Questions and Answers August 2024

Margareth R. Marques, Ph.D. and Mark Liddell, Ph.D.
The following questions have been submitted by readers of Dissolution Technologies. Margareth R. Marques, Ph.D., and Mark Liddell, Ph.D., United States Pharmacopeia (USP), 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: mrm@usp.org

Q In the validation of a dissolution procedure, for the precision evaluation, what is the appropriate precision technique? a) Sampling the same vessel six times and injecting each one of them into the HPLC system; b) Using six different vessels, but pooling the sampling results into one solution and injecting six times into the HPLC system; or c) Using six different vessels, sampling from each vessel, and injecting each of the six samples into the HPLC system.
A According to <1092> The Dissolution Procedure: Development and Validation the precision evaluation typically consists of three main components: repeatability of analysis, intermediate precision, and reproducibility. Ultimately, it is up to your organization to decide which approach to take to verify each of the three components for both the standard solution, the spiked placebo, and the sample solution obtained from a well-characterized dosage form. Keep in mind that the approach used to demonstrate precision may vary depending on the type of solution (e.g., standard solution vs. dissolution sample solution) that is being evaluated. The procedure should be as close as possible to the one used in the routine analysis of dissolution samples solutions obtained from a well-characterized final dosage form.

Q In a dissolution procedure with multiple sampling points at different time intervals, how should we carry out a verification study? As an example, the USP monograph for tamsulosin hydrochloride capsules, in buffer stage, requires sampling at 2, 3, and 8 h. What time point should be chosen for the precision evaluation?
A The validation of any parameter in a dissolution method is done considering the entire dissolution profile and is not determined based on the expected acceptance criteria. Keep in mind that the dissolution test for tamsulosin hydrochloride capsules is formulation dependent. Each formulation is going to have its own specific and discriminative dissolution test. This is the reason for multiple dissolution tests in the USP monograph for tamsulosin hydrochloride capsules.

Q Is there an upper limit for dissolution test? If the assay range for a particular product is 95-105% and one of the dissolution results is 135% and the average of six dissolution results is 103%, what could be the possible reasons for this high dissolution value?
A There is no upper limit for dissolution tests. Dissolution results cannot be compared with assay results. Dissolution and assay tests measure different parameters of the product, and the sample is treated in a totally different manner for each of these tests.

If dissolution results above 100% are observed, an investigation should be conducted to identify possible reasons for high results. Here are some examples of parameters that could be investigated:

• Filter validation: material, type (syringe filter, canula tip filter, etc.), pore size, and construction of filters.
• Sampling methodology: is the sample withdrawn at the appropriate time and at the appropriate position within the dissolution vessel?
• Interference of other components in the formulation or the dissolution media components used in the dissolution test.
• Uniformity of dosage unit range for the batch being evaluated.
• Cleaning method validation for dissolution equipment and sampling. If using an autosampler, carryover from previous runs should be considered

Q Some dissolution test media contain sodium dodecyl sulfate. This reagent is commercially available with different purities, like 85%, 93%, or 99%. Which quality grade should be used in dissolution test?
A This question should be addressed as part of the dissolution method validation. Ideally, it is recommended to use the highest quality grade of the surfactant to minimize possible interference in the quantitative determination of the amount of drug released from the dosage form and to minimize variability in the composition of the dissolution media.

Q If the six dissolution results fail stage 1 (S1) (Acceptance Table 1 in USP general chapter <711> Dissolution) but are within the limits of stages 2 and 3 (S2 and S3), should an out of specification results investigation be done or shall the test continue with S2 and S3?
A The three stages described in Acceptance Table 1 are part of the evaluation of routine dissolution results for immediate-release dosage forms. A batch is considered out of specification if it fails S3. Then, and only then, should an investigation for out of specification results be initiated.

Q If enzymes are added to the dissolution medium when there is evidence of cross-linking, should a verification be done?
A The use of enzymes in the dissolution medium when there is evidence of cross-linking in gelatin capsules should be evaluated as part of the dissolution method validation procedure. See USP general chapters <1092> The Dissolution Procedure - Development and Validation and <1094> Capsules - Dissolution Testing and Related Quality Attributes for more information related to this topic.

Q Section 1.2.2 Stability in USP general chapter <1092> The Dissolution Procedure: Development and Validation states: “The solution containing the drug substance is stored under conditions that ensure stability. The stability of this solution is analysed over a specified period of time (for at least the time of the entire dissolution procedure), using a freshly prepared solution at each time interval for comparison. The acceptable range for solution stability is influenced by the drug concentration and is typically between 98% and 102% of the expected final concentration.” We understood that expected final concentration means the concentration at the final time point. For dissolution methods with multiple time points, e.g., extended release formulations, is this assumption correct?
A Section 1.2.2 is a subsection of 1.2 Determining Solubility and Stability of Drug Substance in Various Media. This section is preparatory work before the dissolution method is even considered; therefore, the reference to the concentration range of 98-102% of the expected concentration does indeed refer to the final expected concentration at the end of the dissolution experiment. Keep in mind that the stability of any solutions used in a dissolution test should be established considering the entire test time, including the quantitative step. This means that the time required to carry out the quantitative analysis step must also be considered and is likely to be longer than the last sampling point of the dissolution method. All solutions used during the dissolution test (sample solutions, all standard solutions, dissolution medium, diluent, etc.) must have an expiry date and storage conditions defined based on dissolution method development and validation data. This information must be stated clearly in the final version of the dissolution method.

Q USP general chapter <711> Dissolution states: “If the dosage form containing gelatin does not meet the criteria in the appropriate Acceptance Table (see Interpretation, Immediate-Release Dosage Forms, Extended-Release Dosage Forms, or Delayed-Release Dosage Forms) because of evidence of the presence of cross-linking, the dissolution procedure should be repeated with the addition of enzymes to the medium, as described below, and the dissolution results should be evaluated starting at the first stage of the appropriate Acceptance Table. It is not necessary to continue testing through the last stage (up to 24 units) when criteria are not met during the first stage testing, and evidence of cross-linking is observed.” Does this mean that once a capsule drug product has gone through S1, S2, and S3 and does not meet Acceptance Table limits, the test with enzymes must be only done in Stage 1?
A No. If the capsules failed the dissolution test at any stage because of the presence of cross-linking, the test may be stopped, dissolution medium with the appropriate enzyme in the appropriate amount is prepared, and, using new capsules, the test is repeated starting at S1 and carried out through S2 and S3 if needed, with enzymes in the dissolution media. The use of enzymes is justified only when failures are observed during the specific testing stage and there is evidence of cross-linking.

Q In the USP monograph for Ursodiol Tablets, the dissolution medium is simulated intestinal fluid TS, prepared without pancreatin, and adjusted with 0.1 N sodium hydroxide or 0.1 N hydrochloric acid to a pH of 8.0. The preparation of the simulated intestinal fluid TS in the Test Solutions section of USP directs to adjust the pH of this test solution to 6.8. Which pH should be used in the dissolution test of ursodiol tablets?
A The simulated intestinal fluid preparation instruction in the Test Solutions section of the USP-NF are general test solution preparation instructions. The instructions in USP monograph supersedes the general preparation instructions in any other sections of the USP-NF. Therefore, the simulated intestinal fluid TS for the use in the dissolution test of ursodiol tablets should be prepared according to the instructions in the monograph, i.e., the pH should be adjusted to 8.0 as stated in the dissolution medium description of the monograph.