Question and Answer Section — August 2014

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 When the acceptance criterion for disintegration is not more than 15 min, how should the results be rounded?

The results from a disintegration test are usually in two categories, acceptably disintegrated or not acceptably disintegrated. This will result in counting the units that disintegrated acceptably, and the count will be in whole numbers. No rounding is necessary. For information on rounding USP test results, see USP General Notices, item 7.20. The results are going to be rounded to the same number of decimal places that is in agreement with the acceptance criterion.

Q Is there any guideline stating that only glass vessels can be used in dissolution?

See USP General Chapter <711> Dissolution, under Apparatus, Apparatus 1 (Basket), first paragraph. Vessels can be made of glass or any other inert material. Be aware that some compounds adsorb to glass and others to plastic. You need to verify which type of construction vessel is the most appropriate for the samples being evaluated.

Q Are there any standard filters to be used in dissolution testing?

The selection of the filter (membrane type and pore size) should be made using a case-by-case approach. Interference may depend on the drug substance or on the formulation composition.

Q Is it mandatory to use sinkers in the dissolution testing of capsules?

No, it is not mandatory. Sinkers are only used if the dosage form floats or if it sticks to the vessel surface. See more information in the USP General Chapters <1092> The Dissolution Procedure: Development and Validation and <1094> Capsules—Dissolution Testing and Related Quality Attributes.

Q Can disintegration testing be eliminated if we are performing dissolution testing for each product batch?

The only dosage form that requires both dissolution and disintegration tests is orally disintegrating tablets. For all other dosage forms, only one test is performed, dissolution or disintegration.

Q Currently we have not more than 15 min as acceptance criterion for the disintegration of core tablets and not more than 30 min for film-coated or plain tablets. Are these criteria acceptable?

A dissolution test should be developed first. Then, depending on the BCS classification of the drug, the release mechanism of the dosage form, and product behavior during the dissolution test, it may be possible to replace the dissolution test with a disintegration test. The disintegration test needs to be discriminative for your formulation. The acceptance criteria are selected using a case-by-case approach and supported by experimental data.

Q What is the difference between using a basket and using a paddle with a sinker? For a capsule, when should a paddle be used instead of a basket?

If the dosage form floats, a basket might be the first choice. The default basket in USP is the one with 40 mesh. If the formulation clogs this basket, the alternatives are 20 or 10 mesh. If the formulation clogs even the 10-mesh basket, then the alternative is to use a paddle. The hydrodynamics inside the vessel when baskets are used may be not appropriate for certain formulations even at 100 rpm. In this case, it may be better to use a paddle with a sinker.

Q Are there any upper limits for the amount of active ingredient released during dissolution testing? Can we use the upper limit from the Assay test as upper limit for dissolution? If the product has an overage, should the acceptance criterion be based on the overage?

There are no upper limits in dissolution testing. If you see results at 100% or above very often, you should investigate. It may be because of inadequate filtration or sampling procedures, interference of the ingredients in the formulation, or some deviation in the manufacturing process. In the United States, overages are allowed only in very special cases, and they need to be justified and approved by FDA. Dissolution results, in most cases, are calculated based on the product label claim. Exceptions are transdermal systems and osmotic pump tablets where the results are calculated based on the labeled dose released.

Q Under S3 in Acceptance Table 1 in USP General Chapter <711> Dissolution, it says that you need to repeat the test with 12 more units. Is it mandatory to run this test in a dissolution test assembly that can accommodate 12 vessels at the same time? If I have a dissolution assembly that has only six vessels, can I run two tests to obtain the 12 results?

It is not mandatory to run the test in equipment that can accommodate 12 vessels. You can do two runs of six vessels.

Q In the case of cross-linking in gelatin capsules, when we are going to add the enzyme to the dissolution medium, should this addition be made in each vessel or in the bulk medium?

If you have a failure in the dissolution test because of cross-linking in gelatin capsules, you will repeat the test with additional units. You are not going to add the enzyme to the vessel containing the capsules that failed the test. You are going to start the dissolution test all over again with clean vessels, transferring the dissolution medium to the vessels, waiting for the temperature to reach 37.0 ± 0.5 °C in all vessels, and so forth. It is easier, and results in lower variability, if you prepare the dissolution medium with the enzyme in bulk. If you add the enzyme to each vessel, you need to weigh at least six portions of the enzyme powder, transfer it to each vessel, mix, and wait until it is dissolved. It is easier to prepare 8 L, 10 L, or another appropriate volume in bulk. Even though the enzymes have good solubility in aqueous solvents, dissolution in the dissolution medium will take time.

Q Will qualified pepsin (i.e., within expiry date, of the specified activity, etc.) always solve crosslinking issues in dissolution?

It is important to check if the failure is really because of cross-linking and if the pepsin activity was determined by the hemoglobin procedure as stated in USP. Because the text in <711> Dissolution is not very clear, it is possible that the appropriate steps are not being followed. There are some papers in the literature showing data that cross-linking can be so severe that the enzymes will not work and that the product can be bioinequivalent. We do not have any data about quantifying severe cross-linking. The papers just mention a case where the capsule does not open even in the presence of enzymes. For more details, we suggest you do a literature search.

Q Can enzymes be used in the dissolution testing of soft gelatin capsules delivered vaginally?

Enzymes can be added to the dissolution medium when the failure is due to cross-linking for any type of gelatin capsules used by any route of administration.

Q Can enzymes be used in the comparison of dissolution profiles with media at pH of 1.2, 4.5, and 6.8?

If you are seeing cross-linking at an early stage in product development, you need to discuss this with your product development group. The major causes of cross-linking are aldehydes, high temperature, and high humidity. Your formulation components may have traces of aldehydes or may be degrading and generating aldehydes. Another possibility is that the capsules are not stored in the appropriate conditions. Several papers in the literature discuss cross-linking that was observed at early stages in product development, and some excipients in the formulation were replaced or a better grade of excipient was used. Our recommendation is to look at these papers and discuss this issue with your development group.

Q How can capsule rupture be quantified?

There is no way to quantify rupture. The capsule opens or it does not. The only quantitative procedure is dissolution.

Q Is USP Apparatus 3 suitable for dissolution testing of immediate-release capsules?

Yes, USP Apparatus 3 (reciprocating cylinder) can be used for immediate-release capsules. See USP General Chapter <1094> Capsules—Dissolution Testing and Related Quality Attributes, published in the First Supplement of USP 37. Apparatus 3 may be advantageous for lipophilic formulations or formulations containing poorly soluble drugs because the high agitation provides better interaction with the dissolution medium.

Q Should the addition of enzymes to the dissolution medium in the case of gelatin capsule crosslinking be validated?

Yes, the entire process must be validated as follows: (1) check the pH of the medium; (2) select the appropriate enzyme for this pH value; (3) verify the enzyme activity determination procedure; (4) document how to calculate the amount of enzyme in your dissolution method; (5) document the procedure to justify that cross-linking in the gelatin capsule is the cause of the dissolution failure; (6) verify if any special filtration procedure will be necessary if enzyme is added to the medium; (7) determine if the enzyme interferes with the quantitative procedure; (8) if the dissolution medium contains surfactant or any other compound that may denature the enzyme, define all the steps and the duration of the pre-treatment step with enzyme. To verify, validate, and define all the items listed above, you need to have capsules with crosslinking. Therefore, you have to select a method to force cross-linking with the capsules to be used with your samples. All this information must be included in the final version of your dissolution procedure along with very clear instructions.