(完整版)USP-1092-溶出度试验的开发和验证(中英文对照版).docx

（ 1092）溶出度试验的开发和验证【中英文对照版】
INTRODUCTION
前言
Purpose
目的
The Dissolution Procedure: Developmentand Validation
<1092>provides a comprehensive approach covering items to considerfor developing and validating dissolution
procedures and the accompanyinganalytical procedures. It
addresses the use of automation throughout the testand
provides guidance and criteria for validation.It also addresses thetreatment of the data generated and the interpretation
of acceptance criteriafor immediate-and modified-release
solid oral dosage forms.
溶出实验:开发和验证（1092）指导原则提供了在溶出度方法开发和验证过程
中以及采用相应分析方法时需要考虑的因素。

本指导原则贯穿溶出度实验的全部过程，并对方法提供了指导和验证标准。

同时它还涉及对普通制剂和缓释制剂所生成的数据和接受标准进行说明。

Scope
范围
Chapter<1092>addresses the development andvalidation
of dissolution procedures,with a focus on solid oral dosage forms.Many of the concepts presented, however, may be
applicable to other dosageforms and routes of administration. General 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
1.2Determining 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
2.4.3Sampling
2.4.3取样
2.4.4Cleaning
2.4.4清洗
2.5数据处理
2.6溶出方法评估
3.ANALYTICAL FINISH
3.完成分析
3.1Sample Processing
3.1样品处理
3.2Filters
3.2过滤
3.3Centrifugation
3.3离心
3.4Analytical Procedure
3.4分析方法
3.5Spectrophotometric 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多个溶解度试验
6.5 Interpretation of Dissolution Results
6.5溶出结果说明
6.5.1 IMMEDIATE-RELEASE DOSAGE FORMS
6.5.1即时释放剂型
6.5.2 DELAYED-RELEASE DOSAGE FORMS
6.5.2延迟释放剂型
6.5.3 EXTENDED-RELEASE DOSAGE FORMS
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 mon pore sizes range from 0.20to70mm,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～
70 μm，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 e of thecorrect
filter dimensions will improve throughput and recovery,and also e 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 1shows 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 solubilityof 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 e 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 ofenzymes 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 enzymescan
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 Apparatus1(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– 200mL)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. Apparatus3(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,Apparatus4may 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-,or80-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 variable, and should be free of significant
stabilityproblems.High variability in the results can make it
difficult to identifytrends or effects of formulation not highly 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。