Estimation of in Vivo Performance of Sulfamethoxazole and Trimethoprim From Oral Suspensions Using in Vitro Release Data From a Mini Paddle Apparatus

Abstract

Objective: To estimate plasma concentrations-time profiles of sulfamethoxazole (SMZ) and trimethoprim (TMP) from oral pediatric suspensions through in vitro data generated with a mini paddle apparatus and dissolution media of physiological relevance. Post-marketing evaluation of pediatric formulations is always necessary. Methods: Dissolution profiles of SMZ/TMP were obtained with a mini paddle apparatus at 100 rpm and 200 ml of 0.1 N HCl (pH 1.2), pH 4.5 acetate buffer, and pH 6.8 phosphate buffer. The reference and three multi-source pediatric formulations were tested. Drugs were quantified by a UV derivative method. Dissolution profiles were compared with model-independent and model-dependent methods. Plasma levels were estimated with dissolution data and published in vivo information. Percent of prediction error (%PE) for Cmax and AUC0-inf at each condition was calculated. Results: In all conditions, similar dissolution profiles were found excepting for TMP of C drug product at pH 1.2 (f2<50). With model-independent comparisons significant differences in in vitro release performance of SMZ and TMP from all multi-source formulations were found (*P<0.05). When comparing the hypothetical Cmax and AUC0-inf of both drugs with in vivo data PE<15% were found only with reference and one formulation at pH 1.2. Conclusion: The mini paddle apparatus and dissolution media of pH 1.2 were the best conditions to estimate in vivo plasma concentrations of SMZ and TMP from reference. These settings seem adequate to evaluate in vitro performance of multi-source formulations. It is necessary to carried out human studies with the used fixed-dose combination formulations to correlate in vitro/in vivo data.