Influence of dissolution medium buffer composition on ketoprofen release from ER products and in vitro–in vivo correlation

Abstract

The purpose of this work was to investigate the influence of dissolution medium composition on the in vitro release of ketoprofen from a series of ER products and the impact of the different buffer media on the in vivo–in vitro (IVIV) relationship. The products investigated were coated micro bead preparations having increasing levels of coating to retard drug release. Four common dissolution media; USP phosphate buffers of pH 7.2 and 6.8, phosphate (modified isotonic) buffer pH 6.8 and a fasted state simulated intestinal fluid without lipid components (FaSSIFLF) of pH 6.5, were employed in the USP 2 apparatus. Release profiles were compared to the corresponding in vivo release profiles, obtained following deconvolution of the plasma level versus time profiles obtained from a 10-subject five-period cross-over study. Despite the relative similarity in composition of the media employed, significant differences in release profiles were observed reflecting media differences in buffer capacity, ionic strength and pH. As a consequence, the quality and shape of the IVIV relationship changed significantly, the only apparent IVIVC incorporating all four ER products, which was non-linear, was obtained using the phosphate (modified isotonic) buffer of pH 6.8. This data was fitted, using a non-linear least squares method, by the equation of Polli et al. [J. Pharm. Sci. 85 (1996) 753] and gave an alpha parameter estimate of 2, consistent with initial dissolution being more rapid in vitro than in vivo. The systematic shift in profiles, particularly with buffer capacity, underlines the sensitivity of IVIV relationship to medium composition and hence the current difficulties in making a rational choice of an appropriate single dissolution medium.