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

被引:10
作者
Yu, Hongmei [1 ]
Zhang, Baoxi [1 ]
Liu, Meiju [1 ]
Xing, Wenhui [1 ]
Hu, Kun [1 ]
Yang, Shiying [1 ]
He, Guorong [2 ]
Gong, Ningbo [1 ]
Du, Guanhua [2 ]
Lu, Yang [1 ]
机构
[1] Chinese Acad Med Sci, Peking Union Med Coll, Inst Materia Med, Beijing Key Lab Polymorph Drugs, Beijing 100050, Peoples R China
[2] Chinese Acad Med Sci, Inst Materia Med, Beijing City Key Lab Drug Target Identificat & Dru, Beijing 100050, Peoples R China
基金
北京市自然科学基金;
关键词
fluconazole; cocrystal; hydrate; stability; dissolution; CO-CRYSTALS; CRYSTALLIZATION; POLYMORPHISM; SALTS; FORMS;
D O I
10.3390/pharmaceutics14112486
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页数:17
相关论文
共 44 条
  • [11] Chinese Pharmacopoeia Commission, 2020, Chinese Pharmacopoeia 1
  • [12] DIFFERENTIAL THERMAL ANALYSIS OF COCRYSTAL PEAK IN LINEAR-HIGH PRESSURE POLYETHYLENE BLENDS[J]. CLAMPITT, BH. JOURNAL OF POLYMER SCIENCE PART A-GENERAL PAPERS, 1965(2PA)
  • [13] Dash A.K., 2001, PROFILES DRUG SUBSTA, P67
  • [14] Fluconazolium oxalate: synthesis and structural characterization of a highly soluble crystalline form[J]. Dayo Owoyemi, Bolaji C.;da Silva, Cecilia C. P.;Diniz, Luan F.;Souza, Matheus S.;Ellena, Javier;Carneiro, Renato L. CRYSTENGCOMM, 2019(07)
  • [15] Crystal engineering: structure, property and beyond[J]. Desiraju, Gautam R. IUCRJ, 2017
  • [16] fda, ABOUT US
  • [17] Synthon hierarchy in theobromine cocrystals with hydroxybenzoic acids as coformers[J]. Goldyn, Mateusz;Larowska, Daria;Nowak, Weronika;Bartoszak-Adamska, Elzbieta. CRYSTENGCOMM, 2019(48)
  • [18] Versatile Salts as a Strategy to Modify the Biopharmaceutical Properties of Venlafaxine and a Potential Hypoglycemic Effect Study[J]. Gong, Ningbo;Zhang, Yong;Wang, Ying;Yu, Hongmei;Zhang, Baoxi;Zhang, Hailu;Lu, Yang;Du, Guanhua. CRYSTAL GROWTH & DESIGN, 2020(05)
  • [19] Solubility Advantage of Pharmaceutical Cocrystals[J]. Good, David J.;Rodriguez-Hornedo, Nair. CRYSTAL GROWTH & DESIGN, 2009(05)
  • [20] CHARACTERIZATION OF POLYMORPHIC FORMS OF FLUCONAZOLE USING FOURIER-TRANSFORM RAMAN-SPECTROSCOPY[J]. GU, XJ;JIANG, W. JOURNAL OF PHARMACEUTICAL SCIENCES, 1995(12)