Photochemical Behavior of Sitafloxacin, Fluoroquinolone Antibiotic, in an Aqueous Solution.

Abstract

Sitafloxacin hydrate (STFX hydrate: (Ϫ)-7-[(7S)-1) Fluoroquinolones are important synthetic antimicrobial agents and they have been widely used as therapeutic agents for general bacterial infectious diseases. However, some fluoroquinolones are known to induce phototoxicity as a side effect.2) A large number of studies have been reported to elucidate the mechanism of phototoxicity of fluoroquinolones. We reported that carbon centered radical (· C), hydroxyl radical (· OH), and singlet oxygen ( 1 O 2 ) are generated during photodegradation of fluoroquinolones in neutral aqueous solutions.3) The fluoroquinolones substituted at the 8-position by fluorine generated a high degree of 1 O 2 and · OH against photoirradiation. Such reactive species were related to DNA damage. 4) Some fluoroquinolones are photo-labile compounds and the phototoxicity might arise from photodegradation products. This study was done based on such a background. This report describes the photochemical behavior of STFX in aqueous solution including the identification of major photodegradation products of STFX, the mechanistic consideration of photodegradation, and the effect of pH. Furthermore, the possibility improving the photostability of STFX was examined in the presence of chloride ion. ExperimentalMaterials STFX was synthesized at Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.Structural Elucidation of Photodegradation Products Ninety-four milligrams of STFX hydrate was dissolved in 1 l of purified water and irradiated with fluorescent lamps (Biophotochamber LX-2100 (TAITEC Co., Tokyo)) at approximately 10000 lux for ca. 350000 lux · h. After irradiation, the solution was loaded onto a preparative HPLC system and fractionated.Preparative HPLC was carried out on a gradient system consisting of an LC 10AD pump (Shimadzu Co., Kyoto) equipped with a SPD-6A UV/vis detector (Shimadzu Co.). HPLC conditions were as follows: column, TSKgel ODS-80T M (21.5 mm i.d.ϫ300 mm, Tosoh Co., Tokyo); eluent, 0.05 M phosphate buffer (pH 2.4) : acetonitrileϭ82 : 18 (from 0 to 65 min) to 50 : 50 (from 65 to 100 min); flow rate, 5.0 ml/min (from 0 to 65 min) to 7.0 ml/min (from 65 to 100 min); injection, 2 ml; detection, 278 nm; column temperature, 40°C.The collected fractions were concentrated and lyophilized. Then the sample was redissolved in water and loaded onto a desalting preparative HPLC. HPLC conditions were as follows: column, TSKgel ODS-80T M (21.5 mm i.d.ϫ300 mm, Tosoh Co.); eluent, 0.1% acetic acid and acetonitrileϭ30 : 70; flow rate, 7.0 ml/min; injection, 2 ml; detection, 278 nm; column temperature, 40°C. Isolated photodegradation products were elucidated by using a 1 H-NMR (JNM-GSX500 FT-NMR spectrometer (500 MHz), JEOL Co., Tokyo) and electron impact (EI), chemical ionization (CI), fast atom bombardment (FAB)-MS (JMS-HX110 mass spectrometer, JEOL Co.) spectra.Kinetics of Photodegradation STFX was dissolved in Britton-Robinson buffer solutions of pH 2.0-11.0 and 0.1 mol/l sodium hydroxide (pH 13.0) (STFX, about 50 mg/ml). Each sample solution (2 ml...

Analytical methods for determination of new fluoroquinolones in biological matrices and pharmaceutical formulations by liquid chromatography: a review

“…It was found that SPA was more sensitive to light in the zwitterionic form and more stable in the acidic region. With respect to wavelength dependence the conclusion was that SPA was more labile at the maximum absorption wavelength [47]. Overall, these results demonstrate that dehalogenation at position 8 is a significant photodegradation mechanism for these fluoroquinolones.…”

“…One of the major drawbacks of fluoroquinolones is their photosensitivity. It has been proposed that a high degree of halogenation may lead to low photostability and, consequently, to the formation of photoproducts that can induce adverse effects and toxicity [47,74,75]. Therefore, a considerable interest has arisen in the investigation of the process of degradation.…”

“…It is suggested that light irradiation generates toxic photoproducts intermediates (e.g. carbenes) and reactive oxygen species that may attack cell components and cause tissue damage, leading to remarkable phototoxicity of fluoroquinolones [47,74,75,77,78]. An increased incidence of phototoxicity was observed in dihalogenated fluoroquinolones and also in molecules that contain a methoxy group at position 5 and molecules with a cyclopropyl or ethyl group at position 1 [39].…”

Photodegradation of fluoroquinolone antibiotic gatifloxacin in aqueous solutions

“…Knapp et al [11] found that enrofloxacin photodegraded rapidly following first order kinetics and was transformed into ciprofloxacin in sunlit mesocosms. Araki et al [13] found that sitafloxacin photodegradation also followed first-order kinetics, and the photolytic rate was affected by the matrix pH and Cl − . In previous studies, such aqueous photoreactive dissolved matter as Fe(III), NO 3 − and humic acids (HA) was shown to have significant impacts on the photochemical reaction kinetics and pathways of organic pollutants in surface waters [14−16].…”

New Findings on the Structure-Phototoxicity Relationship and Photostability of Fluoroquinolones with Various Substituents at Position 1

“…Araki et al (1) reported that a carbon-centered radical ( ⅐ C) was generated at position 8 by scission of the COCl bond of an 8-chloro quinolone under UV irradiation, and excess chloride ions immediately reacted with it. As a result, the COCl bond was recovered and the apparent photostability was increased.…”