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Questions and Answers May 2016

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 Where can we find the requirement for a minimum of three-fold medium volume for sink conditions in USP?
A Section 1.3 Choosing a Medium and Volume in the USP General Chapter <1092> The Dissolution Procedure: Development and Validation gives a definition of sink conditions. Sink conditions is 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 properties of the dosage form. A medium that fails to provide sink conditions may be acceptable if it is appropriately justified.

Q We are developing a fixed combination tablet containing glimepiride and metformin. Are there any special recommendations for developing a dissolution test for a product like this one?
A Because glimepiride (BCS Class 2) and metformin (BCS Class 3) have very different solubilities in aqueous systems, there is a good chance that separate dissolution tests may be needed for each drug substance. Keep in mind that the dissolution test needs to be sensitive to the critical quality attributes of the product.

Q On page 5 of the USP Dissolution Toolkit (1), it is recommended that during mechanical calibration after equilibration, the medium temperature measured in all vessels should agree within a range of 0.4 °C (e.g., 36.7-37.1 °C), but on page 7 of the same document, it is recommended that during the performance verification test (PVT), the temperature of the medium-filled vessels placed in the assembly should be equilibrated to 37 ± 0.5 °C. What is the rationale for selecting different temperatures for vessels containing medium instead of the 37 ± 0.5 °C range?
A The USP Dissolution Toolkit provides information on the mechanical verification as well as the performance verification of a dissolution test assembly using USP Apparatus 1 (basket) or USP Apparatus 2 (paddle). The two temperature ranges in your question are for different purposes. Within the mechanical verification sections, a qualification of the temperature control mechanism is described. In that section, the set point for the temperature mechanism is exactly at 37 °C, and the temperature achievable in each of the vessels is within 0.2 °C of the set point for a range of 0.4 °C. For the PVT, a separate use of temperature control is given. When conducting the PVT, the temperature should be within 0.5 °C of 37 °C as is consistent with the USP General Chapter <711> Dissolution.

Q Why do some USP monographs, like Doxycycline Hyclate Capsules or Tetracycline Hydrochloride Tablets, state a distance of 4.5 ± 0.5 cm between the bottom of the vessel and the paddle and for other monographs, like Minocycline Hydrochloride Tablets, the distance is 2.5 ± 0.2 cm?
A The larger distance is used to accommodate larger tablets or capsules that may be hit by the paddle during the test if the distance is just 2.5 ± 0.2 cm.

Q During a dissolution test for a fixed combination product, one active substance meets the criteria at the S1 level but the other one fails. Should we perform the test at S2 stage for both active substances?
A The monograph dissolution test will present the tolerances for each component linked by the word AND. The tolerances are met when the tolerances for both components are reached. This condition is independent of the analytical procedure applied. If component A has a tolerance of NLT 85% and component B a tolerance of NLT 80% and the results do not meet the S1 criteria for both components, testing proceeds to S2.

Q We have a dissolution test assembly with paddles (USP Apparatus 2) and four 4-L vessels. The dimensions of the vessels are the same as those indicated in the USP General Chapter <711> Dissolution. For the mechanical verification test we followed the Dissolution Toolkit procedure (1). The Performance Verification Test (PVT) should be performed with USP Prednisone Tablets RS in a 500-mL dissolution medium. Because the diameter of the 4-L vessels is larger than the one for 1-L and 2-L vessels (98 to 106 mm), it is impossible to perform the PVT described. Also, there are no provisions in the acceptance criteria for this assembly configuration. How can we perform the PVT in this case?
A At present, USP offers no specific PVT for Apparatus 2 with 4-L vessels. The mechanical approaches in the Dissolution Toolkit will provide some measure of control of the apparatus itself. However, full verification of the suitability would be better demonstrated by having it produce suitable results with a standard material. In this context, suitable results might be (1) results that are consistent with experience or (2) results that are consistent with ranges provided for USP Prednisone Tablets RS from a collaborative study. For the first approach, the experience could be with a product lot that you have manufactured that has shown consistent dissolution performance over time. In this approach, you would have developed control charts over time for the apparatus. Deviations from your experience could then be spotted and remedial action taken. In the second approach, you would have to rely on a material that was supplied by an independent organization, as is the case for Apparatus 2 (1 L with Prednisone Tablets). As noted above, at present USP does not provide such a material.

