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.