dx.doi.org/10.14227/DT160109P44

Question and Answer Section - February 2009

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 What tolerance is allowed between results obtained with manual and automatic sampling?
A There are no official tolerances for the variability associated with manual and automatic sampling. This should be evaluated on a case-by-case basis. When results are not highly variable, one possible approach is to use two concurrent runs with the same sampling intervals and six units for each, using manual and automated sampling methods. Compare the results obtained from each with the criteria used for intermediate precision. If the results are highly variable (i.e., the relative standard deviation [RSD] is above 20% in the earlier time points and about 10% in the later time points), perform the comparison by pulling the sample from the vessel simultaneously by manual and automated procedures for each time point. Be warned that the hydrodynamic effects of the probe will not be obtained with simultaneous sampling. Attention should be paid to the volume correction in the second case. More information can be found in the paper: Gray, V. A.; Brown, C. K.; Dressman, J. B.; Leeson, L. J. A new general information chapter on dissolution. Pharm. Forum. 2001, 27 (6), 3432�3439.

Q Are there any specific requirements stating that the dissolution test has to be done with the whole capsule if the product is a capsule?
A The instruction in the USP General Chapter <711> Dissolution, page 272, of USP 31 under Procedure, Apparatus 1 and Apparatus 2, Immediate-Release Dosage Forms is to place one dosage unit in the apparatus. If the product is intended to be taken by the patient as a whole capsule, the dissolution test should be performed with the introduction of the whole capsule into the apparatus. If the product labeling instructions recommend that the patient open the capsule and disperse its contents in an appropriate liquid or sprinkle it on some type of food, the dissolution test should be performed in a way that is as close as possible to what the patient is going to do with the product.

Q We are developing 200-mg mebendazole tablets that are going to be marketed outside the United States. We used the dissolution test described in the USP monograph for this product, and we are getting about 50% of the tablet label claim released. Do you have any suggestions for what may be the problem?
A If you are going to use a USP monograph for a product not marketed in the United States, the first step is to search the FDA website to see the product strengths approved for the USA. You can do this search in the Orange Book or at Drugs@FDA available at www.fda.gov/cder. Doing this search for mebendazole tablets, you will see that the product approved by FDA is a 100-mg tablet. Therefore, the dissolution conditions stated in the USP monograph for Mebendazole Tablets were selected for a tablet containing 100 mg of the drug substance. The USP dissolution test for this product uses 900 mL of medium. If you are getting about 50% of the tablet label claim dissolved with this volume, there is a good chance that if you use a larger volume, such as 1500 mL, 1800 mL, or even 2000 mL, the amount of drug dissolved is going to be higher.

Q What is the maximum upper limit for the amount of drug dissolved in dissolution tests?
A There are no upper limits for dissolution tests. The highest amount of drug dissolved depends on the range of uniformity of dose for each batch of product. In the dissolution test, one dosage unit is introduced in each vessel; it is not a composite sample as used in the assay test. Content uniformity is going to depend on the variability of the manufacturing process. You can have units that are at the lowest limit, but you can have units that are the highest limit of the uniformity of dose. Please keep in mind that the dissolution test is not an assay for the amount drug in the product, but a measure of the amount of drug dissolved under controlled conditions.

Q Q Can you suggest some references on the procedures for setting dissolution acceptance criteria?
A Here are some suggestions. More information can be found in Chemical Abstracts and at www.NCBI.NLM.NIH.GOV (access free of charge).

Cholayudth, P. Using the Bergum method and MS Excel to determine the probability of passing the USP dissolution test. Pharm. Technol. 2006, 30 (1), 88�94.

Hofer, J. D.; Gray, V. A. Examination of selection of immediate-release dissolution acceptance criteria. Pharm. Forum 2003, 29 (1), 335�340.

Wojcik, R. C. Setting dissolution specifications. Dissolution Technol. 1997, 4 (3), 12�20.

Hokanson, G. C. Setting specifications for solid oral dosage forms: leveraging development experience. Am. Pharm. Rev. 2001, 4 (2).

Hauck, W. W.; Foster, T.; Sheinin, E.; Cecil, T.; Brown, W.; Marques, M.; Williams, R. L. Oral dosage form performance tests: new dissolution approaches. Pharm. Res. 2005, 22 (2), 182�187.

Dumont, M. L.; Berry, M. R.; Nickerson, B. Probability of passing dissolution acceptance criteria for an immediate release tablet. J. Pharm. Biomed. Anal. 2007, 44, 79�84.