溶出度试验的开发和验证

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 USP general chapters need to be justified.

<1092>章节讨论了溶出度实验的开发和验证，重点是口服固体制剂。所提出的许多概念也可能适用于其他剂型和给药途径。关于设备和方法的修改部分在USP通则中给出了合理的说明。

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

在进行溶解度实验的开发和验证时，常遵循指导原则<1092>，具体内容如下：

1. PRELIMINARY ASSESSMENT (FOR EARLY STAGES OF PRODUCTDEVELOPMENT/DISSOLUTION METHOD DEVELOPMENT)

1.前期评估（对产品开发以及溶出度方法开发的前期研究评估）

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

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.

为获得准确试验结果，过滤是样品制备的一个关键步骤。过滤的目的是为了除去溶出液中未溶解的药物和辅料。如果不把未溶解的药物和辅料从样品溶液中除去，那么未溶解的药物颗粒将会继续溶解使试验结果出现偏差，因此，如果取样管中没有过滤器，应立即对溶出度样品进行过滤。

Filtration also removes insolubleexcipients that may otherwise interfere with the analytical finish. Selectionof the proper filter material is important and should be accomplished, andexperimentally justified, early in the development of the dissolutionprocedure. Important characteristics to consider when choosing a filtermaterial are type, filter size, and pore size. The filter that is selectedbased on evaluation during the early stages of dissolution procedure developmentmay need to be reconsidered at a later time point. Requalification has to beconsidered after a change in composition of the drug product or changes in thequality of the ingredients (e.g. particle size of microcrystalline cellulose).

过滤也可除去可能会干扰分析测定的不溶性辅料。选择适当的过滤材料是非常重要，应该在早期溶出方法开发的过程中通过实验确定和完成。在选择滤膜时有必要重点考虑滤膜的材料、型号和孔径大小。通常对早期阶段溶出方法开发过程的评价选择过滤器，但在后期试验中如果制剂成分改变或组成成分质量变化可能需要重新考虑过滤器，（例如：微晶纤维素粒径的改变）。

Examples of filters used in dissolutiontesting can be cannula filters, filter disks or frits, filter tips, or syringefilters. The filter material has to be compatible with the media and the https://www.360docs.net/doc/b76442591.html,mon 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.

用于溶出试验的过滤器有管路过滤器、过滤盘或玻璃过滤器、滤头或针头式过滤器。过滤材料必须与介质和药物相适合。常见孔径大小范围：0.20～70μm，如果需要也可使用其他孔径大小的过滤器。如果原料药的粒度很小（例如，微分化颗粒或纳米颗粒），找到一个合适的过滤器过滤这些小颗粒至今仍具有挑战性。

Adsorption of the drug(s) by the filtermay occur and needs to be evaluated. Filter materials will interact withdissolution media to affect the recovery of the 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。通过试验比较过滤和未过滤的标准溶液和样品溶液的含量差别，验证该过滤器是合适的。首先制备一个合适的标准溶液和样品溶液。例如，在烧杯中制备一个标准溶解样品，用磁力搅拌器搅拌使药物完全溶解。对于标准溶液，比较过滤溶液（弃去的适当体积后）和未过滤溶液的含量测定结果；对于样品溶液，比较过滤（弃去适当体积后）、离心、未过滤样品溶液的含量测定结果。

1.2 Determining Solubility and Stability of DrugSubstance in Various Media

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。当需要确定溶出度试验中溶出介质的组成时，有必要评估缓冲液、pH值、以及不同的表面活性剂（如果需要）对药物的溶解度和稳定性的影响。在37℃温度条件下，采用摇瓶溶解法（平衡溶解度）测定原料药在不同介质中的饱和浓度，来评估药物的溶解性。为了消除溶出介质中药物和缓冲液之间离子的潜在影响，使用盐酸和氢氧化钠的混合物对溶解度进行研究，这是一种典型的缓冲溶液。在某些情况下，评估药物在37℃以外条件下（即，25℃）的溶解度可能也是必要的。在溶解度试验过程中应检查上清溶液的pH值，以确定在溶解过程中pH值是否改变。也可使用其他可供选择的方法进行溶解度测定。

Typical media for dissolution mayinclude the following (not listed in order of preference): diluted hydrochloricacid, buffers (phosphate or

acetate) in the physiologic pH range of 1.2–7.5, simulatedgastric or intestinal fluid (with or without enzymes),and water. For somedrugs, incompatibility of the drug with certain buffers or salts may influencethe choice of buffer. The molarity of the buffers and acids used can influencethe solubilizing effect, and this factor may be evaluated.

溶出的典型介质包括（未按照优先顺序列出）：稀盐酸、在生理pH值范围为1.2-7.5缓冲溶液（磷酸盐或者醋酸盐）、模拟胃液或肠液（含有或不含有酶）和水。对于一些药物，与药物不相容的特定缓冲液或盐可能会影响缓冲剂的选择。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）。稳定性试验应考虑到有足够的时间来完成或重复分析过程。当因室温或冷藏贮存时降低药物的溶解度而发生沉淀时，物理稳定性也需要关注。

1.3 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.

当开发一个溶出试验方法时，首先要满足漏槽条件，漏槽条件定义为溶出介质体积至少为药物达到饱和溶液所需体积的三倍。当满足漏槽条件后，溶出度结果能够更好的反映药物制剂的质量。在适当条件下，介质不满足漏槽条件也是可

以接受的。溶解介质的组成和体积应根据溶解度的试验结果进行调整。例如，表面活性剂种类和浓度选择，需要根据药物溶解度数据和溶出曲线进行调整。

The use of 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 in Capsules–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试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.

合理设计一个试验保证数据稳定性（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%。，指导原则对溶出度试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。在溶出度试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）。试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，影响试验结果的可靠性。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试验结果。如果检测结果表明脱气对溶出结果没有影响，该试验就可以作为不需要进行脱气的理由进行说明。如果脱气对试验结果有影响，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

胶囊壳型号金属线长度直径（cm）软木塞孔数量

#0，延长释放12 0.8 4

#1和#2 10 0.7 3

#3和#4 8 0.55 2

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，试验时应小心，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，单点试验就足够了。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。药典中规定溶解度试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 f

similarityfactor may not be useful when more than 85% is dissolved 2

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.

f

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2

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