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
