Cocrystallization with nutrient ferulic acid towards reducing the dissolubility behaviors of antifungal drug 5-fluorocytosine: An integrated theoretical and experimental case research

Abstract

The present investigation aims to fully exploit the structural dominance and liver protective efficacy of phenolic acid nutraceutical ferulic acid (FUA) towards decreasing antifungal drug 5-fluorocytosine (FTS) in solubility and dissolution rate through a cocrystallization stratagem, thereby achieving some fire-new understandings for addressing the side effects generated by the fast and inappropriate absorption from FTS. Toward this end, the cocrystalline complex of FTS with FUA, viz. FTS-FUA, as the first cocrystal of FTS with phenolic acid nutrient of hydroxycinnamic acid subgroup is directionally assembled and fully characterized. The crystal structure determined by the single-crystal X-ray diffraction method demonstrates that FUA molecules in the lattice seize the polar sites in situ of FTS founded on the compact hydrogen-bond interaction, therefore leading to the formation of a rigid S-shaped module (RSM) with hydrophobic potentials, which induces a simultaneous down-regulation of the cocrystal in solubility and intrinsic dissolution rate versus raw drug FTS itself. The experimental outcomes are strongly verified by relevant theoretical investigations. The molecular electrostatic potential and the mutual penetration distance authenticate that the RSM's polarity in the cocrystal is lower than that of FTS per se, which complies with the abatement in polarity attributable to the reinforced hydrogen-bonds energy as per topology analysis with atoms in molecules theory, thus giving a remarkable improvement in hydrophobicity for the cocrystal. As a result, the current contribution not only provides a new crystallization form for FTS, but also exemplifies the feasibility of cocrystallization clue from integrated experimental with a systematic theoretical approach to overcome intractable adverse effects of the antifungal agent.