title: Application of ascorbic acid 2-glucoside as a solubilizing agent for clarithromycin: solubilization and nanoparticle formation.
abstract: Clarithromycin (CAM) was co-ground with l-ascorbic acid 2-glucoside (AA-2G), a newly developed food additive, to improve the solubility characteristics. The complete solubilizing effect of AA-2G was observed for the ground mixture with 1:1 molar ratio. When ground mixtures of CAM and AA-2G (2:1) were dispersed into water, not only the solubilization of CAM was observed but also nanoparticle formation with a mean particle diameter of 280 nm. The CAM particles obtained in this manner were stable in suspension for at least 7 days. Zeta potential analysis showed that positive charges on the particle surface may be contributing to the stability of the suspension. 1H NMR spectrum of CAM dissolved in a phosphate buffer (pH 5.5) showed a signal derived from the N,N-dimethylamino group at 2.73 ppm, while that of an equimolar ground mixture of CAM with AA-2G in D2O (pH 5.5) showed clearly two signals at 2.65 and 2.77 ppm derived from the splitting of the two methyl groups. The 13C NMR spectrum of the equimolar ground mixture dissolved in D2O exhibited two signals derived from N,N-dimethyl carbons of desosamine group at 37.2 and 42.3 ppm, whereas unprocessed CAM showed no resonance signal arising from those carbons. Moreover, the carbon resonance at 163 and 173 ppm arising from the ketone group in the CAM lactone ring shifted downfield to 177 and 180 ppm after the co-grinding with AA-2G. The formation of nanoparticles was only observed when CAM was co-ground with AA-2G in the molar ratio of 2:1, which might be attributable to a grinding-induced interaction in the solid-state via the ketone group in lactone ring of CAM.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inoue
authors.forename: Sachie
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tozuka
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Moribe
authors.forename: Takuya
authors.initials: T
authors.lastname: Kumamoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D017291:Clarithromycin / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D009682:Magnetic Resonance Spectroscopy; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D000900:Anti-Bacterial Agents; C065378:ascorbic acid 2-O-glucoside; D017291:Clarithromycin; D001205:Ascorbic Acid