Design, Preparation, Characterization and Evaluation of Five Cocrystal Hydrates of Fluconazole with Hydroxybenzoic Acids

Abstract

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.

Hydrophilic Cocrystals with Water Switched Luminescence

“…Additionally, TGA spectra demonstrated that the dehydration rates of 2PYTC, 2PYTC‐H‐W, 4PYTC, and 4PYTC‐H‐W samples were calculated to be 4.29 %, 4.83 %, 4.41 %, and 4.90 %, respectively (Figure S16b, 4e), indicating the excellent water re‐absorption ability of heated cocrystals. Moreover, the Fourier‐transform infrared (FTIR) spectrum (Figures S16c, 4f) revealed the symmetric and asymmetric stretching vibrations of two O‐H bonds in the water molecules of 2PYTC and 4PYTC cocrystals, specifically within the range of 3200–3700 cm −1 [52] . The presence of hydrogen bonds made the peaks broader.…”

“…Moreover, the Fourier-transform infrared (FTIR) spectrum (Figures S16c, 4f) revealed the symmetric and asymmetric stretching vibrations of two O-H bonds in the water molecules of 2PYTC and 4PYTC cocrystals, specifically within the range of 3200-3700 cm À 1 . [52] The presence of hydrogen bonds made the peaks broader. After heating, the broad peak of water molecules disappeared in the heated samples of 2PYTC-H and 4PYTC-H, whereas the symmetric stretching vibrations of N-H became prominent at 3438 cm À 1 and 3359 cm À 1 .…”

Enhancing Solubility and Dissolution Rate of Antifungal Drug Ketoconazole through Crystal Engineering

“…. .N synthons in cocrystals between the nitrogen heterocycle complex and dicarboxylic and phenolic acids [14,[35][36][37][38], we were encouraged to investigate the possibility of KTZ cocrystallization with dicarboxylic acids and phenolic acids. It is likely to form (C=O)−O−H.…”

“…The conformation of the KTZ molecule is distinctly different in these four multi-components mainly concerning the orientations of the ring planes. It could be concluded that the introduction of CCF molecules into the crystal lattice or hydrogen bonds between the API and CCF enables the torsion of the API conformation, and, at the same time, the API molecule with flexible conformation forms a more matching spatial arrangement between the API and CCF, which promotes the formation of cocrystals [35,50]. conformation overlay of KTZ is conducted by superimposing R1 and R2 (Figure 6).…”

Pharmaceutical cocrystal and their role in improving solid state properties of active pharmaceutical ingredients

“…Thermal methods comprise techniques that measure the alteration in the thermal properties of a sample as a function of temperature change. The most common techniques in the analysis of cocrystals are differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and hot stage microscopy [70] . DSC is a helpful tool for rapid screening of cocrystals during the stage of synthesis.…”