Cocrystallization-driven self-assembly with vanillic acid offers a new opportunity for surmounting fast and excessive absorption issues of antifungal drug 5-fluorocytosine: a combined theoretical and experimental research

The current research takes advantage of the low solubility and hepatoprotective activity of the phenolic acid nutrient vanillic acid (VAA) to reduce the solubility and dissolution rate of the antifungal drug 5-fluorocytosine (FCY) via a cocrystallization strategy, thus gaining new insights into surmounting the dose-limited hepatotoxicity caused by the rapid and almost complete absorption of FCY. An FCY-phenolic acid nutraceutical cocrystal, namely, FCY–VAA–H2O, was directionally self-assembled and structurally characterized. The single-crystal X-ray structural analysis showed that water and VAA molecules occupy the polar sites of FCY in situ through strong hydrogen-bonding interplays, establishing a key plane structure (KPS) with hydrophobicity, which down-regulates the solubility and dissolution rate of the cocrystal as compared with FCY itself. The conclusion is supported by systematic theoretical studies. Molecular electrostatic potential (MEP) calculations revealed a polarity decrease in KPS in the cocrystal relative to free FCY, in accordance with the polarity diminution induced by intensive hydrogen-bonding energy, through the reduced density gradient (RDG) analysis, implying an obvious potentiation in hydrophobicity. Thereby, the theoretical calculations achieved positive correlations with the experimental measurements.