Collaborative Development of Two-Tier Dissolution Testing for Gelatin Capsules and Gelatin-Coated Tablets using Enzyme-Containing Media

Editor's Note: In Pharmacopeial Forum, Volume 24, Number 5, September-October, 1998, changes are proposed for <711> DISSOLUTION that expand the use of two-tier testing to soft gelatin capsules and gelatin-coated tablets. According to the proposed changes, the amount of pepsin is specified as NMT 750,000 units per liter and the amount of pancreatin is specified as NMT 0.05 g per liter. The revision also states that for monographs using water as the medium, the new medium will be water with pepsin. In the same issue of Pharmacopeial Forum, the gelatin capsule working group published the article, "Collaborative Development of Two-Tier Dissolution Testing for Gelatin Capsules and Gelatin-Coated Tablets using Enzyme-Containing Media," in the Stimuli to the Revision Process. This article provides the experimental rationale and data supporting the proposed two-tier dissolution testing. An abstract of this article was provided courtesy of the United States Pharmacopeial Convention.*

Abstract

A Gelatin Capsule Working Group (including participants from the FDA, industry, and the USP) was formed to assess the noncompliance of certain gelatin capsule products with the required dissolution specifications and the potential relationship to changes in bioavailability. Available information indicated that satisfactory dissolution might be obtained for bioavailable products upon the addition of pepsin or pancreatin enzymes to the dissolution medium. In vitro studies were conducted using pepsin in simulated gastric fluid and in water, or using Pancreatin USP (1X) in simulated intestinal fluid. The Working Group developed a protocol using differentially stressed gelatin capsules to determine the relationship of in vitro to in vivo performance. Stressed capsules were also compared to unstressed capsules in two bioequivalence studies. The research showed that moderately stressed capsules(which were bioequivalent to unstressed capsules) did not meet current dissolution test specifications but did pass the test upon the addition of enzymes to the medium. Overstressed capsules(which failed to demonstrate bioequivalence) failed to meet the dissolution test specifications with and without enzymes in the medium.

The Working Group recommends the addition of a second tier to the standard USP and NDA/ANDA dissolution tests: the incorporation of enzyme into the dissolution medium. If the drug product fails the first tier but passes the second tier, the product's performance is acceptable. This two-tier dissolution test is appropriate for all gelatin capsule and gelatin-coated tablet products at any time, including at release of a batch for marketing.