Cocrystals of Fluconazole with Aromatic Carboxylic Acids: Competition between Anhydrous and Hydrated Solid Forms

摘要

Through cocrystallization of the broad-spectrum antifungal agent fluconazole (FLZ) with a number of nutraceuticals, we have isolated three distinct solid forms of the drug, namely, anhydrous cocrystal with vanillic acid (VA) and anhydrous and hydrated cocrystals of 4-hydroxybenzoic acid (4OHBA). The new cocrystals have been thoroughly investigated by different analytical techniques, including powder and single crystal X-ray diffractometry (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), scanning electron microscopy (SEM), and dissolution and solubility methods. Analysis of hydrogen bond patterns in the crystals has shown structural similarity in the packing of FLZ molecules between the new crystal forms and the structures taken from the CSD. Comparing the theoretical lattice energies of multicomponent crystals and their constituents, we have found that hydrated crystal forms are more energetically preferable than the anhydrous cocrystals. Analysis of noncovalent interaction energies performed within the framework of quantum theory of atoms in molecules and crystals (QTAIMC) has confirmed the structure-forming role of water molecules in the hydrated cocrystal of FLZ with 4OHBA. Thermal analysis and SEM investigations have shown that the dehydration behavior of FLZ monohydrate (FLZ center dot H2O) is highly sensitive to particle size and morphology of crystals. The pH-solubility behavior of the cocrystals has been investigated at different pH values using eutectic concentrations of the components, and the driving force of the cocrystal formation process for each solid phase has been estimated. Possible cocrystallization pathways between FLZ and 4OHBA have been examined under mechanochemical conditions. A two-step formation mechanism of cocrystallization reaction, which includes generation of an anhydrous [FLZ+4OHBA] (1:1) cocrystal as an intermediate, has been proposed.