Zotepine is an atypical antipsychotic drug used in the treatment of schizophrenia. However, its poor dissolution properties limit its therapeutic efficacy. In this investigation, a series of nanosuspension-containing zotepine were prepared employing media milling method with an aim to improve its dissolution properties and oral bioavailability. Briefly, Box-Behnken design was applied to investigate the influence of various independent variables such as X- amount of stabilizer, X- amount of milling agent, and X- milling time on the performance of the formulation. Dissolution studies revealed enhancement of dissolution rate as compared to pure drug. Solid state characterization (DSC, PXRD, and SEM) studies demonstrated no polymorphic changes in drug after lyophilization of media-milled nanosuspension. In vivo pharmacokinetic studies of lyophilized nanosuspension was carried out in rat and the results exhibited significant improvement in C and AUC, about 450.0 and 287.45%, respectively, suggesting amelioration in oral bioavailability by 2.87-fold higher as compared to pure drug. Accelerated stability studies of the optimized lyophilized formulation at 40°C and 75% RH suggested stability of the nanocrystals for at least a 6-month period. The obtained nanocrystals successfully showed dissolution enhancement and improved oral bioavailability of poorly water-soluble drug, zotepine.
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