10.1021/acs.cgd.7b00805
The research explores the development of new solid forms of the active pharmaceutical ingredient (API) agomelatine to enhance its solubility. Agomelatine, a poorly soluble 'non-ionizable' amide acting as a melatonergic antidepressant, typically has low water solubility, leading to low oral bioavailability. The study reports the preparation and characterization of three salts of agomelatine (hydrogensulfate, mesylate, and besylate) and their solvated forms. These salts were prepared by crystallizing agomelatine with sulfuric acid, methanesulfonic acid, and benzenesulfonic acid, respectively. The crystal structures of these salts were determined using single-crystal X-ray diffraction and powder X-ray diffraction. The study also employed solid-state NMR measurements and DFT calculations to confirm the salt formation and protonation state of agomelatine. The results showed that the formation of these sulfonate salts significantly increased the dissolution rate of agomelatine, with the mesylate salt achieving up to approximately 200 times faster dissolution compared to the pure polymorph of agomelatine. This research highlights the potential of salt formation as an effective strategy to improve the solubility of poorly-ionizable pharmaceutical compounds.
