Affiliation:
1. Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
2. 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
Abstract
To improve the solubility and dissolution rate of the BCS class II drug ketoconazole, five novel solid forms in 1:1 stoichiometry were obtained upon liquid-assisted grinding, slurry, and slow evaporation methods in the presence of coformers, namely, glutaric, vanillic, 2,6-dihydroxybenzoic, protocatechuic, and 3,5-dinitrobenzoic acids. Single-crystal X-ray diffraction analysis revealed that the hydroxyl/carboxylic acid. . .N-imidazole motif acts as the dominant supramolecular interaction in the obtained solid forms. The solubility of ketoconazole in distilled water significantly increased from 1.2 to 2165.6, 321.6, 139.1, 386.3, and 191.7 μg mL−1 in the synthesized multi-component forms with glutaric, vanillic, 2,6-dihydroxybenzoic, protocatechuic, and 3,5-dinitrobenzoic acid, respectively. In particular, the cocrystal form with glutaric acid showed an 1800-fold solubility increase in water concerning ketoconazole. Our study provides an alternative approach to improve the solubility and modify the release profile of poorly water-soluble drugs such as ketoconazole.
Funder
the Beijing Natural Science Foundation
the CAMS Innovation Fund for Medical Sciences
the Chinese Pharmacopoeia Commission Drug Standard Promoting Fund
the Key R&D Program of Shandong Province
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
Cited by
2 articles.
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