USP-1092-溶出度试验的开发和验证(中英文对照版)

（1092）溶出度试验的开辟和验证【中英文对照版】之
青柳念文创作
INTRODUCTION
前言
Purpose
目标
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 modifiedrelease solid oral dosage forms.
溶出实验:开辟和验证（1092）指导原则提供了在溶出度方法开辟和验证过程中以及采取相应分析方法时需要思索的因素.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尺度.同时它还涉及对普通制剂和缓释制剂所生成的数据和承受尺度停止说明.
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辟和验证，重点是口服固体制剂.所提出的许多概念也可以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.
在停止溶解度实验的开辟和验证时，常遵循指导原则
<1092>，详细内容如下：
1. PRELIMINARY ASSESSMENT (FOR EARLY STAGES OF PRODUCTDEVELOPMENT/DISSOLUTION METHOD DEVELOPMENT) 1.前期评估（对产品开辟以及溶出度方法开辟的前期研究评估）
1.1 Performing Filter Compatibility
1.2 Determining Solubility and Stability of DrugSubstance in Various Media
1.3 Choosing a Medium and Volume
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
2.1 Deaeration
2.2 Sinkers
2.3 Agitation
2.4 Study Design
2.4.1 TimePoints
2.4.2 Observations
2.4.3 Sampling
2.4.4 Cleaning
2.5 Data Handling
2.6 Dissolution Procedure Assessment
3. ANALYTICAL FINISH
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
4. AUTOMATION
4.1 Medium Preparation
4.2 Sample Introduction and Timing
4.3 Sampling and Filtration
4.4 Cleaning
4.4 清洗
4.5 Operating Software and Computation of Results
5. VALIDATION
5.1 Specificity/Placebo Interference
5.1专属性/抚慰剂（辅料）干扰
5.2 Linearity and Range
5.3 Accuracy/Recovery
5.4 Precision
5.4.1 REPEATABILITY OF ANALYSIS
5.4.2 INTERMEDIATE PRECISION/RUGGEDNESS
5.4.3 REPRODUCIBILITY
5.5 Robustness
5.6 Stability of Standard and Sample Solutions
5.7 Considerations for Automation
6. ACCEPTANCE CRITERIA
6.1 ImmediateRelease Dosage Forms
6.2 DelayedRelease Dosage Forms
6.3 ExtendedRelease Dosage Forms
6.4 Multiple Dissolution Tests
6.5 Interpretation of Dissolution Results
6.5.1 IMMEDIATERELEASE DOSAGE FORMS
6.5.2 DELAYEDRELEASE DOSAGE FORMS
6.5.3 EXTENDEDRELEASE DOSAGE FORMS
1. PRELIMINARYASSESSMENT (FOR EARLY STAGES OF PRODUCT DEVELOPMENT/DISSOLUTION METHODDEVELOPMENT) 1. 前期评估（产品开辟/溶出度方法开辟的初期阶段）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.
在开端溶出方法开辟之前，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停止适当
的筛选是非常重要的.
1.1 Performing Filter Compatibility
Filtrationis a key samplepreparation 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.
为获得准确试验成果，过滤是样品制备的一个关键步调.过滤的目标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，那末未溶解
的药物颗粒将会继续溶解使试验成果出现偏差，因此，如
果取样管中没有过滤器，应当即对溶出度样品停止过滤.
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).
过滤也可除去可以会干扰分析测定的不溶性辅料.选择适当的过滤资料是非常重要，应该在早期溶出方法开辟的过程中通过实验确定和完成.在选择滤膜时有需要重点思索滤膜的资料、型号和孔径大小.通常对早期阶段溶出方法开辟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质变更可以需要重新思索过滤器，（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 0.20 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途经滤器、过滤盘或玻璃过滤器、滤头或针头式过滤器.过滤资料必须与介质和药物相适合.罕见孔径大小范围：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 casebycase basis. Different
filter materials exhibitdifferent drugbinding
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.
