Rethinking the Use of Water as a Dissolution Medium

Carol Noory,(A) Nhan Tran,(A)* Larry Ouderkirk,(A) Sara Brown,(B) Jesse Perry,(B) José Lopez,(C) Miquel Colon,(C) Marisol Faberlle,(C)Kermit Henry,(D) Julie Rorberg,(E) Syed Nasir Ali,(F) and Vinod Shah (A)

Food and Drug Administration

* e-mail address for correspondence: nooryc@cder.fda.gov

Dissolution testing is used widely by the pharmaceutical industry and regulatory agencies to assure the continued quality of many oral dosage forms relative to the approved lot tested for bioavailability/bioequivalence. As reliance on the dissolution test as a predictor of continued bioavailability and bioequivalence increases, the test conditions have come under increasing scrutiny. It is questioned whether dissolution tests can predict in vivo dissolution and absorption when the in vitro test conditions do not well simulate the physiological environment of the gastrointestinal tract.
Many USP dissolution tests still specify water as the dissolution medium. When dissolution procedures were first being added to the monographs, the default "First Case" was usually specified (Pharmacopeial Forum 3 (1), Jan-Feb 1977, pp. 22-25). This consisted of 900 mL of water medium with USP Apparatus 1 (Basket Method) at 100 rpm, or later, USP Apparatus 2 (Paddle Method) at 50 rpm. Products not meeting the "First Case" tolerance specification of NLT 75% "Q" in 45 minutes using this method were asked to submit data for a new procedure.
Water lacks buffering capacity and thus, in some instances, the pH of the medium may change as the drug dissolves (as in the case of salts). Also, because water is not representative of the gastrointestinal environment, it is not considered a physiologically relevant medium.
FDA has undertaken a study to evaluate simple, alternative dissolution media that can serve as a quality control test, for products currently having water as the media. Several FDA field laboratories have been involved in the undertaking. Samples of the innovator (brand name) drug product along with FDA approved generic products are collected and screened for release profile performance in media of various pHs (e.g., pH 1.2, 4.5, and 6.8). Dissolution aliquots are taken at 15, 30, 45 and 60 minutes, and the profiles are assayed in each alternative test medium and compared to the profiles generated using water. A medium having comparable or better performance than the water medium is selected for the final testing, in which the collected products are tested using the new medium versus the USP-specified water medium. The data are then reviewed and a final recommendation forwarded to the USP for consideration as a Compendial monograph requirement. Food and Drug Administration field laboratories have studied the products, listed in Table 1 .
All products performed at least as well in the alternative media as they did in water. For some products, it was recommended to USP that the tolerance be increased based on the dissolution results obtained in the alternative medium.
In conclusion, in vitro dissolution is of primary interest to drug regulators at FDA, as both a quality control tool and as a potential surrogate marker of drug bioavailability and bioequivalence. Using a dissolution medium that better simulates the environment of the gastrointestinal tract will help make dissolution testing conditions more physiologically relevant to in vivo absorption and useful in evaluating the quality and stability of these drug products.

A Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD 20857
B Food and Drug Administration, Baltimore District Laboratory, Baltimore, MD 21201
C Food and Drug Administration, San Juan District Laboratory, San Juan, PR 00901
D Food and Drug Administration, Southeast Regional Laboratory, Atlanta, GA 30309
E Food and Drug Administration, Seattle District Laboratory, Bothell, WA 98041-3012
F Food and Drug Administration, Philadelphia District Laboratory, Philadelphia, PA 19106