物释放100%的时间点。在开发过程中，最后时间点的选择是为了反映药物释放曲线。对于含有多个活性成分的产品，需要确定每种活性成分的药物释放。

Delayed-release dosage formsusually require specifications for at least two time points。 therefore, it isimportant during development to evaluate the entire dissolution profile. In thecase of enteric-coated dosage forms, the functionality of the coating isusually proven by challenge in an acid medium, followed by a demonstration

ofdissolution in a higher-pH medium. Chapter <711> gives a standard buffer medium for that stage of testing but other mediamay be used if justified. The timing of the acid stage is typically 2 h, andrelease in the buffer is similar to the timing

forimmediate-release forms. Fordelayed-release dosage forms that are not enteric coated, setting of specificationsis different. Unlike delayed release, the onset of release is not determined by theexperimental design, which is the pH change。 multivariatespecifications,therefore, may be needed to definetime ranges and corresponding percentageranges

延迟释放剂型通常需要至少设计2个时间点，因此，在开发过程中对整个溶出曲线进行评估是非常重要的。至于肠溶包衣制剂，通常用在酸介质中的抗酸能力来证明包衣作用，然后证明在一个较高的pH值介质中的溶出度，在<711>章节给出了标准的缓冲介质中的溶解行为（如果经过验证其他溶出介质也是可以使用的）。酸中释放时间通常是2小时，与速释制剂在缓冲液中释放时间类似。对于没有进行肠溶包衣的缓释剂型，规格设定是不同的。不像延迟释放，不能通过实验设计、pH值变化来确定初始释放,因此，多种规格的制剂可能需要确定时间范围和相应的百分比范围。

So-called infinity points canbe useful during development studies. To obtain an infinity point, the paddleor basket speed is increased at the end of the run (after the last time point)for a sustained period (typically, 15–60 min), after which time an

additionalsample is taken. Although there is no requirement for 100% dissolution in theprofile, the infinity point can be compared to content uniformity data and mayprovide useful information about formulation characteristics during initialdevelopment or about method bias.

所谓的无穷点在开发研究中是有用的。为了获得一个无穷大点，在运行结束后（一般是最后一个取样时间点）增加桨或篮的转速，并维持一段时间（通常是15～60分钟），在这段时间后，取样测定。虽然在溶出曲线中不要求100%的溶出，但是无限点可以比较药物的均一性，并可以提供有用的信息，用于评估初始开发过程中的制剂特性或方法偏差。 2.4.2 OBSERVATIONS 2.4.2 观察

Visual observations and recordings ofproduct dissolution and disintegration behavior are useful because dissolutionand disintegrationpatterns can be indicative of variables in the formulation ormanufacturing process. For visual observation, proper lighting (with appropriateconsideration of photo-degradation) of the vessel contents and clear visibilityin the bath are essential.Documenting observations by drawing sketches andtaking photographs or videos can be instructive and helpful for thosewho arenot able to observe the real-time dissolution test. Observations are especiallyuseful

during method development andformulation optimization. It is importantto record observations of all six vessels to determine if the observation isseen in all six vessels, or just a few. If the test isperformed to assist with formulation development, provide any uniqueobservations to theformulator. Examples of typical observations include, butare not limited to, the following:

观察并记录产品的崩解和溶出行为是有用的，因为崩解和溶出方式可以为处方和工艺提供详细的信息。观察过程中，为清晰观察溶出杯中内容物，提供适当程度的光（适当考虑光降解）是必不可少的。绘制草图、拍摄照片或录像记录观测结果，对那些不能够实时观察溶出度实验的人来说是有用的。观察溶出过程变化对方法开发和配方优化特别有用。重要的是要记录所有六个溶出杯的观察结果，以确定是否在六个容器中观察到该结果，或者仅仅是几个溶出杯观察到该结果。如果测试的目的是为了协助处方开发，为处方设计提供任何观察到的独特现象。通常观察到的现象包括，但不限于以下内容：

1.Uneven distribution of particles throughout the vessel. This can occur when particlescling to the sides of the vessel, when there is coning or mounding directlyunder the apparatus (e.g., below the basket or paddle), when particles float atthe surface of the medium, when film-coated tablets stick to the vessel, and/orwhen off-center mounds are formed.

2.Air bubbles on the inside of the vessel or on the apparatus or dosage unit.Sheen on the apparatus is also a sign of air bubbles. This observation wouldtypically be made when assessing the need to deaerate the medium.

3.Dancing or spinning of the dosage unit, or the dosage unit being hit by thepaddle. 4.Adhesion of particles to the paddle or the inside of the basket, which may beobserved upon removal of the stirring deviceat the end of the run.

5.Pellicles or analogous formations, such as transparent sacs or rubbery, swollenmasses surrounding the capsule contents.

6.Presence of large floating particles or chunks of the dosage unit, especiallyat the surface of the media.

7.Observation of the disintegration rate (e.g., percentage reduction in size ofthe dosage unit within a certain time frame).

8.Complex disintegration of the coating of modified or enteric-coated products,[e.g., the partial opening and splittingapart (similar to a clamshell) orincomplete opening of the shell], accompanied by the release of air bubbles andexcipients.

9.Whether the dosage form lands in the vessel center or off-center, and ifoff-center, whether it sticks there.

10.Time required for the complete dissolution of the capsule shell or for tabletdisintegration.

1.颗粒在整个容器内分布不均。这可以发生在颗粒附着到容器的两侧，篮下或者桨下有锥型堆积物，当物品浮在介质表面，当薄膜衣片粘在杯壁，和/或当偏离中心的堆状物形成。

2.气泡在容器内或仪器上或单片制剂上。仪器上的光泽也是气泡的标志。在评估是否需要进行溶出介质脱气时会进行这些观察。 3.单位制剂摇晃或者旋转，或溶出桨击中单位制剂。 4.实验结束后，颗粒粘附于桨或篮内。

5.薄膜或类似的结构，如透明囊或橡皮囊，围绕胶囊内容物的膨胀部分。 6.尤其在溶出介质表面，存在大量的漂浮颗粒或块状物。

7.观察的崩解速度（例如，在一定的时间范围内，在剂量单位大小的百分比减少）。 8.包衣修饰或肠溶性产品的复杂崩解[例如，部分开放和分裂（类似于翻盖）或不完整的外壳开口]，伴随气泡和辅料的释放。

9.剂型是否位于中心还是偏离中心，如果偏离中心，是否粘附。 10.胶囊壳完全溶解或片剂崩解所需的时间。

Observationsalso help to document that the proper procedure has been followed, or more importantly,that a deviation has occurred. Examples include the confirmation that a dosageform is actually in the vessel during the test or that more than one dosageform are inadvertently in the same vessel, or that a filter from theautosampler has dropped into the vessel.

