Trimorphic forms of 5-fluorocytosine–gentisic acid with enhanced hydration stability

Abstract

Polymorphism in drug molecules is studied extensively; however, the existence of polymorphs in a cocrystal system has not been widely addressed in the scientific arena. In the present work, the authors report the trimorphic forms of an anti-fungal drug 5-fluorocytosine (5FC) with gentisic acid (GEA) as a coformer. The crystal structures of the three forms namely 5FC-GEA F-I, 5FC-GEA F-II and 5FC-GEA F-III were determined by single-crystal X-ray diffraction techniques and further characterized by various spectroscopic (FT-IR), thermal (DSC & hot-stage) and powder X-ray diffraction techniques. Form-I and Form-III were obtained as pale brown-coloured block-shaped crystals during crystallization, while Form-II was obtained as colourless fine needles. Form-I and Form-II cocrystal structures were formed with a supramolecular acid–amide heterosynthon, while the third form Form-III was crystallized as a salt and the primary interaction was through a carboxylate–pyrimidinium heterosynthon between GEA and 5FC. Form-I and Form-II are packing polymorphs, whereas Form-III is a synthon polymorph. Thermal analysis by DSC and hot-stage showed phase transformation of Form-II and Form-III to Form-I. From the Hirshfeld surface analysis, the O⋯H/H⋯O interactions were found to be the major contributor to crystal packing in all three polymorphs. The DSC results and lattice energy calculations suggested that Form-I is the stable form. Various crystallization approaches were employed for polymorphic screening and to achieve the phase pure forms. All three polymorphs were subjected to accelerated stability studies (40 °C/70–75% RH and 40 °C/90–95% RH), which revealed that all three polymorphs were found to be stable unlike 5FC, which converts to a monohydrate form at 90–95% RH.