Questions and Answers August 2022
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 If the acceptance criteria in the USP individual monograph is not less than (NLT) 80% (Q), what is the meaning of Q?
A Q is defined in the USP general chapter <711> Dissolution as the amount of dissolved active ingredient specified in the individual monograph, expressed as percentage of the labeled content of the dosage unit.
Q Is it possible to have dissolution results greater than the assay results obtained from the same product batch? For example, the mean assay result is 99.0% and dissolution results of about 108%.
A The amount of dissolved drug should not exceed the assay results obtained for the product. When this occurs, you should investigate the possible reasons for high dissolution results. Typically, possible causes for the dissolution value exceeding the assay value include: difference in solubility of the active ingredient in the assay media versus the dissolution media - both methods should be validated; improper selection of the type and pore size of filter material used in the assay and/or dissolution procedure; inadequate evaluation of possible interference of the placebo; inadequate sampling procedure; and/or high variability in the manufacturing process. With this in mind, it is also helpful to check the uniformity of dosage units for the particular batch being evaluated.
Q Regarding the dissolution test for delayed-release dosage forms, where the drug substance is unstable in acidic medium, how can the amount of drug released in the acid stage can be quantified?
A Determine the amount of drug that is remaining in the dosage form after the acid stage. To do this, remove the dosage form from the vessel and determine the amount of drug in the dosage form using the procedure for uniformity of dosage units or an adaptation to the assay procedure. Then, perform the acid stage with 6 new units, and transfer them directly to the buffer stage to determine the amount released in the buffer stage.
Q We are a dissolution instrument supplier and sometimes our customers would like our engineer to provide the service of performance verification test (PVT) test for them. We would like to know if we can provide them with this service.
A Yes, a contractor/third party can verify/qualify any dissolution equipment. Keep in mind that an additional objective of the PVT is to verify the analyst technique and to ensure that the analyst is following the entire procedure and using proper technique.
Q In the USP monograph for Cimetidine Tablets, under Apparatus 1, it is stated “100 rpm, a 20-mesh basket may be used for 800-mg strength tablets.” What is the mesh size for the other label claims, e.g., 200 mg or 400 mg?
A The default basket mesh size in USP is 40 mesh. The monograph will state the mesh size only in cases where the mesh size is different from 40 mesh. If the monograph does not mention the mesh size, 40 mesh should be used.
Q In the USP general chapter <711> Dissolution, under Procedure, Apparatus 1 and Apparatus 2, Immediate-Release Dosage Forms, it states: “Note — Where multiple sampling times are specified, replace the aliquots withdrawn for analysis with equal volumes of fresh Dissolution medium at 37° or, where it can be shown that replacement of the medium is not necessary, correct for the volume change in the calculation. Keep the vessel covered for the duration of the test and verify the temperature of the mixture under test at suitable times.”
If it is not stated in a particular monograph to replace the dissolution medium, is the default to replace the aliquot drawn with fresh dissolution medium?
A Yes.
Q In that case, if the medium is not replaced, is this volume change considered a big enough change to the method to require validation?
A This needs to be evaluated in a case-by-case approach. There is no standard rule. Checking this at validation is too late. This question should be evaluated during method development. Typically, two issues may arise:
1) Depending on the sample volume withdrawn at each time point, the volume of medium remaining in the vessel may make it difficult to to sample at the appropriate sampling point.
2) If the samples are withdrawn and the medium is not replaced, you may approach the active ingredient solubility limit and the dissolution rate may be reduced. Therefore, generally the recommendation is to always to replace the medium to ensure that the volume remains constant throughout the test.
Q We are verifying the dissolution test for calcium in the USP monograph for calcium with vitamin D Tablets. When evaluating accuracy, due to the characteristics of the raw material calcium carbonate, it is difficult to add it to the vessel, as it floats and sticks to the vessel wall. Do you have any suggestions to minimize this problem?
A In situations like the one you are describing, the best approach is to have the formulation or placebo mixed/ granulated/prepared by the appropriate group, e.g., research and development or the formulation group, in your organization. Then transfer the prepared amount of material equivalent to the amount in the dosage form to the dissolution vessel.
Q The dissolution test in the USP monograph for Cabergoline Tablets states that the medium is degassed with helium. We performed the dissolution test with and without degassing and we did not observe any significant variation in the dissolution profile. Can we perform the test without degassing?
A It is not mandatory to degas all dissolution media. In some instances it is necessary to to verify whether degassing the media has an appreciable effect on the dissolution results for the specific formulation, especially considering that helium is expensive and there may be issues with supply. When degassing is necessary, the recommendation is to use the procedure described in the USP general chapter <711> Dissolution. Other deaeration/ degassing procedures may be used with appropriate validation.
Q We are evaluating dissolution results using the Acceptance Table 1 from the USP general chapter <711> Dissolution and noticed that S1 stage results are outliers that may not comply with S3 stage criteria. We started an investigation and before finalizing it, shall we continue to S2 stage analysis in parallel to the investigation?
A The results you obtained are not outliers. They are just results not meeting the acceptance criteria. It is up to your organization to decide if you are stopping at S1 or if you are going to continue to the other two stages. Because the investigation of out-of-specification results in dissolution should also include the manufacturing and any other groups associated with the production of the batch, you may need to generate additional results to better evaluate the issue.
USEFUL RESOURCES FOR DISSOLUTION, DISINTEGRATION, AND DRUG RELEASE TESTING (all are free of charge)
USP Dissolution Methods Database
https://www.usp.org/resources/dissolution-methodsdatabase
It lists the test conditions as stated in USP monographs for finished products.
The database allows you to search by (via drop-down lists):
- Monograph name
- Dissolution medium: composition, surfactant (if used), pH, volume, and deaeration (if used)
- Apparatus: type and rotation speed, dip rate, or flow rate
- Duration of the test
- Analytical finish
- Exceptions: any additional information not covered by the previous items such as type of sinker, use of special software, use of a wavelength other than the one for maximum absorbance, etc.
Acceptance criteria can be found in the USP monographs.
FDA-Recommended Dissolution Methodshttps://www.accessdata.fda.gov/scripts/cder/dissolution/
It lists the test conditions recommended by the US FDA. It allows search only by drug substance name. It does not contain acceptance criteria. The printable version may facilitate the searches.
USP Performance Verification Testhttps://www.usp.org/small-molecules/pvt
For additional information regarding the performance verification test and instrument qualification procedures.
Dissolution Toolkit Procedures for Mechanical Calibration and Performance Verification Test Apparatus 1 and Apparatus 2https://www.usp.org/sites/default/files/usp/document/our-work/chemical-medicines/dissolution-toolkitversion2.pdf
This toolkit provides procedures that help manufacturers and others to evaluate the correct set-up, operation, and performance of the basket and paddle apparatuses and the test assembly.
Calculation Tool for the Performance Verification Test (PVT) of Dissolution Assemblieshttps://apps.usp.org/app/USPNF/pvtCalculationTool/
This calculation tool allows the evaluation of the performance of a dissolution assembly by comparing the results obtained from the PVT to limits given in the Acceptance Criteria for PVT Tablets.