过滤时可以会发生药物的吸附，需要停止评估.过滤资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详细问题停止思索.分歧的过滤资料表示出与药物连系的分歧特性.由于药物与滤膜连系引起药物从滤液中损失的比例，可以依赖于药物浓度.因此，应采取预期浓度范围内分
歧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资料，最大限度地减少滤膜吸附干扰，润湿滤膜对减少吸附也是需要的.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停止比较，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 smallvolume filtration can lead to loss ofsample through holdup 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，可以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，而且溶液迅速堵塞滤膜.
Filters used for USP Apparatus 4 needspecial attention because they are integrated in the flowthrough 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
活动过程中使用.不溶颗粒会沉积在过滤器，发生活动阻力. 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，关于过滤器滤膜资料和孔径大小可以用近似的方式通过手动过滤停止选择.在自动化系统中通过过滤器的流量和过滤器的堵塞可以是至关重要的.通过试验比较过滤和未过滤的尺度溶液和样品溶液的含量不同，验证该过滤器是合适的.首先制备一个合适的尺度溶液和样品溶液.例如，在烧杯中制备一个尺度溶解样品，用磁力搅拌器搅拌使药物完全溶解.对于尺度溶液，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成果；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成果.
1.2 Determining Solubility and Stability of DrugSubstance in Various Media
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 shakeflask 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，有需要评估缓冲液、pH值、以及分歧的概况活性剂（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，采取摇瓶溶解法（平衡溶解度）测定原料药在分歧介质中
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停止研究，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℃）的溶解度可以也是需要的.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停止溶解度测定.
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.
溶出的典型介质包含（未依照优先顺序列出）：稀盐酸、在生理pH值范围为1.27.5缓冲溶液（磷酸盐或者醋酸盐）、摹拟胃液或肠液（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以会影响缓冲
剂的选择.所使用的缓冲液和酸的体积摩尔浓度可以改变药
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）可以添加一定比例的概况活性剂（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概况活性剂时应涵盖所有常常使用种类的概况活性剂，比方阴离子、非离子型和阳离子，当已经确定一个合适的概况活性剂时，应对概况活性剂的分歧浓度停止研究，以确定达到漏槽条件所需的最低浓度.一般情况下，概况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常使用的概况活性剂，表中提供了CMC的近似临界值，以便我们参考，此外，表中所列概况活性剂其实不全面，不克不及解除未列出的概况活性剂.其他概况活性剂，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，概况活性剂的加入量以知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 highpurity grade. Obtaining polysorbate 80 from different sourcescan affect its suitability when performing highperformance liquidchromatography (HPLC) analysis.
由于使用分歧级此外概况活性剂会影响药物的溶解度，因此要节制概况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使用.在使用HPLC方法停止分析时，分歧来历的聚山梨酯（吐温）80会影响它的适用性.
There may be effects of counterions 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值可以会影响概况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，可以防止这种现象发生.
Table 1. Commonly Used Surfactants with Critical
Micelle Concentrations
表1 罕见概况活性剂的临界胶束浓度Routinely, the dissolution medium is buffered; however, the u搜索引擎优化f 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：水的质质变更取决于它的来历，而
水的pH值不像缓冲溶液可以严格节制；此外，若药物和辅
料的溶出对pH值敏感时需要思索使用缓冲液.别的使用水
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（有充分适当的来由），也是可以承受的. 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.
需要时，应该对原料药的稳定性停止考查，在所选择的
溶出介质中加入辅料，在37℃条件下停止考查.这种升高的
温度会潜在的降低溶液的稳定性（降解）.稳定性试验应思
索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
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.
当开辟一个溶出试验方法时，首先要知足漏槽条件，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.当知足漏槽条件后，溶出度成果可以更好的反
映药物制剂的质量.在适当条件下，介质不知足漏槽条件也
是可以承受的.溶解介质的组成和体积应根据溶解度的试验
成果停止调整.例如，概况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停止调整.
The use of enzymes in the dissolutionmedium is permitted, in accordance with Dissolution <711>, when dissolution failures occur as a result of crosslinkingwith gelatin capsules or gelatincoated 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取酶停止方法开辟的研究.根据第5节验证，使用酶方法依照溶出度方法学验证的要求停止验证.
