Abstract

Using the in vitro dissolution data and bioavailability data we present our results of in vitro-in vivo correlation of different modified release formulations of theophylline. As part of our ongoing study an experimental modified release capsule formulation, containing theophylline (200 mg)- loaded microspheres (Formulation F4), was developed, characterised and its in vitro and in vivo performance was then compared with that of the three market modified release formulations of theophylline (200 mg) - two tablets (Formulations F2 and F3) and one capsule (Formulation F1). Formulations F1, F2 and F3 were analysed to find out the best market sample with acceptable bioavailability. All the four formulations were evaluated for in vitro theophylline release using different dissolution test conditions. Pharmacokinetic evaluation of these formulations was carried out in six healthy volunteers and the parameters were established using non-compartmental analysis. In vitro-in vivo correlations were established from the generated dissolution and bioavailability data. In vitro studies indicated that only formulation F1 showed pH-dependent drug release while the other three formulations, including experimental formulation F4, showed almost condition-independent dissolution behaviour. The bioavailability studies indicated that amongst the market formulations (F1, F2, F3), formulations F1 and F2 were bioequivalent but F3 failed to demonstrate acceptable dissolution and bioavailability. Thus, switchability of formulation F3 for formulations F1 or F2 is questionable. A good correlation (R²=0.9986, slope=1.0614 and intercept= 0.1824, supporting Level A correlation) was observed for microsphere formulation, F4, under conditions of Test # 1. Although experimental formulation F4 showed acceptable dissolution behavior and bioavailability, it did not, however, exhibit bioequivalence with two other market samples, either F1 or F2. Dissoluton conditions of Test # 1 (dissolution medium, pH 1.2 simulated gastric fluid without pepsin for 1 h followed by pH 6 phosphate buffer for rest period) reflects highly significant correlation (R² > 0.98) with corresponding bioavailability for all the four formulations.