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
During the dissolution testing of one of our products, a lot of foaming occurred in the dissolution vessel. Could an antifoaming agent be used?
A
Yes, an antifoaming agent such as some alcohols can be used, but it should be used in the smallest possible amount, and it should be demonstrated that it does not interfere with the dissolution profile of the drug product or with the quantitative step in the dissolution test. When following a compendial dissolution procedure, the need for an antifoaming agent should be part of the medium description. Changes to official methods are addressed in the USP General Notices, section 6.30 Alternative and Harmonized Methods and Procedures.
Q
What are the options for performing the evaluation of intrinsic dissolution rate with a drug substance in a salt form if it is converted to the free acid or free base in the medium?
A
Salts of weak acids or weak bases will form the associated free acid or free base depending on the pH of the medium. The pH of the medium should be designed to prevent this during the test because the intrinsic dissolution of the salt is the object of the study. For the salt of a weak acid, the pH of the medium should be at least two pH units higher than the pKa of the conjugate acid.
Q
How is intrinsic dissolution rate evaluated with a compound that changes into a different solid phase in the medium?
A
Ideally, the intrinsic dissolution rate is characteristic of the initial physical state of the sample. If a change in the physical state of the sample occurs, the test will not reflect the dissolution of the starting material. However, indication may be given that such change has occurred, and that would have value for the researcher. Such a change may be confirmed by other methods.
Q
Can the intrinsic dissolution rate be evaluated only at the early time points (e.g., within 5 min), beyond which it undergoes a solid phase transformation?
A
If a change in physical state occurs rapidly during the test, then the value of the intrinsic dissolution evaluation of the sample is diminished. Any determination will be a product of confounding variables. It may be advisable to investigate other media.
Q
In the FDA Recommended Dissolution Methods database (www.accessdata.fda.gov/scripts/cder/dissolution In the FDA Recommended Dissolution Methods database (www.accessdata.fda.gov/scripts/ cder/dissolution), there is a column titled "Recommended Sampling Times (minutes)." Can we assume that the last time point mentioned in this column is the one in the tolerances for that particular product?), there is a column titled "Recommended Sampling Times (minutes)." Can we assume that the last time point mentioned in this column is the one in the tolerances for that particular product?
A
No. The times in the column Recommended Sampling Times (minutes) are the recommended times for the dissolution profile. The time for the tolerances is included in the profile, but it should not be assumed that it is the last one. Keep in mind that the time for the final tolerances should be, in most cases, the one where the dissolution test continues to be responsive to changes in critical quality attributes and performance parameters.
Q
We are starting a PVT using the new Prednisone Tablets, Lot P1I300. Can I choose the single-stage test or the two-stage test? What is the difference between the single-stage and two-stage procedures?
A
The PVT can be performed as either a single-stage or a two-stage procedure. The test is not valid if the decision is not made before starting.
The single-stage and two-stage procedures differ in the procedure and the criteria applied to the results. For 6-, 7-, or 8-position test assemblies, the single-stage procedure means that two runs are performed, and the results compared with the criteria. For those same test assemblies, the two-stage procedure allows the results after one run (first stage) to be compared with the criteria. If the results conform to the first-stage criteria, then the PVT has been completed successfully. If the results do not conform to the first-stage criteria, the second run is performed. For 12-position test assemblies, only the single-stage procedure is used.
The geometric mean and %CV are calculated for the results based on the number of runs. Where more than one run is performed, the %CV and geometric mean is the pooled result from both runs. This is most easily done after converting results to natural logarithms. The detailed procedure is given on the reference standard certificate for this lot.The certificate can be accessed at http://www.usp.org/pdf/EN/referenceStandards/certificates/1559505-P1I300.pdf
USP provides a PVT calculation tool on its website. Results from the calculation tool can be used to check the results of your calculations. To use the tool, go to http://www.usp.org/USPNF/pvtToolStatement.html.