Improving the Solubility of Agomelatine via Cocrystals

Four cocrystals of agomelatine with urea (1), glycolic acid (2), isonicotinamide (3), and methyl 4-hydroxybenzoate (4) in 1:1 stoichiometry were successfully synthesized via six kinds of synthons. The structures of 1–4 were determined by the single crystal X-ray diffraction, in which 1–3 form two-dimensional hydrogen bonded frameworks between agomelatine and coformers, while 4 displays a one-dimensional chain structure. The results of differential scanning calorimetry measurements indicate that the melting points of 1–3 are between those of agomelatine and coformers, while the melting point of 4 is below those of agomelatine and coformer. After the formations of cocrystals, the solubility of agomelatine is much improved, and the solubility values of 1–4 in phosphate buffer of pH 6.8 are approximately 2.2, 2.9, 4.7, and 3.5 times as large as that of agomelatine Form II, and 1.6, 2.1, 3.4, and 2.5 times as large as that of agomelatine Form I. The solids of 1–4 can keep their crystalline forms in phosphate buffer of pH 6.8 for 3.5, 2.0, 6.0, and 15.0 h, respectively.