发生偏差时，观察也有助于证明所进行操作方法的正确性或哪些操作方法是重要的。实例包括在实验期间确认在容器中实际存在的是一种剂型，或同一容器无意中存在多种剂型，或自动进样器的过滤器掉进容器中。

Figure 1. An example of a plotof dissolution as a cumulative process. Concentration, C, is the amountof drug released per volume of medium, and t represents time. This type of

plotis readily observed in constant-volume dissolution systems, such as Apparatus 1or Apparatus 2, or Apparatus 4 in closed-loop configuration.

图1.作为一个累积溶出率的例子。浓度（C）是每体积溶出介质药物释放量量；t代表时间。这种类型的溶解曲线在体积恒定的溶解系统很容易观察到，如仪器1或仪器2，或在仪器4闭环结构中。

Figure 2 An example of a plot of theobserved concentration of the sample taken for an interval that is negligiblysmall in relation to the time of the overall dissolution process. This concentrationis propostional to the instantaneous or fractional dissolution rate(dc/dt).This type of plot is readily observed in continuous-flow dissolution systems,such as Apparatus 4 in openloop configuration.

图2.在一个时间区间观察到样品浓度的释放曲线对于整个溶解过程是非常小的，这个浓度与瞬时或部分溶出速率呈正比(dc/dt)。这种类型的溶解曲线在体积恒定的溶解系统很容易观察到，比如仪器4开环结构中。

Cumulative dissolution profiles represent the totalamount of drug dissolved from the formulation over time. Whencumulativedissolution is measured in

aconstant-volume system, no correction forthe amount lost in sampling needs to be made. Ifsample is removed from thesystem, the amount consumed in analysis must be accounted for in thecalculation. Recirculatedsampling with Apparatus 1 or Apparatus 2, or withApparatus 4 in the closed-loop configuration (Figure 3), are allexamples ofsystems that will produce cumulative dissolution rates. WithApparatus 4 in the open configuration (Figure 4), cumulativeratesaccounting for the total amount of drug dissolved across the testinginterval are obtained by collecting and analyzing the entireoutflow from eachindividual flow-through cell. With Apparatus 3 (Figure 5), the medium ineach tube is sampled at theend of the programmed interval, and the analyzedconcentration represents the cumulative dissolution rate during that interval.

累计溶出曲线代表药物随着时间从制剂中的溶出总量。当在一个恒定体积系统中测定累计溶出度时，取样损失量不需要进行校正。如果样品从系统中移除分析时消耗的量必须在计算时进行说明。用仪器1或仪器2或仪器4封闭系统结构（图3）进行循环采样是所有平衡系统产生累积溶出速率的例子。用仪器4开放结构（图4）通过收集和分析每个流通池的整个流出量的累积溶出速率在检测时间间隔占药物溶出总量的比值。用仪器3（图5）在程序间隔的终点对每个管中的溶出介质进行采样，并且所分析的浓度表示在该时间间隔累积溶出速率。 Fractional dissolution ratesare typically measured for a discrete interval. A series of such rates willproduce a step function asthe dissolution profile. At any time, the cumulativedissolution rate from this type of profile is the sum of the precedingintervals.This type of profile is represented by Apparatus 3 using multipletubes or Apparatus 4 in the open-loop configurationwhere the total outflow iscollected and analyzed for successive intervals.A number of algebraic andnumerical methods exist for transforming cumulative and fractional dissolutionresults. The differencein amount released for successive time points can becalculated, and the average release rate is determined by the formula:

Result = (M2 ?M1)/(t2 ?t1) M = mass or percentage of label claim t = time

通常在离散区间测定部分溶出速率，一系列这样的溶出速率将产生溶出曲线阶梯函数。在任何时间，这种类型溶出曲线的累积溶出速率是先前时间间隔的速率总和。这种类型的曲线代表仪器3用多个试管或仪器4开放系统结构在连续间隔收集总流出量进行分析。在许多代数和数值方法中存在累积转化和分级溶出实验结果。计算连续时间点释放量的差值，平均释放率由下列公式确定：

结果=（M2-M1）/（t2-t1） M=标示量要求的质量和比例 t=时间

As the difference of t2fromt1is reduced, the average rate can be considered to approachan instantaneous rate. Samplingconsiderations and physical constraints onmeasurement of the mass transfer at the medium interface of the dosage formmakethe measurement of true instantaneous dissolution impractical for routinedetermination in the laboratory. Fractional dissolution is measured forintervals where the difference between t2and t1issmall, relative to the total test time. The design of

Apparatus 4 in the openconfiguration permits a direct measurement of the fractional dissolution oversmall time intervals. Forexample, if a 4-mL fraction of outflow for Apparatus 4running 16 mL/min is sampled, either by in situ detection or offline, the

amount of drug detectedrepresents the dissolution occurring in a 15-s interval.

减小t2和t1的差值，平均速率接近于瞬时速率。取样的考虑和在介质界面的剂型质量转移的物理限制使实验室常规测定真正瞬时溶出的方法不切实际。在时间间隔对分级溶解度进行测定时，相对于总的测定时间，t2和t1之间的差是小的，仪器4在开放系统的设计允许在较小的时间间隔直接分级测定溶解度。例如，如果仪器4样品运行速度16ml/min，流出量4ml，或者在原位检测或者离线检测，检测到的药物的量代表在15s时间间隔发生的溶出量。

Pooled dissolution has beenused in a number of monographs. The pooled dissolution procedure produces anaverage releaserate for the units tested by combining equal volumes from eachvessel or cell and performing analysis of only the oneresulting solution. Becausethis approach uses only the average release rate for comparison with theacceptance table, thepooled dissolution procedure has been viewed as reducingthe amount of data available from the dissolution test and, thus,reducing itsvalue. However, it should be noted that the pooling of equal sample volumes isequivalent, from a calculationstandpoint, to determining the arithmetic mean ofthe individual sample results.

