To modulate the physicochemical properties of fluconazole (FLZ), a multifunctional antifungal drug, the crystal engineering technique was employed. In this paper, five novel cocrystal hydrates of FLZ with a range of phenolic acids from the GRAS list, namely, 2,4-dihydroxybenzoic acid (24DHB), 3,4-dihydroxybenzoic acid (34DHB, form I and form II), 3,5-dihydroxybenzoic acid (35DHB), and 3,4,5-trihydroxybenzoic acid (345THB) were disclosed and reported for the first time. Crystals of these five hydrates were all obtained for single-crystal X-ray diffraction (SCXRD) analysis. Robust (hydroxyl/carboxyl) O−H. . . N_arom hydrogen bonds between acids and FLZ triazolyl moiety were observed to be dominant in guiding these crystal forms. The water molecule plays the role of supramolecular “linkage” in the strengthening and stabilization of these hydrates by interacting with FLZ and acids through O−H. . . O hydrogen bonds. In particular, the formation of FLZ−34DHB−H₂O (1:1:1) significantly reduces hygroscopicity and hence improves the stability of FLZ, the latter of which is unstable and easily transforms into its monohydrate form. Increased initial dissolution rates were observed in the obtained cocrystal forms, and an enhanced intrinsic dissolution rate was obtained in FLZ−35DHB−H₂O (1:1:1) in comparison with commercialized FLZ form II.

To improve the solubility and dissolution rate of the BCS class II drug ketoconazole, five novel solid forms in 1:1 stoichiometry were obtained upon liquid-assisted grinding, slurry, and slow evaporation methods in the presence of coformers, namely, glutaric, vanillic, 2,6-dihydroxybenzoic, protocatechuic, and 3,5-dinitrobenzoic acids. Single-crystal X-ray diffraction analysis revealed that the hydroxyl/carboxylic acid. . .N-imidazole motif acts as the dominant supramolecular interaction in the obtained solid forms. The solubility of ketoconazole in distilled water significantly increased from 1.2 to 2165.6, 321.6, 139.1, 386.3, and 191.7 μg mL⁻¹ in the synthesized multi-component forms with glutaric, vanillic, 2,6-dihydroxybenzoic, protocatechuic, and 3,5-dinitrobenzoic acid, respectively. In particular, the cocrystal form with glutaric acid showed an 1800-fold solubility increase in water concerning ketoconazole. Our study provides an alternative approach to improve the solubility and modify the release profile of poorly water-soluble drugs such as ketoconazole.