Another option is to use media thatfollow more closely the composition of fluids in the stomach and intestinaltract. These media may contain physiological surfaceactive 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 immediaterelease (IR) dosage forms, in particular those containinglipophilic drug substances, and may help in understanding the dissolutionkinetics of the product related to the physiological makeup of the digestivefluids. Results of successful modeling of dissolution kinetics have beenpublished,mainly for IR products. In the case of extendedrelease 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).
另外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概况活性成分，如牛黄胆酸.这
些溶出介质也可以含有乳化剂（卵磷脂）和增加渗透压的
组分，比方生理盐水溶液.同时，缓冲液的离子强度或体积
摩尔浓度是可以节制的.设计的溶出介质摹拟了进食和空肚
状态下的胃和肠内状态.这些溶出介质对速释制剂（IR）建
平面内溶解行为模子方面是非常有用的，特别是这些速释
制剂中含有脂溶性的原料药，可以有助于懂得和消化液的
生理组成相关的制剂溶出动力学.溶解动力学的模子已成功
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停止评估.体外性
能测试其实纷歧定需要在空肚和餐后状态建立溶出介质模子.
An acid stage is part of the testing ofdelayedrelease 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 acasebycase 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停止抗酸包衣的
药物.根据详细情况停止处理，可以的处理方案包含：酸性
介质中添加概况活性剂或者调整质量尺度）
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，应注意采纳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，以包管药物的稳定性.有些时候
加入这些抗氧剂是不敷的.化合物疾速降解形成稳定的降解物，单独监测降解物或与原料药结合监控可以比只分析原料药更适合.与高效液相色谱分析比较（包含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 flowthrough 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., smallvolume 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毫升分歧.通常情况下，溶出介
质的体积应当知足漏槽条件.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来由）.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），或畅通池（仪器4）.当某些仪器需要较少体
积的溶出介质（例如，100200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.一般来讲，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, delayedrelease dosage forms, and nondisintegratingtypeproducts, such as coated beads. Apparatus 4 (flowthrough cell) may offeradvantages
for modifiedrelease dosage forms and immediaterelease 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 assuspensiontype extendedrelease 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 tonondisintegrating, oral modifiedrelease 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, andflowthrough 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，可使用其他官方仪器.已发现仪器3（往复气缸）适用于品味片、软胶囊、缓释制剂和不崩解型产品（如包衣小球）.仪器4（畅通池）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，常常使用的仪器包含立式分散池，浸入细胞，畅通单元仪器适用部分制剂（see Semisolid DrugProducts—Performance Tests <1724>）.
Some changes can be made to thecompendial apparatus; for example, a basket mesh size other than the
typical40mesh basket (e.g., 10, 20, or 80mesh) 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停止一些调整；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），通过充足的数据停止详细的说明后也可使用.必须
注意的是篮网孔径必须是平均的而且知足<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 smallvolume apparatuswith mini paddles and baskets may be considered for lowdosage strengthproducts. A rotating bottle or dialysis tubes may have utility for microspheresand implants, peak vessels, and modified flowthrough
cells for special dosageforms including powders and stents.
非药典溶出仪器具有优于药典尺度仪器的合适设备、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.旋转瓶或透析管可以适用于微球、植入制剂，改进的畅通池适用于特殊剂型包含粉末和支架. 2. METHODDEVELOPMENT
2. 方法的开辟
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.
合理设计一个试验包管数据稳定性（即较低的变异性），而且可以分明反映出样品稳定性问题.成果的高变异难以确定处方变更的趋势和处方变更对溶出度成果的影响.样本大小影响所观察到的变异性.如果在10分钟 12个样本的相对尺度偏差（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成果定义为高变异性.
然而，在方法开辟过程中，可使用较小的样本量，需要对
分析作出相应的断定.大多数溶出成果，表示出较少的变异性.在溶出度试验开辟过程中应对发生变异的原因停止研
究，只要有可以，应测验测验减少变异性.引起变异性的两
个最可以的原因是制剂自己（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
于查找发生变异的原因或者溶出度测定方法自己是否会发
生变异性.任何时间内剂量含量不克不及平均地分散在整个
容器中，异常成果便可以发生.根据分歧的问题，通常的调
节方法包含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.
在处方开辟和制剂工艺中，可以找到发生变异的许多原因.例如，含量平均度的差别，工艺的纷歧致，辅料的相互。