许多著作中提到了混合溶解度，混合溶解度过程通过连接每个体积或流通池检测样品单元和仅在一个合并溶液中进行分析产生一个平均释放速率。因为这种方法仅使用了平均释放速率与验证表进行比较，混合溶出过程被认为减少了溶出实验的可接受数据量，因此数值降低。但是，应该注意从计算的角度考虑样品体积等量混合和确定每个样品算术平均值结果是相同的。

The use of the f2similarityfactor in the comparison of dissolution profiles is discussed in Assessmentof Drug Product Performance—Bioavailability,Bioequivalence, and Dissolution <1090>.

使用f2相似因子比较溶出曲线在“Assessment of Drug

ProductPerformance—Bioavailability,Bioequivalence, and Dissolution <1090>”中进行了讨论。

Forthe purpose of correlation with in vivo data, parameters of mathematical modelsare obtained by fitting to dissolutiondata to establish a continuous functionalrelationship called IVIVC (see <1088>).

对于体内数据的相关性，通过拟合溶出数据获得参数的数据模型来建立一个连续的函数关系称作IVIVC（参见<1088>） 2.6Dissolution Procedure Assessment 2.6 溶出方法评估

Thedissolution procedure requires an apparatus, a dissolution medium, and testconditions that together provide a method that is sensitive to changes incritical

quality attributes, yet sufficiently rugged and reproducible forday-to-day operation. The method should be able to be transferred betweenlaboratories.

溶出度实验方法由仪器、溶出介质，和测试条件一起组成，建立溶出方法，该方法能够敏感反应产品的关键属性变化，同时能够适用于日常操作，并且能够在实验室之间进行转移。

The idealdissolution procedure will not contribute an unacceptable degree of variabilityand will provide a profile with adequate points below 85% dissolved. If 85%dissolved occurs before 15 min, then f2 comparisons may not be appropriate.

理想的溶出方法的变异程度是可以接受的，溶出低于85%将提供足够多的取样点。如果在15分钟之前溶出度达到85%，f2相似因子将不再适用。 There are many ways tochallenge the sensitivity of the method. One option is to compare dissolutionprofiles of formulationsthat are intentionally manufactured with meaningfulvariations for the most relevant critical manufacturing variable,

forexample,±10%–20% change to the ranges of these variables. Similarly, samples that havebeen stressed may be used to demonstratesensitivity to changes on stability.This concept may be used to establish the factors that are most significant intheirinfluence on the dissolution rate. These studies can focus on eitherthedissolution parameters (e.g., media concentration, agitationrate, anddeaeration) or the product attributes (e.g., excipient ratios, particle size,compression). The ultimate goal is tounderstand the release mechanisms anddetermine whether the dissolution procedure can show change in the criticalqualityattributes of a drug product.

有很多方式来挑战该方法的灵敏度。一种选择是通过故意制造出最相关的关键变量，例如，±10%～20%的变化来比较制剂的溶出曲线。同样，已被强调的样品可以用来证明对稳定性的变化的敏感性。这一概念可以用来建立最显著影响溶出率的因素。这些研究可以集中在溶出参数（例如，介质浓度，转速，和脱气）或产品属性（例如，辅料比例，颗粒大小，压缩）。最终的目标是为了理解释放机理，并确定溶出度方法是否可以表明制剂关键质量属性的变化。 3. ANALYTICAL FINISH 3. 完成分析

Thedissolution step has been described as an involved sample preparation. Thesample handling and analytical procedure that are used to determine the amountof drug substance dissolved during the dissolution procedure are termed the“analytical finish.” Although spectrophotometric determinations and HPLC areused most commonly and are discussed in this chapter, any suitable analyticaltechnology may be used. Section 5. Validation describes criteria for themethods.

溶出实验已被描述为复杂的样品制备过程。在溶出实验过程中，样品处理和分析程序用于确定药物的溶出量，这在溶出实验中被称为“完成分析”。虽然本章

讨论的分光光度法和高效液相色谱法是最常用的分析方法，其他适宜的分析技术也可以使用。在第5节验证中详细描述方法验证标准。 3.1 Sample Processing 3.1 样品处理

After thesamples are withdrawn from the dissolution medium, they may require additionalprocessing to make them suitable for the analytical methodology used todetermine the amount released. For example, filtration may be used to removeundissolved particulate matter, or samples may need to be protected

fromexposure to light or may need refrigerated storage.In addition, samples mayhave to be diluted to a level that is within the linear range of the method.With analysis by HPLC, dilution of the sample with mobile phase may benecessary to reduce the effect on the separation of injecting dissolutionmedium. Other types of treatment may be necessary depending on the productformulation, such as the inactivation or elimination of interference caused bycomponents of the formulation by the addition of appropriate reagents. However,separation may not be possible or needed in all cases. In some cases, in situmeasurements obtained with methods such as fiber optics or electrochemicaldetermination may be useful.

溶出样品在取样后，需要进一步的处理，使药物释放量能够满足分析方法的测定要求。例如，过滤可用于除去未溶解的颗粒物样品，或者样品需要避光，或者需要冷藏贮存样品。此外，样品可能需要稀释至该方法线性浓度范围内进行测定。使用高效液相色谱法时，尽可能采用流动相稀释样品以减少溶出介质对样品测定的影响。根据制剂处方，其他类型的处理方式也是需要的，例如加入适当的试剂消除或者减少处方组分引起的干扰。但是，在上述所有情况下，也存在分离是没

必要进行或者不可能做到的。在一些情况下，原位测量方法，比如纤维光学或电化

学测定可能是有用的。 3.2 Filters 3.2 过滤

The topic of filtration is discussed in section 1.1 Performing FilterCompatibility.

在上面1.1章节中已经进行描述。 3.3 Centrifugation 3.3 离心

Centrifugation of samples isnot preferred, for several reasons: dissolution can continue to occur until thesolids are removed, a concentration gradient may form in the supernatant, andenergy imparted may lead to increased dissolution of the drug substanceparticles. Possible exceptions, when centrifugation could be preferred, mightinclude the use with compounds that adsorb onto all common filters, orsituations when the potential filter leachables and extractables might interferein the quanti tative

step of the dissolution test (e.g., when fluorescenceprocedures are used in quantitation). Centrifugation may prove useful duringmethod development for evaluating the suitability of the filter material.

