ESTIMATION OF IN VITRO AND IN VIVO PERFORMANCE OF METRONIDAZOLE ORAL DOSAGE FORMS

Abstract

Objective: To estimate plasma concentrations-time profiles of metronidazole commercial tablets through in vitro dissolution data using the Inverse Release Function approach and a convolution method. Methods: Dissolution profiles of metronidazole reference tablets (500 mg) were obtained using USP Apparatus 1 at 100 rpm, USP Apparatus 4 at 16 ml/min, and 0.1 N HCl, pH 4.5 acetate buffer and pH 6.8 phosphate buffer as dissolution media. Additionally, three generic drug products were tested using USP Apparatus 1 and pH 4.5 acetate buffer. Drug was quantified at 278 nm until 60 min. Dissolution parameters such as mean dissolution time, area under the cumulative dissolution curve, and dissolution efficiency were calculated. Metronidazole plasma levels were predicted considering the in vitro release data and published information. Percent of prediction error (PE) for Cmax and AUC0-inf at each condition was calculated. Results: When comparing dissolution profiles with common dissolution parameters (USP 1 vs. 4) significant differences were found (*P<0.05). Values of PE for Cmax and AUC0-inf were within range (±15%) only with USP Apparatus 1 and pH 4.5 acetate buffer. Using these conditions when comparing generic drug products vs. reference formulation, significant differences were found (*P<0.05) and values of PE for AUC0-inf were out of the range. Conclusion: The obtained information suggests using USP Apparatus 1 and pH 4.5 acetate buffer to predict the in vivo performance of metronidazole tablets. The impact of in vitro differences of all generic formulations was confirmed with differences in predicted in vivo performance.