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Questions and Answers August 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 We have a product that is a capsule containing one tablet with one active ingredient and excipients and the other active ingredient in the powder form. How should we develop the dissolution test? Should we open the capsule and separate the tablet and have two different dissolution tests?
A The dissolution test needs to be carried out in a way that mimics the user/patient use as close as possible. If the user is going to take the entire capsule at each dosing, the dissolution test should be done in the same way. Depending on the solubilities of the active ingredients present in the formulation, you may need to have separate tests for each drug substance, and the dissolution test will be performed on the intact capsule. Read the instructions for the patient to see how this product should be administered.

Q Is there a recommendation for the limit of variation in the dissolution results? We could not find any information in the USP general chapter <711> Dissolution. Should we include the standard deviation when reporting dissolution results?
A The variability in dissolution results have two components: the variability from the manufacturing process and the variability from the dissolution procedure. As these two components are product/process dependent, there are no official limits for the variability in dissolution results. For quality control purposes, the dissolution results should be evaluated according to the appropriate acceptance table in the USP general chapters <711> Dissolution and <724> Drug Release. There are some instances where these acceptance tables may not be useful. In such cases, new criteria tables may need to be developed and justified. There are some USP monographs where the acceptance table is in the monograph text. For any other purpose and to build up a history/knowledge of the product, you need to evaluate the individual results, the average, and the standard deviation at each timepoint in the dissolution profile.

Q In the validation of automated sampling systems for an extended-release dosage forms, do we need to sample all the points in the dissolution profile or can we stop earlier, as soon as the product meets the acceptance criteria?
A You do not need to have the acceptance criteria for the product in order to validate the dissolution procedure automation. Validation will typically consider the entire dissolution profile. The validation of any automated sampling systems needs to be done as early as possible in the project.

Q We are developing a dissolution test for a delayedrelease tablet that contains an active ingredient that is unstable in acid medium. How can we quantify the amount of active ingredient released in the acid stage?
A You can quantify how much active ingredient remains in the dosage form after being tested in the acid stage. You will want to use an assay procedure that can quantify the active and degradation products. Supplemental information can be obtained by quantifying the active remaining in the dosage form at the end of acid stage testing. If you use that approach, the buffer stage testing will require new samples.

Q When doing the dissolution test of a particular product we are finding very high variability in the results, and these results are very high. Do you have any recommendations?
A You can start the investigation by verifying that there is no interference from the formulation in the quantitative step, that the filter was well-selected and validated, and that the sampling was done following the appropriate procedure. Also, you should discuss your observations with the manufacturing/development group because the problem may be an indication that there were deviations in the manufacturing of the product/samples.

Q Do you have any suggestions on possible brands or vendors for sinkers?
A You can find several suppliers of sinkers on the internet using the keywords “dissolution sinker.” Most of the vendors of dissolution equipment also have some models of sinkers. Keep in mind that the size and design of the sinker need to be selected in a case-by-case approach, so it is advisable to test different models. You can also make your own sinkers following the instructions in the USP general chapter <1092> The Dissolution procedure: development and validation.