Design, Preparation, Characterization and Evaluation of Five Cocrystal Hydrates of Fluconazole with Hydroxybenzoic Acids
Hongmei Yu,
Baoxi Zhang,
Meiju Liu,
Wenhui Xing,
Kun Hu,
Shiying Yang,
Guorong He,
Ningbo Gong,
Guanhua Du,
Yang Lu
Affiliations
Hongmei Yu
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
Baoxi Zhang
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
Meiju Liu
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
Wenhui Xing
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
Kun Hu
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
Shiying Yang
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
Guorong He
Beijing City Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
Ningbo Gong
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
Guanhua Du
Beijing City Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
Yang Lu
Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
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.
