注：本文为Dissolution Technologies Questions and Answers November 2017 部分翻译。

原作者：

Margareth Marques，William Brown
U.S. Pharmacopeia, Rockville, MD, USA 

Q I need to validate a dissolution method for a product that has three time points in the acceptance criteria: 1 hour NMT20%, 3 hours 30%-50%, and 7 hours NLT 85%. How should I validate linearity?

Q：这样一个品种（1h溶出不大于20%，3h溶出30%~50%，7h溶出不低于85%）的溶出方法验证，线性应该如何做？

A The validation of any parameter of the dissolutionprocedure is done by taking into account the entire dissolution profile and notbased on the final acceptance criteria of the product. The linearity range should encompass the entire dissolution profile. You need to select at least five points in the profile from less than the lowest expected concentration to more than the highest concentration expected from the product under test. You do not need to have the acceptance criteria of the product to validate the dissolution method. This validation needs to be done as soon as possible in the project when, in most cases, the final acceptance criteria has not yet been selected.

A：溶出过程的任何参数的验证都是通过考虑整个溶出情况来完成的，而不是根据产品的最终验收标准来进行的。线性范围应包括整个溶出曲线。您需要在从低于测试产品预期的最低浓度到高于预期的最高浓度选择至少五个点。您不需要用产品的验收标准来确认溶出方法。这种验证需要在项目中尽快完成，在大多数情况下，最终验收标准尚未选定。

Q In the development of a dissolution procedure, which parameters (pKa, drug absorption, etc.) should be considered in the selection of the pH of the dissolution medium?

Q：在溶出方法的开发中，在选择溶出介质的pH值时，应考虑哪些参数（pKa、药物吸收等）？

A The main objective of the dissolution testis to be discriminative for the critical quality attributes of the formulation.The dissolution conditions should be selected considering this concern. You should start with the pH values that are within the physiological range of the route of administration of the product, consider the release mechanism of the dosage form and how it is supposed to perform in vivo. You can use pH outside the physiological range and any other unusual conditions if that provides more discriminatory power. The choice of such a medium would need to be justified with data obtained with your formulation.

A：溶出试验的主要目的是对产品的关键质量属性进行鉴别。溶出条件的选择应考虑到这一点。你应该从产品作用涉及的生理范围内的pH值开始，考虑剂型的释放机制以及它应该如何在体内作用。任何其他不寻常的条件如果具备更高的区分力，生理范围之外的pH值也可以接受。这种特殊介质的选择需要提供产品数据来证明其合理性。

Q We are developing a dissolution test for a product that has four drug substances. Three of them are readily soluble in water and one has very low solubility in water. The product is anextended-release tablet and the time to reach the plateau in the dissolution profile is taking a very long time. Can we use surfactants to speed up the dissolution?

Q：我们正在研制一种含有四种药物成分的复方的溶出试验。其中三种可溶于水，其中一种在水中溶解度很低。该产品是一种缓释片，在溶出曲线上到达平台需要很长的时间。我们能用表面活性剂加速溶出吗？

A If there is a big difference in solubility of the different drug substances present in the formulation, it may be necessary to develop a separate test for the one that is poorly soluble in water. In your case, it may be appropriate to have one test for the three drug substances with good solubility in water and another one, probably with the addition of surfactant, for the drug substance that has low solubility inwater. Considerations of the discriminatory power for the critical quality attributes of the product will in form any decisions in the development of a dissolution procedure.

A：如果在处方中存在的不同的药物的溶解度有很大的差别，可能需要对难溶于水中的一种进行单独的试验。在你的例子中，可能更恰当的是对于水中溶解度好的三种药物建立一种溶出方法，对于水中溶解度低的药物开发另一种加入表面活性剂的溶出条件。溶出方法开发的每个决定都要考虑方法对产品关键质量属性的区分力。

Q Can we use sinkers when carrying out the disintegration test of capsules as they float during the test?

Q：当胶囊进行崩解时限考察时漂浮，可以使用沉降篮么？

A No, the capsules often float during disintegration testing. If disintegration time is affected by the floating samples, you may evaluate if the use of disks will be suitable for testing the product.

