溶出度实验的开发和验证讲解

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1、 THE DISSOLUTION PROCEDURE: DEVELOPMENT AND VALIDATIONINTRODUCTIONPurpose 目的The dissolution procedure: development and validation provides a comprehensive approach covering items to consider for developing and validating dissolution procedures and the accompanying analytical procedures. It addresses

2、 the use of automation throughout the test and provides guidance and criteria for validation. It also addresses the treatment of the data generated and the interpretation of acceptance criteria for immediate- and modified-release solid oral dosage forms.溶出度试验的开发和验证目的是为溶出度的测定提供了全面的开发和验证的方法以及相应的分析技术。本

3、指导原则贯穿溶出度测定的全部过程，并对方法验证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产生的数据和接受标准进行说明。Scope 范围Chapter addresses the development and validation of dissolution procedures, with a focus on solid oral dosage forms. Many of the concepts presented, however, may be applicable to other dosage forms and routes of administration.

4、 General recommendations are given with the understanding that modificaions of the apparatus and procedures as given in USP general chapters need to be justified.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 follows the sequence of actions often p

5、erformed in the development and validation of a dissolution test. The sections appear in the following sequence.在进行溶解度实验的开发和验证时，常遵循指导原则，具体内容如下：1. PRELIMINARY ASSESSMENT (FOR EARLY STAGES OF PRODUCTDEVELOPMENT/DISSOLUTION METHOD DEVELOPMENT) 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 Compatibil

6、ity 滤膜相容性研究1.2 Determining Solubility and Stability of DrugSubstance in Various Media 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 溶出介质和体积选择1.4 Choosing an Apparatus 溶出设备选择（桨法和篮法以及其他方法）2. METHOD DEVELOPMENT 方法开发2.1 Deaeration 脱气2.2 Sinkers 沉降篮2.3 Agitation 转速2.4 Study Design 研究设计2.4.1 Time

7、 Points 取样时间点2.4.2 Observations 观察2.4.3 Sampling 取样2.4.4 Cleaning 清洗2.5 Data Handling 数据处理2.6 Dissolution Procedure Assessment 溶出方法评估3. ANALYTICAL FINISH 完成分析3.1 Sample Processing 样品处理3.2 Filters 过滤3.3 Centrifugation 离心3.4 Analytical Procedure 分析方法3.5 Spectrophotometric Analysis 光谱分析3.6 HPLC4. AUTOM

8、ATION 自动化4.1 Medium Preparation 介质的配制4.2 Sample Introduction and Timing 定时进样4.3 Sampling and Filtration 取样和过滤4.4 Cleaning 清洗4.5 Operating Software and Computation of Results 操作软件和计算的结果5. VALIDATION 验证5.1 Specificity/Placebo Interference 专属性/安慰剂（辅料）干扰5.2 Linearity and Range 线性和范围5.3 Accuracy/Recovery

9、 准确度/回收率5.4 Precision 精密度5.4.1 REPEATABILITY OF ANALYSIS 重复性5.4.2 INTERMEDIATE PRECISION/RUGGEDNESS 中间精密度/耐用性5.4.3 REPRODUCIBILITY 重现性5.5 Robustness 耐用性5.6 Stability of Standard and Sample Solutions 样品溶液和标准溶液的稳定性5.7 Considerations for Automation 自动操作注意事项6. ACCEPTANCE CRITERIA 可接受标准6.1 Immediate-Rele

10、ase Dosage Forms 速释剂型6.2 Delayed-Release Dosage Forms 延迟释放剂型6.3 Extended-Release Dosage Forms 延长释放剂型6.4 Multiple Dissolution Tests 多个溶解度试验6.5 Interpretation of Dissolution Results 溶出结果说明6.5.1 IMMEDIATE-RELEASE DOSAGE FORMS 即时释放剂型6.5.2 DELAYED-RELEASE DOSAGE FORMS 延迟释放剂型6.5.3 EXTENDED-RELEASE DOSAGE

