Question and Answer Section - August 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 factors should be taken into consideration when evaluating f₁ and f₂ in the dissolution profile comparison?
A To compare dissolution profiles using the similarity factor, f₂, some conditions must be met:

• The dissolution results for the products being compared must be obtained using the same test conditions (e.g., medium composition, medium volume, apparatus, and sampling time points).
• At least 12 units of each product should be used to generate each dissolution profile.
• To use mean data, the coefficient of variation at earlier points should not be more than 20% and at the other time points, should not be more than 10%.
• Only one measurement should be considered after 85% dissolution.
• A profile comparison is not necessary for rapidly dissolving products (i.e., more than 85% dissolved in 15 min or less).

Q Is it necessary to consider sink conditions when selecting a discriminative medium?
A A discriminative medium helps to reveal meaningful changes in performance in combination with the other test conditions. It is possible for a dissolution test to be discriminative of meaningful product changes without rigorously adhering to definitions of sink conditions. However, sink conditions help to ensure that the dissolution performance of the product under test is not limited by the solubility of the drug content.

Q How is a discriminative dissolution method developed for a product that does not have a monograph in any pharmacopeia?
A The dissolution method is developed by taking into consideration the physicochemical properties of the drug substance (solubility in the physiological pH range, pKb, crystal form, etc.), the composition of the formulation (type of excipients and their function at the amount being used), where the drug is going to be absorbed in vivo, and the release mechanism of the dosage form. All of this information is going to help in selecting the type and volume of medium and the type of apparatus. Special attention should be paid when the formulation contains a poorly soluble drug because it may be necessary to add surfactants to the dissolution medium.

Once a candidate method is identified, the dissolution profiles of samples representing the product on stability, the product made by varying processing conditions, and the product produced from excipients representing expected variations in source are evaluated. A discriminative method will provide evidence of the differences in the samples.

Q Are there any guidances on the medium volume to be withdraw when running a dissolution test?
A No, there are no guidances defining the volume of medium to be withdrawn at each sampling time point. The volume selected depends on the type of filter used and the quantitative analytical procedure used to quantify the amount of drug substance dissolved. The effect on the total test volume of multiple samples and the decision to replace the volume taken is made in a case-by-case approach.

Q Which USP monographs use USP Apparatus 3 (reciprocating cylinder), and what products using this apparatus has FDA approved?
A The following USP monographs use USP Apparatus 3: Hydroxyzine Hydrochloride Tablets, Liothyronine Sodium Tablets, Lithium Carbonate Extended-Release Tablets, and Oxybutynin Chloride Extended-Release Tablets. According to the FDA database on Dissolution Methods for Drug Products, available at www.accessdata.fda.gov/scripts/cder/dissolution, the following products were approved with USP Apparatus 3: Chlorpheniramine Maleate Extended-Release Tablets, Lanthanum Carbonate Chewable Tablets, and Famotidine Calcium Carbonate and Magnesium Hydroxide Chewable Tablets

Q Is it advisable to use simulated gastric fluid as a routine dissolution medium?
A Simulated gastric fluid is a possible dissolution medium that can be used in routine dissolution testing. Two important points to consider when selecting the composition of a dissolution medium are that the medium should be biorelevant and that the medium should be discriminative.

Q We have a product that is an enteric-coated pellet in a gelatin capsule. Can we do the dissolution test with just the pellets?
A The dissolution of the pellets might provide valuable information during production. However, the dissolution of the gelatin capsule shell will have an effect on the in vitro performance of the product. Therefore, the dissolution of the intact dosage unit is necessary for the assessment of the marketed product.

Q Are there any guidances on how to perform the qualification of disintegration apparatus?
A Disintegration test apparatus should conform to the description given in the USP General Chapter <701> Disintegration.

Q What is the range for adjusting the pH of the dissolution media?
A According to the USP General Chapter <791>, pH is adjusted within 0.05 unit of the specified pH. This range must be verified during the evaluation of the robustness of the dissolution method.

Q In the USP monograph for Metformin Hydrochloride Extended-Release Tablets, there are eight different tests, but all of the tables are labeled as Acceptance Table 2. What is the reason for that?
A The interpretation of dissolution results as given in USP monographs is in two parts. The tolerances represent the first part and give a product-specific limit or set of ranges for acceptable dissolution performance. Conformance to the tolerances can only be evaluated using an acceptance table that, among other things, provides a framework for the stages or levels of testing. To avoid redundancy, the acceptance tables are only presented in the general chapter. A reference to Acceptance Table 2 in the monograph is to the table found in the USP General Chapter <711> Dissolution.