A：不可以，胶囊在崩解考察中漂浮是常见现象。如果样品的漂浮影响了崩解时间，你可以评估一下标准的方法对该品种的适用性。

Q Our lab uses only 2-L vessels. Should the Performance Verification Test (PVT) be carried out with 1-L vessels or is therea specific PVT protocol for 2-L vessels? How should we carry out the PVT in the case of peak vessels?

Q：我们实验室只有2L的溶出杯，性能验证（PVT）是否必须用1L的溶出杯来做？或者是否有适用于2L溶出杯的特殊的性能验证方案？peak杯的性能验证该如何进行？

A The limits for each lot of PVT reference standard tablets are obtained following a multi-site collaborative study usinga well-controlled protocol. One of the protocol conditions is that testing is in 1-L vessels. As the dimensions of the 2-L vessels only differ in height from the 1-L vessel, and in both size vessels the 500-mL of medium does not use the full volume available, it is reasonable to assume that the PVT can give meaningful results if 2-L vessels are used. Any vessel used in dissolution testing should conform with the description given in the USP dissolution general chapter.

A：性能验证中的每一项限制参数，是参考了标准片在多个站点通过可控方案进行研究获得的。控制方案中的一项就是使用1L的溶出杯。由于2L的溶出杯与1L的溶出杯在维度上只是高了一些，并且500ml的介质体积对于两种规格的溶出杯来说都未达到满量程，因此可以推断如果使用2L的溶出杯进行性能验证，结果是有意义的。任何用于溶出实验的溶出杯均需符合USP溶出通则中给出的描述。

Q We are developing a dissolution method. During the filter evaluation, all filters studied adsorbed the active ingredient. Can we use centrifugation instead of filtration?

Q：我们在开发的一种溶出方法。滤膜吸附考察中，所有研究的滤膜均对有效成分有吸附。我们可以采用离心代替过滤么？

A Yes, centrifugation can be used with appropriate justification. Remember that centrifugation may allow the solids to continue to dissolve and may impart additional energy to the sample that may promote additional dissolution and so is not the first choice. If centrifugation is chosen, you need to clearly describe the centrifugation conditions in the final version of the method: speed, time, type of the centrifugation tube, etc.

A：可以，理由恰当可以使用离心法。请记住，离心可以使固体继续溶解，并可能给样品带来额外的能量，从而促进额外的溶解，因此离心法不是首选。如果选择离心，你需要在最终方法中清楚的描述离心的速度、时间、离心管的类型等。

Q Should a dissolution test be developed for vaginal capsules?

Q：阴道胶囊是否需要开发溶出方法？

A For any product in which the drug substanceis in a solid state, a dissolution test is advisable. The dissolution test maybe replaced with a disintegration test with appropriate justification based on the dissolution profile, in vivo absorption, the physical-chemical characteristics of the drug substance and on the release mechanism of the formulation. Discussions with the appropriate regulatory organization will help with this decision.

A：对于任何固体制剂，溶出实验都是适用的。当药物的溶出曲线、体内吸收、理化特性、制剂的释放机制满足某些条件，可以崩解实验代替溶出实验。与相关的监管机构讨论协商将有助于做这个决定。

Q Is it necessary to validate a dissolution test for coated vaginal tablets?

Q：阴道包衣片的溶出方法是否需要验证？

A All dissolution tests should be validated regardless of the dosage form type and route of administration.

A：所有的溶出试验都要经过验证，不论剂型、类型和给药途径如何。

Q Is it necessary to evaluate the filter for the lower doses of a product?

Q：对于低剂量的产品，过滤器有必要进行筛选么？

A  All parameters of the dissolution test should be validated for all doses of the product. In fact, filter interference may be more noticeable at low drug concentrations.

A：溶出试验的所有参数都应对产品的所有剂量进行验证。事实上，在药物浓度低的情况下，过滤器干扰可能更为明显。

Q We evaluated the solubility of our drug substance within the physiological pH range, and it was found that it had high solubility in 0.1 N HCl and in pH 4.0 acetate buffer. We decided to use pH 4.0 acetate buffer because it was the medium used in a paper found in the literature. Is this acceptable?

