Formulation and physical pharmacy evaluation of cocrystals of biopharmaceutical classification system class 2 drugs

Abstract

Introduction: Improving oral absorption of water insoluble drugs is an active field of research. Cocrystallization of drugs with appropriate coformers is a promising approach for enhancing oral bioavailability. Aims: Current study was performed to investigate the possibility of improving dissolution of water insoluble drugs by cocrystals. Methods: Studied drugs were piroxicam, indomethacin, naproxen and gliclazide. Generation of cocrystals was attempted by liquid assisted grinding, slurry, electrospray, and solvent evaporation. A binary phase diagram was developed for gliclazide-succinic acid system. Cocrystals were characterized by thermal methods, X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscopy, surface area measurement. Contact angles and particle sizes of the studied solids were also measured. Apparent solubility, intrinsic dissolution rate (IDR), and powder dissolution profile of cocrystals were compared with other forms of drugs. Physical stability of cocrystals also was evaluated. Results: Electrospray was an efficient and rapid method to produce cocrystals and eutectic mixtures. Electrosprayed cocrystals and eutectics exhibited nano to micrometer sizes with distinct morphologies. Nanococrystals of indomethacin-saccharin displayed a threefold higher dissolution rate than solvent evaporated cocrystal. Gliclazide-succinic acid was found to form a eutectic mixture at 1:1 ratio instead of a cocrystal that has been reported in the literature. In the presence of excipients, electrosprayed eutectic with a mean size of 296 nm showed a superior dissolution than gliclazide. We prepared and characterized piroxicam-resorcinol and piroxicam-methylparaben cocrystals. Piroxicam cocrystals not only failed to improve apparent solubility and IDR but also showed lower values than piroxicam due to induction of phase transformation of piroxicam. Cocrystals performed better than piroxicam in dissolution studies due to the better wettability and reduced size. Discussion: Our study highlighted the usefulness of electrospray for simultaneous preparation and particle engineering of cocrystals and eutectic mixtures. We suggest that care should be taken in interpretation of the dissolution behaviors of cocrystals.