不优先选择离心来处理样品，具体原因有以下几个方面：离心可以使药物继续溶解，直到固体颗粒被去除，在上清液中可形成浓度梯度。离心产生的热量可增加药物颗粒的溶解。但可能会出现例外情况，当所有常见滤膜对药物均有吸附或者所有滤膜均干扰药物的测定时（例如，使用荧光定量），优选离心进行样品处理。在方法开发过程中评价过滤材料的适用性时，可以选用离心方法进行对比研究。

3.4 Analytical Procedure 3.4 分析方法

The usualassay for a dissolution sample employs either a spectrophotometric procedure ora liquid chromatographic procedure.Spectrophotometric determination may bedirect or may provide the detection for HPLC. Spectrophotometric determinationis used often because results can be obtained faster, the analysis is simpler,it is easier to automate, and fewer solvents are needed. The use of directspectrophotometric determination typically requires confirmation ofspecificity. HPLC is preferred for a number of reasons such as providing a widedynamic range that reduces the need to dilute some samples while also providingsensitivity in the analysis of dilute samples, and greater selectivity whenexcipients or multiple drugs in the formulation present a significantinterference. Modern HPLC systems employ autosamplers that provide speed andsimplicity advantages comparable to spectrophotometric analysis.

用于溶出度测定的常用分析方法一般为分光光度法或液相色谱法。分光光度法较高效液相法更简便快捷，更容易实现自动化，并且溶剂量使用较少。直接使用分光光度法测定通常需要确定专属性。首选高效液相色谱法的原因有很多，如提供较宽动态测定范围，减少了需要样品稀释的必要性，提高了低浓度样品的分析灵敏度，并且可用于辅料或者多组分互相干扰样品的测定。目前的高效液相色谱系统采用自动进样器，提高了自动化程度。 3.5 Spectrophotometric Analysis 3.5 光谱分析

Directspectrophotometric analysis may be performed on samples that are manuallyintroduced to the cuvette. Alternatively, samples may be

automaticallyintroduced into the spectrophotometer using autosippers and flow cells. Routineperformance checks, cleaning, and maintenance, as described in the standardoperating procedures or metrology documents, help to ensure reliable operationof these instruments. Cells with path lengths ranging from 0.02 cm to 1 cm aretypically used, and longer path-length cuvettes can be used to increase therange for

quantification of dilute samples. Cell alignment and air bubblescould be sources of error. The shorter path-length cells are used to avoiddiluting the sample。 in all cases, however, acceptable linearity and standarderror need to be demonstrated.

直接分光光度法分析采用手动操作。或者也可以采用自动吸样系统或者流通进样池进行自动化取样。按照标准操作规程或者计量文件的要求对仪器进行常规检查、清洁和维护，有助于确保仪器的可靠运行。分光光度计的比色皿的长度一般为0.02cm～1cm，如果测定浓度较小的样品也可以使用长度较大的比色皿来增加稀释样品的定量范围，样品池的校准和气泡可能是误差的主要来源。较短的比色皿可以使样品不用稀释直接进行测定，然而不管使用什么比色皿，可接受的线性标准以及标准误差有必要进行验证。

The choice of wavelength forthe determination should be based on the spectrum of the drug in solution. Insome cases,where the drug substance can degrade in the dissolution medium(e.g., dosage forms containing aspirin), it is useful to carry out themeasurements at the isosbestic point. Excipients can also have effects, butperforming analysis at multiple wavelengths can minimize their effects. Thecontribution of the absorbance from an excipient at the analytical wavelengthcan sometimes be determined by ratio from its absorbance at a wavelength wherethe absorbance of the drug substance is minimal.

根据药物在溶液中的吸收光谱选择波长必须。在某些情况下，药物在溶出介质中降解（例如，含有阿司匹林的制剂），适合在在等吸收点完成测定。在辅料有干扰的情况下，可以选用多波长进行分析，可以减少干扰。在分析波长处辅料有吸收，有时可通过一定波长下（此波长下药物的吸收最小）辅料的吸光度比确定辅料对吸光度的贡献。

Using a validated analyticalfinish, standard solutions are typically prepared in dissolution media andanalyzed at just one concentration, either at 100% of the dosage strength orthe selected Q value because linearity of the analytical finish has

beenestablished. Prior to validation, dissolution profile analysis, or analysis ofproducts of various strengths, requires using multiple standard solutionscovering the expected range of concentration. A typical media blank, standard,and sample may be analyzed in a sequence that brackets the sample withstandards and blanks, especially at the beginning and end of the analysis.Thestandard and sample solutions should both be prepared in the dissolution mediumin the linear concentration range and measured at the same wavelength. However,small amounts of an organic solvent may be used in the preparation of thestandard, provided that the accuracy criteria can be met during validation.

使用经过验证的分析方法，标准溶液通常用溶出介质制备，仅在一个浓度点进行测定，选取溶出量为100%或者溶出度限度值（Q）均可，因为线性范围已

经经过验证。但是在方法验证之前，溶出曲线分析或者是分析不同剂量的制剂均需要使用多个覆盖规定限度浓度范围的标准溶液进行测定，典型的空白介质溶液、标准溶液和样品溶液均应在溶出的线性浓度范围内采用相同波长进行测量。但是，少量的有机溶剂也可用于制备的标准溶液，只要在验证过程中满足准确度标准。

The absorptivity is calculated by dividing the mean standard absorbance bythe concentration, in mg/mL, divided by the cell path length in cm. Arearrangement of the Beer-Lambert expression gives the absorptivity, a,as:

吸收率的计算标准吸光度的平均值除以浓度（单位为mg/ml），除以比色皿的长度（cm）,吸收率α的计算公式如下（朗伯比尔定律）：

α=A/bc A=吸光度

b=比色皿长度（cm） c=浓度（mg/ml）

Typical units for absorptivitythat are used for dissolution testing are in terms of AU · mL/mg, where AU isabsorbance unit.Historical data may be used to provide an acceptableabsorptivity range for the analyte (using the appropriate path-length cell).This value may be useful in troubleshooting aberrant data.Fiber optics as asampling and determinative method, with proper validation, are an option.

