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Questions and Answers February 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 In USP General Chapter <711> Dissolution under Procedure, Apparatus 1 and Apparatus 2, Immediaterelease dosage forms, it says to verify the temperature of the mixture under test in the vessel at suitable times. Is a suitable time considered to be either directly prior to or directly after sampling? If the answer is yes, what is a reasonable time range for verifying the temperature?
A The chapter does not specify the appropriate times. At the least, the medium is confirmed to be within the specified range in all vessels immediately before starting the test. Keep in mind that every time you introduce a probe inside the dissolution vessel during the test it is going to change the hydrodynamics and this may have an impact in the results.

Q In the development of a new product, we established the dissolution acceptance criteria based on data obtained with pilot and manufacturing batches, and we validated this dissolution procedure. We would like to change the acceptance criteria because results that do not meet these criteria were found during the stability studies. If we do this change, do we need to revalidate the dissolution procedure? Would we lose all the stability studies that were done with the previous acceptance criteria?
A The acceptance criteria for dissolution procedures is selected taking into account the dissolution profiles of at least three batches during product development subjected to stability study. It is very important to know how the samples behave under/after storage and, if any changes occur, what could be the possible consequences of these changes in the in vivo performance of the product. Any changes in the dissolution profile for samples on stability may be a very important source of information. For instance, certain tablet formulations become harder or softer under storage. These changes may result in a slower or faster drug release during the dissolution testing. It will be necessary to evaluate if these changes will have an impact on the in vivo behavior of the product. This body of information can be used to reevaluate the formulation, manufacturing process, quality grade of the formulation components, packaging material, instructions to the patient/practitioner, and so forth.
The validation of any dissolution procedure can be done before the final acceptance criteria are defined. The validation procedure takes into account the entire dissolution profile.

Q We are developing an intramuscular slow-release suspension formulation. We would like to run the dissolution test at neutral pH. However, the drug substance has very low solubility at neutral pH without surfactants, and it dissolves too fast when sodium lauryl sulfate is used. What could be done to solve this issue? Also, because a normal dose of this product has an amount of drug substance that does not dissolve completely when using USP Apparatus 2, can we use part of the dose to do the dissolution test?
A There are several surfactants that can be used in dissolution. You can see a list of surfactants that have already been used in dissolution in the Q&A section of Dissolution Technologies 2005, 12 ( 4), 3 0 (http://www.dissolutiontech.com/DTresour/200511Articles/DT200511_QA.html). The type and amount of surfactant used needs to be justified. See some recommendations on how to select the type and amount in the paper Noory, C.; Tran, N.; Ouderkirk, L.; Shah, V. Steps for Development of a Dissolution Test for Sparingly Water-Soluble Drug Products. Dissolution Technol. 2000, 7 (1), 16-21 (http://www.dissolutiontech.com/DTresour/200articles/200art3.html).
The objective of the dissolution test is not necessarily to dissolve the total amount of drug substance in the dosage form. The dissolution test needs to be sensitive to important changes in critical quality attributes of the product. The recommendation is to use the largest dose of the product that can be administered at one time.

Q The USP General Chapter <711> Dissolution, under For Dosage Forms Containing or Coated with Gelatin, Dissolution Medium with pH ≤ 4.0, says to use a quantity of pepsin that results in an activity of NMT 750,000 Units/L. For pepsin with an activity of 0.7 FIP-U/g, what weight will give an activity of NMT 750,000 Units/L? For dissolution media with pH ≥ 6.8, the USP chapter says to use a quantity of pancreatin that results in a protease activity of NMT 2000 Units/L. How much pancreatin with a protease activity of 350 FIP-U/g will produce the activity stated in the chapter?
A The text in the chapter says that the pepsin activity should be determined by the procedure stated in the Reagent Specifications section of USP, and the procedure to be used for pancreatin is the Assay for protease activity in the USP monograph for Pancreatin. There are no conversion factors for enzyme activity. Enzyme activity is very dependent on the substrate, and the various enzyme activity assays are not equivalent or interchangeable. You need to determine the enzyme activity by the procedures stated in the USP General Chapter <711> Dissolution.

Q The dissolution test results for a particular product have a high variability and are very high. What is the upper limit for the amount of drug released in dissolution testing?
A Typically, there is no upper limit for dissolution results from immediate-release products. The drug content of the samples puts a physical limit on the results. If you are obtaining very variable and high results, you need to do an investigation of possible causes. These causes can be related to the dissolution test, the manufacturing process, or both. Among the possible causes related to the dissolution testing are sampling procedure and timing, filter and filtering procedure, and so forth.

Q We are developing a dissolution method for an immediate-release tablet and are using 0.45-µm nylon membrane filters. We are finding a high variability among the results. We are thinking about changing to a 0.45-µm PTFE filter. Do you have any other suggestions?
A See the USP General Chapter <1092> The Dissolution Procedure: Development and Validation, Filters. You need to select the most appropriate membrane type and pore size for your formulation. In general, the pore size varies from 70 to 0.45 µm, but depending on the formulation, you may need to use 0.22 µm or even 0.10 µm. The filter selection is done experimentally in a case-by-case approach.

Q When gelatin capsules present crosslinking and the dissolution medium contains surfactant, is it possible to use a pretreatment medium containing the enzyme with a composition different from that of the original dissolution medium? This method uses a quantitative procedure where the enzyme causes difficulties with the selected HPLC column.
A The dissolution test should be sensitive to important changes in the critical quality attributes of the product. Once the dissolution conditions have been defined, any changes in those conditions will require demonstration that the method is still sensitive to the critical parameters. It may be easier to select an alternative quantitative procedure where the enzyme has less or no interference than to change the dissolution conditions.