title: The unexpected increase of clotrimazole apparent solubility using randomly methylated β-cyclodextrin.
abstract: Clotrimazole (CTZ) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility were obtained from phase solubility diagrams. β-CD (1.5% w/w) and hydroxypropyl-β-CD (40% w/w) offered poor CTZ solubility enhancements (12 and 384 times, respectively). Unexpectedly, the apparent solubility of CTZ was 9980 times increased from 0.4 µg.mL(-1) (1.42 μM) without CD to 4.89 mg.mL(-1) (14.9 mM) using randomly-methylated β-CD (Me-β-CD) (40% w/w). This is the highest apparent CTZ solubility improvement ever reported in the literature using conventional CDs. Quantitative nuclear magnetic resonance ((1) H-NMR) coupled with two-dimensional nuclear Overhauser effect (NOESY) experiments and molecular docking calculations showed that the highest interactions with Me-β-CD were reported for CTZ two phenyl groups. A lower interaction was reported for chlorophenyl, while imidazole had the weakest interaction with Me-β-CD.
authors.affiliation: Institut Galien Paris Sud, UMR CNRS 8612, Université Paris-Sud, Faculté de Pharmacie, 5, rue J-B. Clément, 92296, Chatenay-Malabry cedex, France; BioCis, Biomolécules : conception, isolement, synthèse-Chimiothérapie Antiparasitaire, UMR CNRS 8076, Université Paris-Sud, Faculté de Pharmacie, 5, rue J-B. Clément, 92296, Châtenay-Malabry cedex, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Pradines
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gallard
authors.forename: Bogdan I
authors.initials: BI
authors.lastname: Iorga
authors.forename: Claire
authors.initials: C
authors.lastname: Gueutin
authors.forename: Gilles
authors.initials: G
authors.lastname: Ponchel
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
authors.forename: Kawthar
authors.initials: K
authors.lastname: Bouchemal
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003022:Clotrimazole / Q000737:chemistry*; D007093:Imidazoles / Q000378:metabolism; D008745:Methylation; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D066244:Proton Magnetic Resonance Spectroscopy; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D007093:Imidazoles; D047392:beta-Cyclodextrins; C029899:imidazole; D003022:Clotrimazole
keywords: bidimensionnal 1H-RMN; clotrimazole; cyclodextrins; molecular docking; solubilization