The use of dissolution rate data to account for differences in the absorption profiles of two controlled/modified-release capsule dosage forms of indomethacin in human volunteers

Abstract

Reliance on in vitro-in vivo correlations using in vitro data obtained from a single dissolution test has frequently been shown to be misleading. The purpose of this study was to investigate the dissolution of indomethacin as a function of pH (pH 4.5 5.0 5.5 6.0 6.2 and 7.0). The official USP dissolution test (Apparatus 1 — rotating basket) for extended-release indomethacin dosage forms was used in all preformulation studies. Results from these studies indicated that indomethacin release from the test product was equivalent to that of Indocid ®. A pilot scale ( n = 8) comparative bioavailability study indicated that the two products were similar but not bioequivalent with respect to the extent of indomethacin absorption and quite different with respect to rate of absorption. Additional dissolution studies utilising the USP Apparatus 1 in buffered media over the pH range 4.5–7.0 were unable to predict these differences. Changing the dissolution apparatus to the USP Apparatus 2 (rotating paddle) over the same pH range revealed dramatic differences in the release of indomethacin from the two formulations. These differences were readily assessed with the use of topographical dissolution profiles. The relatively simple conversion to USP Apparatus 2, with pH profiling, provided a predictive test which may have forewarned of possible in vivo differences between the two formulations.