Question and Answer Section - November 2012

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 Is it necessary to run a dissolution test for a product packed in a sachet?
A It depends on the type of product packed in the sachet. If the contents of the sachet are reconstituted according to the instructions to the patient and the result is a solu-tion, then a dissolution test is not needed. If the result is a suspension, then a dissolution test should be developed. The major points to consider in the development of a dis-solution test for a suspension are: (1) the sample should be reconstituted as directed in the instructions for the patient, (2) the sample should be equivalent to the highest dose that can be administered, and (3) the procedure to intro-duce the sample into the vessel should be evaluated and be well described in the final method.

Q What is the maximum sampling volume that can be withdrawn from the dissolution vessel at each time point in a dissolution profile?
A The volume is defined case-by-case, and it is going to be different for each product. The amount of sample withdrawn from the dissolution vessel depends on the analytical procedure that is going to be used to quantify the amount of drug dissolved. The linearity and the limit of quantification of the analytical method, and the filtra-tion procedure should be taken into consideration when defining the amount of dissolution medium that is going to be removed from the vessel at each time point. The effect on the dissolution process of removal of a volume of the test medium is a consideration. The USPGeneral Chapter <711> Dissolution recommends that the vol-ume not deviate more than 1% from what is given in the monograph test. This is a fair starting point in determining whether the volume sampled should be replaced with fresh medium.

Q We are developing a fixed combination prod-uct containing two anti-cholesterol drugs. One is sparingly soluble in water, and the other is insoluble in water. The products containing only the individual drugs have different dissolution media. One uses pH 6.6 0.05 M sodium citrate buffer, and the more insoluble one has 0.45% sodium lauryl sulfate in pH 4.5 acetate buffer as medium. Which medium should be used for the combination product?
A There are no general rules for a case like this one. Be-cause the solubilities of the two drug substances are very different, it may be necessary to have a separate dissolution method for each drug.

Q Why is the dissolution medium volume usually 500 mL, 900 mL, or 1000 mL? How is this volume defined?
A These volumes are the ones most commonly used, but the volume of dissolution medium is defined based on the sink condition. The solubility of the drug substance is deter-mined in several dissolution media within the physiological pH range. The volume of dissolution medium necessary to obtain a saturated solution considering the highest dose that is going to be marketed is calculated using the solubili-ty data. Sink condition can be defined as at least three times the volume to obtain a saturated solution. A discriminative method is the goal, and this is determined experimentally. Sometimes, a more discriminative test is obtained by violat-ing sink conditions.

Q My product has a dissolution acceptance crite-rion of not less than 80% (Q) in 45 min. How should I report the dissolution results?
A The way you are going to report the results depends on how you are going to use this information. There are no general rules; it is up to your lab to decide how to report them. If you want to evaluate the variability of the product, you may report the six individual results (or all the other results if you go to the other stages listed in the appropriate acceptance table in USPGeneral Chapter <711> Dissolution or in the product specification), the standard deviation, and the average of the six results. Another way would be to list the lowest and highest values, the average, and the stan-dard deviation. Other approaches may be used depending on how the information is going to be evaluated.

Q I am testing a gelatin capsule product, and the dissolution medium is water. The gelatin seems to form a pellicle during the test, and my dissolution results are very low. I have run all three stages of the test in <711> Dissolution. I measured the pH of the water to be 6.9. The two-tier test allows the addition of pancreatin for media with pH not less than 6.8 but says that pepsin needs to be used if the pH is less than 6.8. I know that the activity of pepsin is better in acid media than in media above pH 4. Can I use pancreatin for my dissolution test?
A The wording of the chapter makes it clear that if the me-dium is water, pepsin is used in the second-tier testing of gelatin capsules. USP understands that pepsin has a lower activity from pH 4 to 6.8 than from pH 1 to 4. An Expert Panel has been formed to look at this issue and suggest a solution. However, at this time, you will be limited to follow the procedure found in the chapter.

Q USPChapter <711> allows pepsin to be used in dissolution testing of gelatin capsules. Does USP give some recommendation of a supplier?
A USPgives no recommendation regarding a source of supply. USPReagent Specifications section gives the requirements for purified pepsin that is used in the second tier of the dissolution test. An enzyme activity determination method is described. Enzyme activity is dependent on test conditions and substrate. At present, we do not have a conversion factor that might be applied to a product that displays activity against a substrate and under conditions differing from those given in USP. You would do well to determine the activity of the material in your hands and confirm continuing activity for material that has been stored.

Q Is it mandatory to develop a dissolution test that releases 100% of the product label claim?
A No, the main characteristic of a dissolution test is that it should be discriminative for critical quality attributes. The test should be developed in such a way that if there are any deviations in any of the critical quality attributes (particle size, polymorph forms, amount of key excipients, etc.) for a particular product, the dissolution test is going to show a difference in the dissolution profile. At the early stages of dissolution, method development the timing of the test should correspond to the dissolution profile where release is about 75–80% of the product label claim.