用于溶出实验吸光度的单位通常为AU? mL/mg，其中AU是吸收度单位，历史的资料可用来提供分析物的可接受吸光度范围（使用适当光程的样品池）。这个值在故障排除异常数据时非常有用。光导纤维作为取样和测定的方法，经过适当的验证，也可以是一种选择。 3.6 HPLC 3.6 HPLC法

For HPLCanalysis, the effect on the chromatogram of peaks resulting from injection ofdissolution media require enumeration. A large solvent disturbance may

affectaccuracy and precision of response if it is poorly resolved from the peak ofinterest. This is even more important if large injector volumes (>100 mL)are needed. System suitability tests may evaluate peak shape。 separation of themain peak from solvent disturbance and from closely eluting peaks。 andinjection precision. At a minimum,the precision is critical.

对于HPLC分析，需要列出溶出介质对色谱图的影响。如果目标峰响应值解决不好，溶剂的较大干扰可能影响响应值的准确度和精确度。如果进样量较大（>100毫升）这种影响更为重要。系统适用性实验可评估峰形、溶剂干扰、主峰相邻峰的分离和进样精密度。至少，精密度是关键。

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。由实验准备、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实验。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实验中，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

media containing surfactants or lipidsmay presentproblems. Carryover may occur for successive samples taken over amultipletime-point test, as well as at the beginning of a new test due to thecleaningsolution. This topic is discussed in section 4.4 Cleaning.

当后续样品受残留或先前取样条件的影响，可能会发生交叉污染；第一个样品或条件的影响传递到第二样品。在处理液体时，在样品溶液中先前液体的残留物可能污染后续样品溶液。溶出介质包含表面活性剂或脂质可能会存在一些问题。根据清洗方案在多个时间点测试和在开始新的检测以及连续采样都可能发生残留。这个问题将在4.4节清洁进行讨论。

Interaction of dissolved drugsubstancewith the sampling and transfer devices is an important consideration.Whenadsorption of the dissolved drug substance occurs, it most ofteninvolvessurfaces of the dissolution apparatus or sampling filters and

tubing. Adsorption may be pHdependent in the case ofcharged, dissolved drug substance. Adsorption of thedissolved drug to the partsof the sampling device should be assessed using atypical sample solution(dissolution sample from the product or

drug substance withformulation matrix) with knownconcentration. The typical design is across-validation with aliquots of thesame sample solution passing andbypassing the sampling device (including thesampling probe, filter, tubing,valves, and pump). There is no generalrecommendation that may give preferenceto any kind of material or equipmentconstruction (e.g., glass or specificpolymers). See section 5.7Considerationsfor Automation for more information.

溶解的原料药的取样和设备转移之间的相互作用是需要重点考虑的，当溶解的原料药发生吸附时，通常发生在溶解装置或抽样滤波器和管道的表面上。溶解的原料药在带有电荷时发生吸附可能是pH依赖性的。溶解的原料药到采样装置部件的吸附应当使用已知浓度的典型样品溶液进行评估（使用制剂或原料和辅料混合组分进行溶出的样品）。通常使用同一样品溶液分成两等份，设计一个交叉验证实验，分别通过和绕过取样装置（包括采样探头，过滤器，管道，阀门和泵）。有可能对任何种类的材料或设备结构（例如，玻璃或特定的聚合物）的优先选择不能给出建议。参见5.7自动化注意事项的详细信息。

In addition to the informationin section2.4.3 Sampling,connections of pumps and tubing may be sources of contaminationin automatedsystems. Interferences with the spectroscopic analyticalprocedures, which arecommonly

used for dissolution testing, are less of aconcern. However,interferences must be evaluated if the product underinvestigation containslow-dose metal salts, as do some dietary supplements.

除了在2.4.3取样部分的信息外,泵和管道的连接处可能是自动化系统污染的来源。在溶出测定时，光谱分析方法产生的干扰通常关注较少。但是，研究的制剂如果含有低剂量的金属盐，如做一些膳食补充剂必须对干扰进行评估。

Liquid transfer usually isundertaken viapolymeric tubing. Inert materials such aspolytetrafluoroethylene (PTFE)sometimes cannot be used because of their mechanicalproperties. Where flexibletubes are required, for example in peristaltic pumpsor for coiling in a smallradius, polypropylene (PP) or high-densitypolyethylene (HDPE) may be the preferredmaterials. Depending on the type ofpolymer and its crystallinity and density,leaching of constituents, mainlyplasticizers, may occur. Leachables caninterfere with the

analyticalprocedure. The concentration leached to the samplesolution usually depends onthe surface,the temperature, the exposure time, thehydrodynamic conditions,and the composition of the media.

液体转移通常是通过聚合物管进行。惰性材料如聚四氟乙烯（PTFE），因为它们的机械性能有时也无法使用。需要使用软管时，例如在蠕动泵或用于在小半径环绕，聚丙烯（PP）或高密度聚乙烯（HDPE）是优选的材料。取决于聚合物的类型、结晶度和密度、主要增塑剂，可能产生组分浸出。溶出物可能干扰分析测定。被过滤到样品溶液中的浓度通常取决于表面、温度、暴露时间、流体动力学条件和溶出介质的组成。 4.4 Cleaning 4.4 清洗

In addition to the informationin section2.4.4 Cleaning,automated systems have specific cleaning issues. For example,evaluation of theeffectiveness of purging and rinsing between sampling timesand within-runcondition of the tubing is recommended. Also it is important toevaluate thecleaning process between tests.

除了2.4.4清洁部分的信息，自动系统也有具体的清洁问题。例如，推荐在采样时间和管的批内运行条件评估清洗和冲洗的有效性。在实验之间评估清洁过程也是很重要的。

4.5 Operating Software andComputation ofResults 4.5操作软件和计算的结果

The software systems for dataevaluationand instrument operation must be validated as per 21 CFR 11 (17).

