Cocrystal Hydrate of an Antifungal Drug, Griseofulvin, with Promising Physicochemical Properties

Abstract

Cocrystallization of an antifungal drug, griseofulvin (GF), with an artificial sweetener, acesulfame (Ace-H), resulted in a cocrystal monohydrate with GF and Ace-H in a 2:1 stoichiometric ratio. The cocrystal was characterized by differential scanning calorimetry and thermogravimetric analysis, and its crystal structure was determined by single-crystal X-ray diffraction. The Ace-H molecule is in its enol form in the crystal structure. The cocrystal hydrate shows remarkable thermal stability, which was traced to strong hydrogen bonds in the crystal structure. The dissolution rate of the (GF)2·Ace-H hydrate is significantly improved compared to that of the parent GF, and the aqueous solubility of the cocrystal hydrate is greater than the solubility of GF at 37 °C. Furthermore, the cocrystal hydrate is found to be stable at different relative humidity conditions for up to 13 weeks. The remarkable thermal stability, improved solubility and dissolution rate, and pharmaceutical acceptability of Ace-H make the (GF)2·Ace-H hydrate a preferable solid form for development of GF formulations (Singapore patent application 201107310-3 (ref 1)).