Synthesis of cocrystals/salts of flucytosine: Structure and stability

Abstract

5-Fluorocytosine or flucytosine (FLC) is a well-known drug for anti-fungal treatment and is one of the essential medicines needed in a health system. The main disadvantage of FLC drugs is their instability due to hydration under storage conditions. In the present work, cocrystal/salt screening experiments resulted in three molecular salts of FLC with dihydroxybenzoic acid derivatives, 2,3-dihydroxybenzoic acid (2,3HBA), 3,5-dihydroxybenzoic acid (3,5HBA), and 2,6-dihydroxybenzoic acid (2,6HBA), and two cocrystals with gallic acid (GAA) and glutaric acid (GLA). Since FLC drugs are highly susceptible to hydration, the present work concentrated on the stability of the synthesized molecular salts/cocrystals under different relative humidity (RH) conditions. All the newly formed crystalline adducts were characterized structurally, and the crystal structures were determined using single-crystal X-ray diffraction techniques (SCXRD). The FLC-2,6HBA salt was found to be a monohydrate, whereas the FLC-3,5HBA salt was crystallized as a hemipentahydrate. FLC-2,3HBA and FLC-GLA were crystallized in 2:1 equimolar ratios of FLC and the coformer. The FLC-GAA cocrystal crystallized in a 1:1 equimolar ratio. Two point heterosynthons between FLC and the coformer were observed in all the crystalline structures except FLC-GLA, where the structure was formed through a single point heterosynthon. Stability studies under different relative humidity conditions showed the non-hygroscopicity of the synthesized molecular salts/cocrystals. It was found that the FLC-2,3HBA salt, and the FLC-GAA and FLC-GLA cocrystals did not experience any hydration under the accelerated humidity conditions (both 70-75% RH and 90-95% RH) at ambient temperature (?30 °C). However, FLC-2,6HBA and FLC-3,5HBA were found to be hygroscopic under 70-75% RH conditions. Furthermore, all the synthesized salts/cocrystals except FLC-3,5HBA were found to be stable for 2 months under ambient conditions (?30 °C, 60-65% RH). Therefore, the FLC-2,3HBA salt, and the FLC-GAA and FLC-GLA cocrystals are better candidates for the preparation of new drug products of FLC. © 2018 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.