Q：我们评估了我们的药物在生理pH范围内的溶解度，发现它在0.1mol/L盐酸和pH4.0的醋酸盐缓冲液中溶解度很高。我们决定使用pH4.0醋酸盐缓冲液，因为它是文献中研究使用的介质。这样可以接受吗？

A The justification of any decisions madeduring the development of the dissolution procedure should be done with results obtained with your formulation. Solubility should be evaluated over the physiological pH range, approximately pH 1 to pH 7. Solubility above your chosen pH may be informative. The use of pH 4.0 acetate buffer or in fact any medium needs a justification. If your product is an oral dosage form, the initial evaluation should have been done with 0.1 N HCl because this is the first medium your product is going to encounter when administered. Unusual conditions can be used if they are more discriminative.

A：在溶出方法开发的过程中，任何决定应以你的处方获得的结果为准。溶解度应在生理pH值范围内进行评估，pH值约为1至7。溶解度高，对于选定pH值可能是有益的信息。pH4.0醋酸盐缓冲液的使用，或者实际上任何介质被选用都需要理由。如果你的产品是口服剂型，最初的评估应该是用0.1mol/L盐酸做的，因为这是你的产品在服用时会遇到的第一种介质。不寻常的条件可以使用，如果他们更具区分力。

Q What are the criteria used by USP to definethe Q value in dissolution tests?

Q：USP在溶解试验中定义Q值的标准是什么？

A The dissolution, disintegration, or drug release acceptance criteria in any of the USP monographs is the one approved by FDA for products marketed in the USA. USP defines neither the dissolution test conditions nor the acceptance criteria in any USP monograph. The acceptance criteria are determined considering all release profiles obtained during the development of the product, including those obtained with samples understability studies. The amount released-time pairing is selected based on the discriminatory power for critical quality attributes.

A：在USP任何一篇专著中，溶出、崩解、药物释放的可接受标准源于FDA认可在美国销售的产品。在任何一篇专著中，USP都没有详述溶出条件和可接受标准。可接受标准是根据产品开发过程中所有释放曲线，包括产品稳定性考察所得数据来确认的。基于对关键质量属性的区分力，确定标准规定的释放量和取样时间。

Q Is it acceptable to conduct S2 (as underUSP general chapter <711> Dissolution) with a different analyst? Should we continue the testing on the same day?

Q：换由不同的分析人员进行S2检测（如USP通则<711>溶出实验项下）可接受么？我们需要在同一天进行测定么？

A The dissolution test includes the S1, S2,and S3 levels. Having to go to the S2 or S3 stages is not considered an Out of Specification (OOS) result. As the analyst plays an important role in thedissolution test, it will be appropriate to run all three levels with the same analyst. Dissolution method validation should include estimation of intermediate precision, but changing analysts in the middle of a test might introduce additional variability that could complicate any further investigation. The testing should be completed as soon as possible.

A：溶出试验包括S1、S2和S3水平。进入S2或者S3阶段不考虑超标（OOS）结果。由于分析人员在溶出测定中起着重要作用，所以使用同一个分析员来进行所有三个级别的测定是更合理的。尽管溶出方法验证评估过中间精密度，但是在测试中途改变分析员可能会带来额外的变异，这可能使任何进一步的研究复杂化。测定应该尽快地完成。

Q What level of variability in the concentration of dissolution medium is acceptable? As an example, what are acceptable lower and upper limits for 0.1 M HCl?

Q：溶出介质浓度偏差多少可以接受？比如0.1mol/L盐酸介质可以接受的浓度上下限分别是多少？

A You will verify the robustness of the dissolution procedure during method development. From your observations, limits can be set. There are no rules, and the decision is made on a case-by-case basis.

A：在方法开发的过程中，你可以判断出方法的稳健性。根据你的观察，可以设定限值。这个限值的确认根据案例的不同而不同，没有固定的准则。

Q There is only a lower limit set for dissolution of immediate-release tablets and capsules. What is the upper limit for dissolution testing results?

Q：对于速释片剂和胶囊剂只限定了溶出下限。溶出结果的上限是多少？

A Typically, there is no upper limit set for these dissolution results. Dissolution testing can be viewed as a specialized extraction procedure. The drug content of each dosage unit sets a functional limit on the amount dissolved during testing.

A：通常，溶出测定没有上限。溶出实验是一个提取过程。每个剂量单位中的药物含量限制了测定中溶出的量。

声明：本文转载自药事纵横，作者黄宇新