title: Characterization and evaluation of miconazole salts and cocrystals for improved physicochemical properties.
abstract: Miconazole salts and cocrystals were studied to improve the physicochemical properties of miconazole. Maleate, hemifumarate, and hemisuccinate were prepared and characterized by powder X-ray diffractometry, differential scanning calorimetry, and single crystal X-ray diffractometry. The intrinsic dissolution rate and stability of each miconazole crystal form were compared to those of freebase and nitrate to evaluate the optimal crystal form. Crystal structure analysis indicated that maleate was a salt formed by proton transfer from the acid to the imidazole group of miconazole. Hemifumarate and hemisuccinate were determined to be cocrystals formed by hydrogen bonding between the acids and the base in their crystal lattices. Intrinsic dissolution tests showed that the formation of salts and cocrystals improved the dissolution rate of miconazole. Stability tests of preliminary formulations prepared with each crystal form indicated that maleate and hemifumarate were unstable at 80°C and generated a specific degraded product, i.e., a Michael adduct, between miconazole and the acids. Hemisuccinate had a superior intrinsic dissolution rate and stability, and is thus considered a promising crystal form of miconazole.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Tsutsumi_Shunichirou@takeda.co.jp
authors: Shunichirou
authors: S
authors: Tsutsumi
authors: Motoo
authors: M
authors: Iida
authors: Norio
authors: N
authors: Tada
authors: Takashi
authors: T
authors: Kojima
authors: Yukihiro
authors: Y
authors: Ikeda
authors: Toshiya
authors: T
authors: Moriwaki
authors: Kenjirou
authors: K
authors: Higashi
authors: Kunikazu
authors: K
authors: Moribe
authors: Keiji
authors: K
authors: Yamamoto
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D004355:Drug Stability; D008298:Maleates / Q000737:chemistry; D008825:Miconazole / Q000737:chemistry*; D033362:Powder Diffraction; D012995:Solubility; D053719:Tandem Mass Spectrometry; D014961:X-Ray Diffraction
chemical_list: D000935:Antifungal Agents; D008298:Maleates; D008825:Miconazole