Q Should the dissolution sample withdrawal be done after stopping the rotation of the paddles or should the samples be collected while paddles are rotating? If we do not stop the paddles to collect the sample, when we sample the sixth vessel the total time of the test will be at least 5 min longer than the time stated in the method.
A You cannot stop the agitation during the sampling. You are sampling a suspension that needs to be homogenized and be representative of the content of the entire vessel. You need to contact the technical service of the vendor of your dissolution equipment to see how you can isolate each motor to insert the samples in a staggered way. Another way would be doing the sampling using an automated or semi-automated system.

Q We are developing a dissolution test for a combination product and we are not sure how to evaluate the discriminative power of the method. We tested three different formulations (with variations on the amount of starch and magnesium stearate), and we observed differences in the dissolution profile for each one of them, but all of them reached the same plateau at the same time. Should we consider the entire dissolution profile or only the last point because the quality control lab will collect the sample at only the last point of the profile?
A You need to work together with your research and development and manufacturing groups to determine the critical quality attributes of this formulation that may have an impact on the in vivo performance of the product. In your example, you need to have some kind of evidence if different amounts of starch or magnesium stearate will have an impact in the in vivo performance of the product. You need to consider the entire dissolution profile to evaluate if the dissolution conditions selected are discriminative. The sample point for quality control purposes is not necessarily the last point in the dissolution profile but the point where it is evident that if any deviations in the critical quality attributes of the product occur, you will observe differences in the dissolution profile.

Q We are testing a product using USP Apparatus 3 (reciprocating cylinder) using a dissolution medium that contains 3% polysorbate 80 (Tween 80), and there is much foaming. What can we do to remove or reduce the foaming?
A You can add an antifoam agent to the dissolution medium. One suitable type will be any alcohol with a long aliphatic chain such as octanol. The lowest possible amount of antifoam agent should be used. You also need to verify if there is any interference in the quantitative step of the dissolution test.

Q There are some USP monographs that use pooled sampling in the dissolution test. We would like to carry out the verification of the dissolution test in one of these monographs, and we would like to know how to handle the sampling.
A Pooled sampling is used only for routine analysis. For any other application or evaluation such as dissolution profile, method verification, or method validation, it will be necessary to carry out the quantitative step in each one of the samples withdrawn and not combine them.

Q We are having problems with the dissolution profile of one of our capsule formulations in media with pHs of 4.5 and 6.8. We would like to add papain and pancreatin to these media based on the recommendations in the USP General Chapter <711> Dissolution. We are planning to add 1 g of papain to 1 L of pH 4.5 dissolution medium and 1 g of pancreatin to 1 L of pH 6.8 dissolution medium. We need to know the activity of each enzyme after the addition to the media. Does the activity of the enzyme depend on the pH of the solution or can we assume the potency reported by the supplier of the enzymes in different pH values?
A Enzymes should only be added to the dissolution medium used in the dissolution testing of gelatin capsules if there is evidence that the failure is caused by the presence of cross-linking in the gelatin. For more information see the paper on Revisions to Dissolution <711> and Disintegration and Dissolution of Dietary Supplements <2040> (http://www.dissolutiontech.com/DTresour/201411Articles/DT201411_A01.pdf). If the failure is caused by any other reason, adding enzyme to the dissolution medium will not solve the problem. The amount of enzyme to be added to the dissolution medium should not be defined arbitrarily. The amounts of enzymes to be added to the dissolution medium are stated in the USP General Chapter <711> Dissolution. The activity of the enzyme is determined before its addition to the dissolution medium using the procedures stated in <711>. Enzyme activity is heavily dependent on the substrate and activities determined by different procedures are not equivalent or interchangeable.

Q Is a sinker required if the capsule floats during the dissolution test and the compendial monograph for the product does not call for the use of sinkers?
A The need to use sinkers may be formulation dependent. They are selected in a case-by-case approach. If the compendial monograph does not mention a sinker, it means that a sinker was not necessary for the product for the sponsor of the compendial monograph. If other products are approved for the market and they require the use of sinkers, the compendial monograph can be modified to accommodate these products. If the tablet or capsule floats during the dissolution test and no sinker is used, the results of the test may be compromised.