根据21 CFR11（17）仪器操作系统和数据评估软件必须进行验证。 4.6 Common Deviations from theCompendialProcedures That May Require Validation

4.6药典方法常见偏差需要进行验证

Some common areas of deviationfromcompendial procedures include the following:

? Sample introduction relativeto start ofspindle rotation ? Residence time andpositioning ofsampling probes ? Recirculated versusconsumptive sampling

? Sample volume replacement inconsumptivesampling. 药典方法的一些常见偏差包括： ?主轴开始旋转投入样品引起的偏差 ? 停留时间和采样探头位置 ?循环与消耗采样

?在消耗采样时取样体积更换。 5. VALIDATION 5.验证

Thevalidation topics described in this section are typical but not all-inclusiveand can be viewed in the context of Validation of Compendial Procedures <1225>,as well as the International Conference on Harmonization (ICH) document, Validationof Analytical Procedures (18). Validation for both parts of the dissolutionprocedure, the analytical finish and the dissolution step, willbediscussed in this section. The dissolution step is the release of the drug inthe dissolution medium and sampling. The analyticalfinish is defined insection 3. Analytical Finish. Validation of the analytical finish willevaluate the attributes, linearity andrange, precision, specificity,accuracy/recovery, robustness, and stability of the sample and standardsolutions. Validation of thedissolution step will include evaluation ofprecision and robustness of the dissolution sample preparation. Validation ofthe analyticalfinish is performed either using a standard solution orspiked placebo or by the method of standard addition (spikeddrugproduct as described in Accuracy in <1225>), as specified in thesections below. Validation of the dissolution step requiresthe use of awell-characterized dosage form (e.g., having tight content uniformity anduniform performance). Depending onthe parameter of interest, validationof the sample handling and analytical procedure can be performed in situ, e.g.,within thedissolution vessel. The validation parameters addressed andthe extent of

the validation may vary, depending on the phase ofdevelopmentor the intended use for the data.

本章节所涉及的验证是一些典型的验证，但不包括所有的验证，这些验证在

药典分析方法验证<1225>的上下文中和ICH指导原则分析方法验证。本章节讨论的溶出实验的验证包括溶出和分析两部分验证。溶出步骤是指药物在溶出介质中的释放和取样，分析方法的定义详见第3章节分析方法。分析方法的验证包括专属性、线性和范围、精密度、准确定/回收率、耐用性、对照品溶液和供试品溶液的稳定性。而溶出步骤的验证主要是对溶出样品制备的精密度和耐用性评估。分析方法验证一般使用标准溶液或者空白辅料溶液或通过下面章节中指定的标准加入法（按照<1225>准确度实验中描述的加入标准的药品）。溶出步骤的验证需要使用具有良好特性的产品（例如：具有良好的含量均匀度和溶出均一性）。根据关注的参数，在原来位置，比如在溶出仪里进行分析方法和样品处理的验证。验证参数处理和验证程度会有所不同，这取决于开发阶段或数据的使用目的。

The acceptance criteria are presented as guidelinesonly, and may differ for some products. Manufacturers should document theappropriate acceptance criteria for their products in pertinent StandardOperating Procedures (SOPs) or in validation protocols.Other considerations maybe important for special dosage forms. Validation studies should be performedacross the range of profile time points. For products containing more than asingle active ingredient, the dissolution procedure needs to be validatedfor each active ingredient. It is expected that investigations into

filtersuitability and the potential for glass adsorption will have been undertakenalready (see 1.1 Performing Filter Compatibility). Validation of theseassessments may occur during spiked recovery experiments.

本章节的验证标准仅作为指导，对有些产品可能有所不同。生产厂家应该在相关的标准操作规程（SOP）中或在验证方案中对制剂产品提供合适的可接受标准。对特殊剂型的其他考虑也是重要的。所进行的验证研究应横跨溶出曲线时间点范围。对于复方或者多组分制剂，每一种活性成分的溶出方法均需要进行验证。过滤器的相容性以及玻璃器的潜在吸收已经进行研究（见1.1滤膜的选择和相容性），在加标回收率实验中将对这些评估进行验证。 5.1 Specificity/PlaceboInterference 5.1专属性/安慰剂（辅料）干扰

It isnecessary to demonstrate that the results are not unduly affected by

placeboconstituents, other active drugs, or degradants. The placebo consists of allthe excipients and coatings, with inks and capsule shells included ifappropriate, without the active ingredient. Placebo interference can beevaluated by using a spiked placebo that is prepared by weighing samples of theplacebo blend, dissolving or dispersing them in

dissolution medium atconcentrations that would be encountered during testing, and adding a knownamount of the drug in solution. It may be preferable to perform this experimentat 37°, comparing the solution to a standard solution at the concentrationexpected to be encountered during testing, by using the formula: Result = (AP/AS) × CS × (V/L) × 100 AP =absorbance of the placebo AS =absorbance of the standard

CS =concentration of the standard (mg/mL) V =volume of the medium (mL) L =label claim (mg)

证明安慰剂（空白辅料）成分、其他活性药物或降解产物并非影响实验结果是很有必要的。安慰剂是指除了活性成分以外的所有辅料和包衣材料，在适当的时候还包括油墨和胶囊壳。安慰剂的干扰可以使用加入标准的安慰剂进行评价，通过称取安慰剂的混合样品，将该混合样品溶解或分散在溶出介质中，制备的浓度为测试过程中使用的浓度，然后向溶液中加入一定量药物，优选在37℃实验条件进行这个实验，使用如下公式比较样品溶液和标准溶液在测试过程中预计浓度点的吸光度：

结果= (AP/AS)×Cs×(V/L)×100 AP为安慰剂的吸光度 AS为标准溶液的吸光度 Cs为标准溶液的浓度（mg/ml） V为溶出介质的体积（ml） L为标示量（mg）

Theinterference should not exceed 2%. Note that for extended-release products, aplacebo version of the finished dosage form may be more appropriate than

blendsbecause this placebo formulation will release the various excipients in amanner more nearly reflecting the product than will a simple blend of theexcipients. In this case, it may be appropriate to evaluate potentialinterference at multiple sampling points in the release profile, withworst-case interference expected at the later sampling points.

干扰不能超过2%。值得注意的是：缓释制剂，空白剂型可能比混合物更合适，因为空白剂型比各种辅料简单的混合物更能反映出不同辅料制剂的释放方式。在这种情况下，在多个取样点的释放曲线更适合评估潜在干扰，尤其是后面的取样点预计出现的最坏干扰。

The blank is the dissolution medium withoutdissolved sample, and it is treated in the same manner as the sample. Theeffect of the absorbance of the blank at the analytical wavelength should beevaluated. In most cases, the absorbance of the dissolution medium blank maynot exceed 1% of the standard solution at the

concentration used for analysis.Values >1% should be evaluated on a case-by-case basis.