11、FORMS 延长释放剂型1. PRELIMINARY ASSESSMENT (FOR EARLY STAGES OF PRODUCT DEVELOPMENT/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）Before method development can begin, it is important to characterize the molecule so that the filter, medium, volume of medium, and apparatus can be chosen prop

12、erly in order to evaluate the performance of the dosage form.在溶出方法开发之前，了解颗粒的性质是非常重要的，以便对用以评估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恰当的筛选。1.1 Performing Filter Compatibility1.1 滤膜相容性研究Filtration is a key sample-preparation step in achieving accurate test results. The purpose of filtration is to remove undissolv

13、ed drug and excipients from the withdrawn solution. If not removed from the sample solution, particles of the drug will continue to dissolve and can bias the results. Therefore, filtering the dissolution samples is usually necessary and should be done immediately if the filter is not positioned on t

14、he 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，对溶出液进行过滤通常是必须的，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 insoluble excipients that may otherwise interfere with the analytical finish. Selection of the proper filter material is imp

15、ortant and should be accomplished, and experimentally justified, early in the development of the dissolution procedure. Important characteristics to consider when choosing a filter material are type, size, and pore size. The filter that is selected based on evaluation during the early stages of diss

16、olution procedure development may need to be reconsidered at a later time point. Requalification has to be considered after a change in composition of the drug product or changes in the quality 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

17、，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、尺寸和孔径大小。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 dissolution testing can be cannula filters, filter disks or frits, filter tips, or syringe filters. The filter material has to be compatible wit

18、h the media and the drug. Common pore sizes range from 0.20 to 70 m, however, filters of other pore sizes 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 filter pore size that excludes these small particles

19、.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兼容。常见孔径大小范围：0.2070m，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 filter may occur and needs to be evaluated. Filter materials will interact with dissolution media to affect the recovery of t

20、he individual solutes and must be considered on a case-by-case basis. Different filter materials exhibit different drug-binding properties. Percentage of drug loss from the filtrate due to binding may be dependent on the drug concentration. Therefore the adsorptive interference should be evaluated o

21、n sample solutions at different concentrations bracketing the expected concentration range. Where the drug adsorption is saturable, discarding an initial volume of filtrate may allow the collection of a subsequent solution that approaches the original solution concentration. Alternative filter mater

22、ials that minimize adsorptive interference can usually be found. Prewetting of the filter with the medium may be necessary. In addition, it is important that leachables from the filter do not interfere with the analytical procedure. This can be evaluated by analyzing the filtered dissolution medium

23、and comparing it with the unfiltered medium.过滤时可能会发生药物的吸附，并需要进行评估。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，从滤膜中滤出物不干扰分析检测也是

24、非常重要的，一般可以通过溶出介质过滤前后进行比较得知，滤膜是否干扰样品的测定。The filter size should be based on the volume to be withdrawn and the amount of particles to be separated. Use of the correct filter dimensions will improve throughput and recovery, and also reduce clogging. Use of a large filter for small-volume filtration can

25、 lead to loss of sample through hold-up volume, whereas filtration through small filter sizes needs 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要滤除的颗粒量来选择滤膜尺寸。使用正确的滤膜尺寸将提高溶液的通过率和回收率，并减少滤膜堵塞。使用大尺寸滤膜过滤小体积溶液，将导致样品溶液损失量过大而收集不到所用样品量；反正，使用小尺寸滤膜过滤，需要更高的压力和较长的时间，并且溶液迅速堵

26、塞滤膜。Filters used for USP apparatus 4 need special attention because they are integrated in the flow-through process. Undissolved particles may deposit on the filters, creating resistance to the flow.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 th

27、e filter with regard to material and pore size can be done in a similar manner to manual filtration. Flow rate through the filter and clogging may be critical for filters used in automated systems. Experimental verification that a filter is appropriate may be accomplished by comparing the responses

28、for filtered and unfiltered standard and sample solutions. This is done by first preparing a suitable standard solution and a sample solution. For example, prepare a typical dissolution sample in a beaker and stir vigorously with a magnetic stirrer to dissolve the drug load completely. For standard

