Fluconazole: Synthesis and Structural Characterization of Four New Pharmaceutical Cocrystal Forms

Pharmaceutical cocrystals have emerged over the past several decades as an alternative path for synthesizing stable and/or improved crystalline forms of active pharmaceutical ingredients. In this contribution, we developed a reproducible cocrystallization path for the supramolecular synthesis of four new pharmaceutical cocrystal forms of fluconazole (FLZ), an antifungal multifunctional drug: fluconazole–fumaric acid monohydrate (1:1:1), fluconazole–malic acid (1:1), fluconazole–dipicolinic acid (1:1), and fluconazole–adipic acid (1:1). All the new cocrystals were characterized by powder/single-crystal X-ray diffraction, Raman, Fourier transform infrared spectroscopy, differential scanning calorimetry/thermogravimetric analysis, and hot-stage polarized optical microscopy, and their water solubility was determined. Structurally, although the coformers were different, the same strong O–H···N hydrogen bond between the FLZ molecule and the coformers was observed. The aqueous solubility studies revealed that all the cocrystals were found to exhibit improved aqueous solubility when compared to the commercialized FLZ polymorph.