Questions and Answers November 2017

William Brown and Margareth Marques
The following questions have been submitted by readers of Dissolution Technologies. Margareth Marques, Ph. D. and Will Brown, United States Phamacopeia, authored responses to each of the questions.
*Note: These are opinions and interpretations of the authors, and are not necessarily the official viewpoints of the USP

Email for correspondence: web@usp.org

Q I need to validate a dissolution method for a product that has three time points in the acceptance criteria: 1 hour NMT 20%, 3 hours 30%-50%, and 7 hours NLT 85%. How should I validate linearity?
A The validation of any parameter of the dissolution procedure is done by taking into account the entire dissolution profile and not based 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.

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?
A The main objective of the dissolution test is 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.

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 an extended-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?
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 in water. Considerations of the discriminatory power for the critical quality attributes of the product will inform any decisions in the development of a dissolution procedure.

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

Q Our lab uses only 2-L vessels. Should the Performance Verification Test (PVT) be carried out with 1-L vessels or is there a specific PVT protocol for 2-L vessels? How should we carry out the PVT in the case of peak vessels?
A The limits for each lot of PVT reference standard tablets are obtained following a multi-site collaborative study using a 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.

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?
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.

Q Should a dissolution test be developed for vaginal capsules?
A For any product in which the drug substance is in a solid state, a dissolution test is advisable. The dissolution test may be 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.

Q Is it necessary to validate a dissolution test for coated vaginal tablets?
A All dissolution tests should be validated regardless of the dosage form type and route of administration.

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

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?
A The justification of any decisions made during 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.

Q What are the criteria used by USP to define the Q value in dissolution tests?
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 under stability studies. The amount released-time pairing is selected based on the discriminatory power for critical quality attributes.

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

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?
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.

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?
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.