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试验的可接受数据量，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.
溶出度试验方法由仪器、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.
溶出试验已被描述为复杂的样品制备过程。在溶出试验过程中，样品处理和分析程序用于确定药物的溶出量，这在溶出试验中被称为―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
