Paliperidone Acid-Based Cocrystal for Improving Biopharmaceutical Properties: In Vitro and In Vivo Evaluation

Although it is an effective and well-tolerated antipsychotic, paliperidone is practically insoluble and suffers from low oral bioavailability. The current work aims to develop paliperidone cocrystals using different short-chain acids as coformers to improve biopharmaceutical properties. The formulation showed higher solubility and was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy. In addition, the dissolution rate and oral bioavailability study were assessed in comparison with the pure drug. A cocrystal formulation containing paliperidone and oxalic acid (as coformers) in a 1:2 molar ratio exhibited the highest solubility (9831 ± 113 μg/mL) among screened coformers. Cocrystal structural features evidenced the formation of hydrogen bonds between paliperidone and coformers, while solid-state analyses verified their existence in the less crystalline state. Additionally, the cocrystal showed a faster dissolution rate when compared with the pure drug. Furthermore, the in vitro dissolution pattern of the cocrystal was further mirrored in its higher improvement of bioavailability (2.66-fold) and plasma retention when compared to the drug suspension. These results suggest that the cocrystal provides a feasible solution to unwanted biopharmaceutical properties of paliperidone.