Physicochemical and Anti-fungal Studies of the Pharmaceutical Co-crystal/Salt of Fluconazole

Crystal engineering is one green alternative to organic
synthesis
that can be used to manipulate molecular behavior promptly and economically.
We report the preparation and characterization of the pharmaceutical
organic salt (FLC-C) of fluconazole (FLC) and organosulfonate (NDSA-2H),
based on the sulfonate-pyridinium supramolecular synthon. Structural
studies validate the crystallization of the two-component stoichiometric
crystal with two molecules of water in the triclinic P1̅ space group. The anticipated proton transfer between the
crystal forms leads to ionic interactions, augmenting the organic
salt’s thermal stability. Hirshfeld studies of FLC-C help to
understand the role and significance of different types of intermolecular
interactions responsible for crystal packing. The structural and theoretical
studies indicate the absence of π–π interactions
in FLC-C, which account for the incipience of solid-state emission
in the product. The solubility studies establish augmented aqueous
solubility of FLC-C over pristine FLC at physiological pH values of
2 and 7. Interestingly, in in vitro studies, FLC-C appears to serve
as a potential alternative to FLC, displaying a wide spectrum of antifungal
activity. FLC-C is active against several human pathogenic yeast strains,
including the leading and emerging Candida strains (Candida albicans and Candida auris, respectively), at comparable and/or
lower drug concentrations without showing any enhanced host cell toxicity.
Interestingly, the pharmaceutical co-crystal also displays fluorescence
properties inside the Candida cells.