Synthesis and Characterization of Ezetimibe Pharmaceutical Cocrystal: A Reaction Crystallization Method to Improve Physicochemical Properties and Hypolipemic Activity Evaluation

Abstract

Ezetimibe has significant lipid-lowering activity but presents low aqueous solubility. Co-crystallization techniques can be used to overcome this limitation. However, it is not yet clear whether the solubility of the cocrystal can be maintained after oral administration. In the present study, an ezetimi-imidazole cocrystal was synthetized by the reaction crystallization method, a promising strategy in cocrystal engineering. After conducting characterization tests, we determined the solubility and thermodynamic stability of the cocrystal. Also, the solubility advantage for both water and biorelevant fasted state simulated intestinal fluid (FaSSIF) was calculated. Dissolution was determined under supersaturated conditions, and the hypolipidemic activity of the cocrystal was assessed in vivo. The cocrystal exhibited high solubility and thermodynamic stability in FaSSIF. The solubility advantage was calculated as 22.4 in water and 11.8 in FaSSIF. The dissolution of the cocrystal resulted in supersaturation levels (σmax) of 1.3 in water and 3.3 in FaSSIF and the area under the curve (AUC) increased from 478.49 (ezetimibe) to 2963.62 µg min mL-1(cocrystal) in FaSSIF. The atherogenic index of the animals that received the cocrystal was similar to that of the control group. These results demonstrate that the inherent advantages of the co-crystallization process were maintained, enabling us to elucidate the behavior of the cocrystal.

Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice

“…Pharmaceutical cocrystals are defined as crystalline molecular complexes of fixed stoichiometry between an active pharmaceutical ingredient (API) with other pharmaceutically acceptable molecules [1][2][3]. Cocrystals can improve the physicochemical properties (e.g., stability, solubility, dissolution rate, and/or permeability) of compounds [4][5][6][7][8] and can also be tuned with pharmaceutically acceptable co-formers without altering the chemical structure of the API [1]. Especially, cocrystals are known to be superior to conventional formulations in in vivo pharmacokinetic properties such as absorption and bioavailability (F) [9][10][11].…”