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. . . Narom 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.

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Donepezil has polymorphism. Different crystalline forms can exhibit different physicochemical properties and biological activities. Exploration of intermolecular interactions is essential to reveal the formation mechanism and differences in properties of polymorphs. This study explores the weak non-covalent intermolecular interactions of donepezil polymorphs through fully ab initio quantum mechanical methods, semi-empirical methods, and Hirshfeld surface analysis. The results show that the Hirshfeld surface analysis method can clearly and intuitively reveal the intermolecular interactions. Theoretical calculations using the atom–atom Coulomb–London–Pauli (AA-CLP) method were also performed to understand the interaction energies toward the total lattice energy. The value of the lattice energy was in accordance with the melting points of the donepezil polymorphs and brought to light the nature of thermal stability. In the specific energy distribution, the contribution of the dispersion force is the most prominent. Further interaction energy analysis found that within a distance of 3.8 Å from the center of the donepezil molecule, different crystalline forms of donepezil molecules have different interaction energies with surrounding molecules. The different interaction energies between polymorphs may lead to polymorphs with different physical–chemical properties.

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