Variable stoichiometry and a salt-cocrystal intermediate in multicomponent systems of flucytosine: structural elucidation and their impact on stability.

New cocrystals and a salt-cocrystal intermediate system involving the antifungal drug flucytosine (FCY) and various coformers including caffeic acid (CAF), 2-chloro-4-nitrobenzoic acid (CNB), hydroquinone (HQN), resorcinol (RES) and catechol (CAL), are reported. The crystal structures of the prepared multicomponent systems were determined through SC-XRD analysis and characterized by different solid-state techniques. All FCY multicomponent systems crystallize in anhydrous form with different stoichiometric ratios. The cocrystals FCY-HQN, FCY-RES and FCY-CAL crystallize in 2:0.5, 2:0.5 and 3:2 stoichiometric ratios respectively. In contrast, FCY-CAF and FCY-CNB crystallize in a 1:1 stoichiometric ratio. The FCY-CAF cocrystal is formed via an acid-pyrimidine heterosynthon. Due to the partial proton transfer from the acid group of CNB to FCY, a three-point homosynthon is observed between two FCY molecules and the molecules interact via an N-H...O hydrogen bond between FCY and CNB. In FCY phenolic cocrystals, a single-point O-H...O hydrogen bond is observed. The formation of cocrystals and salt-cocrystal intermediate was further confirmed by difference Fourier map analysis and bond angle differences. Except for FCY-CAL, all the multicomponent systems were reproduced in the bulk scale for further characterization. A detailed Crystal Structural Database search was carried out on the multicomponent systems of FCY with acid coformers and we evaluated the formation of cocrystals/salt based on the ΔpK_a values, the difference in the bond distances and bond angles. Additionally, the prepared multicomponent systems exhibited hydration stability for one month under accelerated conditions [40 (2) °C and relative humidity 90-95 (5)%].