29、solutions, compare the results for filtered solutions (after discarding the appropriate volume) to those for the unfiltered solutions. For sample solutions, compare the results for filtered solutions (after discarding the appropriate volume) to those for centrifuged, unfiltered solutions.在自动化系统的情况下，

30、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 Drug Substance in Variou

31、s Media1.2 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 determined as part of the process of selecting the proper dissolution medium. When deciding the composition of the medium for dissolution testing, it is important to evaluate the influence of buf

32、fers, pH, and if needed, different surfactants on the solubility and stability of the drug substance. Solubility of the drug substance is usually evaluated by determining the saturation concentration of the drug in different media at 37 using the shake-flask solubility method (equilibrium solubility

33、). To level out potential ion effects between the drug and the buffers used in the media, mixtures of hydrochloric acid and sodium hydroxide are used to perform solubility investigations; this is in addition to the typical buffer solutions. In certain cases, it may be necessary to evaluate the solub

34、ility of the drug at temperature other than 37 (i.e., 25). The pH of the clear supernatant should be checked to determine whether the pH changes during the solubility test. Alternative approaches for solubility determination may 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、

35、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 may include the following (not

36、 listed in order of preference): diluted hydrochloric acid; buffers (phosphate or acetate) in the physiologic pH range of 1.27.5; simulated gastric or intestinal fluid (with or without enzymes); and water. For some drugs, incompatibility of the drug with certain buffers or salts may influence the ch

37、oice of buffer. The molarity of the buffers and acids used can influence the 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 (acid

38、ic or buffer solutions) may contain a percentage of a surfactant e.g., sodium dodecyl sulfate (SDS), polysorbate, or lauryldimethylamine oxide to enhance the solubility of the drug. The surfactants selected for the solubility investigations should cover all common surfactant types, i.e., anionic, no

39、nionic, and cationic. When a suitable surfactant has been identified, different concentrations of that surfactant should be investigated to identify the lowest concentration needed to achieve sink conditions. Typically, the surfactant concentration is above its critical micellar concentration (CMC).

40、 Table 1 shows a list of some of the surfactants used in dissolution media. Approximate CMC values are provided with references when available. The list is not comprehensive and is not intended to exclude surfactants that are not listed. Other substances, such as hydroxypropyl -cyclodextrin, have be

41、en used as dissolution media additives to enhance dissolution of poorly soluble compounds. The U.S. Food and Drug Administration (FDA) maintains a database of dissolution methods, including information on dissolution media that have been used (1). Typically, the amount of surfactant added is suffici

42、ent to achieve sink sondition in the desired volume of dissolution medium.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

43、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-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-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 the grade and purity of surfactants because use of different grades could affect the solubility of t

44、he drug. For example, SDS is available in both a technical grade and a high-purity grade. Obtaining polysorbate 80 from different sources can affect its suitability when performing high-performance liquid chromatography (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。

45、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 or pH on the solubility or solution stability of the surfactant solutions. For example, a precipitate forms when the potassium salt for the phosphate buffer is used at a concentration of 0.5 M in combination with SDS. This c

46、an be avoided 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Surfactant 表面活性剂CMC(% Wt/Volume)Re

47、f.Anionic阴离子Sodium dodecyl sulfate (SDS), Sodium lauryl sulfate (SLS) 十二烷基硫酸钠0.180.23%(24)Taurocholic acid sodium salt 牛黄胆酸钠0.2%(3)Cholic acid sodium salt 胆酸钠0.16%(3)Desoxycholic acid sodium salt 脱氧胆酸钠0.12%(3)Cationic阳离子Cetyltrimethyl ammonium bromide (CTAB, Hexadecyltrimethylammonium bromide)十六烷基三甲