空白是指不含溶解样品的溶出介质，按照供试品溶液的处理方法处理空白介质，在分析检测波长评估空白介质对吸光度的影响。在大多数情况下，空白溶出介质的吸光度不得超过用于分析的标准溶液浓度吸光度的1%。如果超过1%，应根据情况进行评估。

If the placebo interference exceeds 2%, modificationof the method may be necessary. Possible modifications include choosing anotherwavelength, subtracting baseline using a longer wavelength, transformingabsorbance values (e.g., first derivative),and using an alternative analyticaltechnique such as HPLC. Other means for minimizing the placebo interferencewould be acceptable with appropriate justification. When other active drugsubstances or significant levels of degradants are present,it is necessary toshow that these do not significantly affect the results. One procedure fordoing this is to measure the matrix in the presence and absence of the otheractive drug substance or degradant: any interference should not exceed 2%.Similar approaches may be used if other techniques are used for the analyticalfinish.

如果安慰剂干扰超过2%，有必要对该方法进行改进，可能的改进方法包括选择另一个检测波长、通过使用较大波长以减少空白吸收、转化吸光度值（例如：一阶导数）或者使用高选择性的方法如HPLC法。如果有合适的理由，其他降低安慰剂干扰的方法也可以使用。当存在其他活性成分或者降解显著时，证明这些不会对结果产生显著影响是有必要的。另外解决的方法是不管其他活性成分或者存在存在的降解产物，对主要成分的干扰均不得超过2%。如果其他的方法用于分析，也可使用类似的方法。 5.2 Linearity and Range 5.2线性和范围

Linearity istypically established by preparing solutions of the drug substance, ranging in concentrationfrom less than the lowest expected concentration to more than the highestconcentration during release. The solutions may be prepared either using eithera standard solution or spiked solution or by the method of standard addition. Aminimum of five concentrations is normally used (see <1225>). Typically,solutions are made from a common stock if possible. The concentration range maynot exceed the linearity limits of the method, including the instrumentation.Organic solvents may be used to enhance drug solubility for the preparation ofthe linearity standard solutions. However, no more than 5% (v/v) of organicsolvent should be present in the final solution unless validated. Linearity istypically calculated by using an appropriate least-squares regression program.Typically, a square of the correlation coefficient (r2 30.98)

demonstrates linearity. In addition, the y-intercept must not beimportantly different from zero.

线性通常制备一系列原料药溶液，浓度范围为低于药物释放过程中的最低点浓度至高于药物释放过程中最高点的浓度。可以使用标准溶液或加标溶液，或者通过标准加入法制备的溶液。通常至少使用5个浓度点（参见<1225>）。通常情况下，如果可能，溶液有一个共同的线性贮备溶液稀释制得。浓度范围不得超过线性方法范围包括仪器的测量范围。线性贮备溶液制备过程中为了增加药物的溶解度，可能会用到有机溶剂，除非经过验证外，有机溶剂的量均不得超过总体积的5%（v/v）。线性方程一般通过最小二乘法计算，相关系数（r2≥0.98）证明线性较好,此外，y轴截距应接近于0。

The range ofthe procedure is the interval between the upper and lower concentrations of thedrug substance (including these levels) that has been demonstrated to have asuitable level of precision, accuracy, and linearity using the procedure aswritten.

线性范围内包括原料药的最低点和最高点在内的所有浓度，均应证明精密度和准确度水平，并且在报告中记录。 5.3 Accuracy/Recovery 5.3准确度/回收率

Accuracy/recoveryis typically established by preparing multiple samples containing the drugsubstance and any other constituents present in the dosage form (e.g.,excipients, coating materials, capsule shell) ranging in concentration fromless than the lowest expected concentration to more than the highestconcentration during release. Accuracy/recovery may be done in conjunction withlinearity determination. The method of standard addition can also be used.Before this activity, it is expected that filter assessment will already havebeen performed, and adsorption of drug onto the glass has also beeninvestigated and ruled out.

准确度/回收率通常是由含有原料药和制剂中存在的其他成分（如辅料、包衣材料、胶囊壳）制备的多个样品，浓度范围的下限为药物释放时低于最低预计浓度值，上限高于释放的最高浓度值。准确度/回收率由线性决定。也可以使用标准加入法。在进行实验之前，过滤器预计对药物的吸附要进行评估，同时要考虑并设法排除由于仪器的玻璃材质部分对样品的吸附而对测试结果造成的影响。 Individual solutions may be directly prepared inthe dissolution medium. Alternatively, to enhance drug solubility it may beappropriate to prepare a stock solution by dissolving the drug substance in asmall amount of organic solvent (typically not exceeding 5% organic solvent inthe final dissolution media) and diluting to the final concentration withdissolution medium.An amount of stock solution equivalent to the targeted labelclaim may be used instead of the drug substance powder. Similarly,for

very lowstrengths, it may be more appropriate to prepare a stock solution than toattempt to weigh very small amounts.

直接用溶出介质制备每一个溶液。或者，如果药物溶解性较差，可以将药物溶解在少量有机溶剂（一般不超过5%）中制备储备液，并用溶出介质稀释到最终浓度。储备液的量与标示量量相当，可用于代替药物粉末。同样地，对于剂量非常小的药物，制备储备液比尝试着称量非常少量的药物进行配制更合适。

The measured recovery is typically 95%–105% of theamount added. Bracketing or matrixing of multiple strengths may be useful. Aspecial case for validation is the Acid Stage procedure described in <711>,Delayed-Release Dosage Forms. The limit of NMT 10% needs to be validated.Recovery experiments for drugs that have low solubility in acidic media may bechallenging or impossible to perform and may need to be addressed on a case-by-casebasis. If the compound degrades in acid, the validation experiment must addressthis fact.

