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

Abstract

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.

Stimuli-responsive fluorochromic organic salt

“…47–51 Therefore, further investigation of the intermolecular interaction is essential to understand its significance. After successful testing of the intermolecular interaction for reproducibility and robustness, it has been utilized to design pharmaceutical cocrystals 29,50 and chromic stimuli-responsive materials. 12,43,51 Recently, we realized solid-state emission tuning in organic complexes based on ionic interactions.…”

“…24–26 Understanding of hydrogen bonds has led to the development of co-crystals, an important crystal engineering outcome through which the physicochemical as well as biological and material properties of precursors can be engineered. 27–29 Solid state emission is a rare but important phenomenon with immense significance for the development of optoelectronics, optical waveguides and routers, and lighting devices. 30–32 The co-crystallization approach has been used for the design of emissive crystals.…”

Sulfonate–Pyridinium Ionic Cocrystal Solvates: Improved Material and Antimicrobial Properties

“…47,48 The approach is a facile way for the improvization of existing and discovery of new drugs, as besides addressing the physicochemical limitations the cocrystals can be utilized to induce novel biological tendencies in the resultant molecular complexes. 49 The first pharmaceutical salt−cocrystal drug, Entresto, introduced by Novartis and accepted by the US-FDA in July 2015, followed by many other approved cocrystal drugs, validated the significance of the cocrystallization approach in the area of drug discovery. 50−55 We have successfully utilized the sulfonate pyridinium intermolecular interaction to design multicomponent crystals.…”

“…Multicomponent crystals have also been successfully utilized to address the solubility limitations of the existing drugs. , The approach is a facile way for the improvization of existing and discovery of new drugs, as besides addressing the physicochemical limitations the cocrystals can be utilized to induce novel biological tendencies in the resultant molecular complexes . The first pharmaceutical salt–cocrystal drug, Entresto, introduced by Novartis and accepted by the US-FDA in July 2015, followed by many other approved cocrystal drugs, validated the significance of the cocrystallization approach in the area of drug discovery. − …”