48、基溴化铵0.033%0.036%(0.921.0 mM)(5,6)Benzethonium chloride (Hyamine 1622) 苄索氯铵0.18% (4 mM)(2)Nonionic非离子Polysorbate 20 (Polyoxyethylene (20) sorbitan monolaurate, Tween 20)聚山梨酯20（吐温20）0.07%0.09%(3,7)Polysorbate 80 (Polyoxyethylene (80) sorbitan monooleate, Tween 80)聚山梨酯80（吐温80）0.02 %0.08%(3,7)Caprylocap

49、royl polyoxyl-8 glycerides (Labrasol) 辛酸癸酸聚乙二醇甘油酯0.01%(4)Polyoxyl 35 castor oil (Cremophor EL) 聚氧乙烯蓖麻油350.02%(8)Polyoxyethylene 23 lauryl ether (Brij 35) 聚氧乙烯月桂醇醚0.013%(9)Octoxinol (Triton X-100) 辛苯聚醇0.01%0.03%(3, 10)Zwitterion两性离子Lauryldimethylamine N-oxide (LDAO) 月桂基二甲基胺N-氧化物0.023%(11)Routinely, t

50、he dissolution medium is buffered; however, the use of purified water as the dissolution medium is suitable for products with a dissolution behavior independent of the pH of the medium. There are several reasons why purified water may not be preferred. The water quality can vary depending on its sou

51、rce, and the pH of the water is not as strictly controlled as the pH of buffer solutions. Additionally, the pH can vary from day to day and can also change during the run, depending on the drug substance and excipients. Use of an aqueousorganic solvent mixture as a dissolution medium is discouraged;

52、 however, with proper justification this type of medium may be acceptable.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 the drug substa

53、nce should be carried out, when needed, in the selected dissolution medium with excipients present, at 37. This elevated temperature has the potential to decrease solution stability (degradation). Stability should allow for sufficient time to complete or repeat the analytical procedure. Physical sta

54、bility may be of concern when precipitation occurs because of lower solubility 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 a Medium and Volume1.3 溶出介质和体积的选择When dev

55、eloping a dissolution procedure, one goal is to have sink conditions, which are defined as having a volume of medium at least three times the volume required to form a saturated solution of drug substance. When sink conditions are present, it is more likely that dissolution results will reflect the

56、properties of the dosage form. A medium that fails to provide sink conditions may be acceptable if it is appropriately justified. The composition and volume of dissolution medium are guided by the solubility investigations. For example, the choice and concentration of a surfactant need to be justifi

57、ed from 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 dissolution medium is permitted, in accordance

58、 with Dissolution , when dissolution failures occur as a result of cross-linking with gelatin capsules or gelatin-coated products. A discussion of the phenomenon of crosslinking and method development using enzymes can be found in CapsulesDissolution Testing and Related Quality Attributes . Validati

59、on should be performed with the method using enzymes according 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，这同溶出度指导原则一致。在“CapsulesDissolution Testing and RelatedQuality Attributes”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 that follow more

60、closely the composition of fluids in the stomach and intestinal tract. These media may contain physiological surface-active ingredients, such as taurocholates. The media also may contain emulsifiers (lecithin) and components such as saline solution that increase osmolality. Also, the ionic strength

61、or molarity of the buffer solutions may be manipulated. The media are designed to represent the fed and fasted state in the stomach and small intestine. These media may be very useful in modeling in vivo dissolution behavior of immediate-release (IR) dosage forms, in particular those containing lipo

62、philic drug substances, and may help in understanding the dissolution kinetics of the product related to the physiological make-up of the digestive fluids. Results of successful modeling of dissolution kinetics have been published, mainly for IR products. In the case of extended-release dosage forms

63、 with reduced effect of the drug substance on dissolution behavior, the use of such media needs to be evaluated differently. In vitro performance testing does not 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

64、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 of delayed-rel

65、ease products by Method A or Method B in For drugs with acid solubility less than 10% of the label claim or drugs that degrade in acid the usefulness of the acid stage in detecting a coating failure is compromised. This would be handled on a case-by-case basis. Possible resolutions include the addition of surfactant to the aci