回收率测得值通常为加入量的95%~105%。多规格制剂括号法或矩阵化是常用方法。在<711>缓释剂型中描述了酸性阶段的分析验证的例子。需要对NMT不超过10%这个限度进行验证。在酸性介质中低溶解度药物的回收率实验有挑战性或者不可能进行，需要根据具体情况进行说明，如果药物在酸性条件下降解，验证实验中须对这一事实进行说明。 5.4 Precision 5.4精密度

5.4.1 REPEATABILITY OFANALYSIS 5.4.1重复性

Forthe analytical finish, repeatability is evaluated by obtaining replicatemeasurements of standard and/or spiked placebo/standard addition solutions. Itcan be determined by calculating the RSD of the multiple injections orspectrophotometric readings for each standard solution, or by using theaccuracy or linearity data. ICH guidance, Validation of AnalyticalProcedures:Methodology, recommends that repeatability should beassessed using a minimum of nine determinations covering the specified rangefor the procedure (i.e., three concentrations and three replicates of eachconcentration) or using a minimum of six determinations at 100% of the testconcentration. A typical acceptance criterion is an RSD of <2%. Thedemonstration of the repeatability for the dissolution step is conducted byperforming the dissolution step on separate units of a well-characterized dosageform or equivalent composite.

对于分析方法，通过获得标准和/或加入安慰剂/标准加入溶液的重复测定结果对重复性进行评估，通过多次进样或者每个标准溶液分光光度计读数或者使用精密度或者线性数据来计算RSD值， ICH指导原则，分析方法的验证：方法，推荐重复性测定用覆盖特定分析范围的九个确定浓度点（三个浓度点，每个浓度

点重复制备三份样品）或在100%测试浓度点至少制备6份样品溶液进行测试，通常可接受的标准：RSD<2%。通过采用质量好的制剂或与制剂相等组成（原料+辅料）进行溶出步骤的独立单元的重复性证明。 5.4.2 INTERMEDIATEPRECISION/RUGGEDNESS 5.4.2中间精密度/耐用性

Assuming thatthe major contributor to the variance is from the dissolution

step,intermediate precision may be evaluated to determine the effects of randomevents on the precision of the dissolution procedure. This evaluation istypically done later in the development of the drug product and is required forfull method validation. For many analytical procedures intermediate precisionis typically assessed by determination of contributions to variance and,possibly, by a comparison of means. The use of an experimental matrix design isencouraged for evaluation of intermediate precision because interaction effectsmay be observed more clearly relative to a single variable experiment. Indissolution testing, a ruggedness approach that compares means alone is oftentaken to investigate the factors that contribute to intermediate precision. Theruggedness can be evaluated across the range of product strengths.

Typicalvariations to be studied include different days, analysts, and equipment. If possible,ruggedness can be evaluated using a drug product lot if well characterized, forexample, by having tight content uniformity and uniform performance, but ifthis type of lot is not available, a premeasured placebo with activeingredients may be used to investigate the intermediate precision. The use ofsuch a spiked placebo would additionally support the assessment of thecontribution of the analytical finish to the observed variability of results.

假设溶出步骤是产生偏差的主要因素，可以用中间精密度评估，以确定随机事件对溶出精密度的影响。这种评估通常在制剂开发后完成，需要对方法学进行充分验证。对于很多分析方法，中间精密度通常通过确定偏差来源进行评估，通过比较分析的方式。鼓励使用实验室矩阵设计对中间精密度进行评估，因为与单因素实验相关的相互作用会更清楚地观察到。在溶出度测定时，耐用性实验方法可以采取单独比较的方法来研究中间精密度的影响因素。这些影响因素可能是由中间精密度引起的。耐用性实验可以评估制剂的浓度范围。研究过程中的典型的变化，包括不同天、不同操作人员和设备。如果可能，耐用性实验可以用较好质量特征的制剂批次进行评估，例如：较好的含量均匀度。但如果这种批次的不可获得测，可用活性成分加安慰剂进行中间精密度研究。使用加入标准的安慰剂（空白辅料）将支持观察到的变化结果对分析方法误差的影响。

Thedissolution procedure on the same lot of well-characterized dosage form may berun by at least two different analysts from the same laboratory, with eachanalyst preparing the standard solutions and the medium and following thedefined

extraction/quantification procedure. Typically, the analysts usedifferent dissolution baths, spectrophotometers or HPLC equipment (includingcolumns), and autosamplers, and they perform the test on different days. Fullprofiles are assessed where relevant to the product. This procedure may not benecessary at each strength。 instead, bracketing with high and low strengths maybe acceptable.

同一批次质量特征较好的制剂的溶出实验可以由同一实验室至少两个不同的分析人员进行，每个分析人员制备标准溶液和溶出介质和依据明确的提取和定量步骤进行。通常情况下，分析人员用不同的溶出液、分光光度计或HPLC（包括色谱柱）和自动进样器，在不同天进行实验。与制剂相关的曲线进行全面的评估，这个分析操作对每个浓度可能不是必须的，而是使用高浓度和低浓度进行分析是可以接受的。

Acceptancecriteria for intermediate precision or for ruggedness are predetermined. Atypical acceptance criterion for ruggedness is that the difference in the meanvalue for dissolution results between any two conditions, using the samestrength,does not exceed an absolute 10% at time points with <85% dissolvedand does not exceed 5% for time points >85%. Acceptance criteria may beproduct specific, and other statistical tests and limits may be used.

中间精密度的可接受标准或耐用性是预先确定的。通常耐用性的可接受标准是使用相同浓度，在任何两个条件之间溶出结果平均值的差，在溶出度小于85%的时间点，绝对误差不能超过10%；大于85%的时间点，绝对差值不能超过5%，可接受标准可以用于特定产品、也可以使用其他统计方法和范围。 5.4.3 REPRODUCIBILITY 5.4.3重现性

Reproducibilityfollows the general concepts of intermediate precision, but is performed by twodifferent analysts at different labs.

重现性遵照中间精密度的一般概念，但在不同实验室由两位不同的分析人员进行实验。 5.5 Robustness 5.5耐用性

Evaluation ofrobustness, which assesses the effect of making small, deliberate changes tothe dissolution conditions, typically is done later in development of the drugproduct and is a requirement for full method validation. It is performed usinga

well-characterized lot of drug product, for example having tight contentuniformity and uniform performance. The number of

replicates(typically 3 or 6) is dependent on the intermediate precision. All profilepoints should be evaluated.

本文来源：https://www.bwwdw.com/article/yd8o.html