Abstract
Alalevonadifloxacin mesylate (ALA), pro-drug of levonadifloxacin is a new antibiotic approved in India to treat infections caused by Gram-positive bacteria. Alkyl mesylates (AMs) are known genotoxic impurities (GTI’s) formed in drug substances isolated as mesylate salts. Time-dependent selected reaction monitoring (t-SRM)-based gas chromatography tandem mass spectrometry (GC-MS/MS) method has been developed for trace estimation of AMs, namely, methyl methane sulfonate (MMS), ethyl methane sulfonate (EMS) and isopropyl methane sulfonate (IMS) in ALA. Liquid-liquid extraction (LLE) procedure using dichloromethane (DCM) as an extracting solvent was employed to extract AMs from the drug substance. Automatic selective reaction monitoring (auto-SRM) tool was applied to identify the most intense SRM pair of the ions to achieve the highest sensitivity. The method was validated in terms of specificity, linearity, sensitivity, precision, and accuracy. The limit of quantitation (LOQ) for the MMS, EMS and IMS were 5, 10, and 20 ng/g of ALA, respectively. For all analytes, the correlation coefficient (R) were greater than 0.9975 in the concentration range of 3.0–260 ng/mL. Mean recovery of all analytes was in the range of 91.77 to 97.65%.
Highlights
A broad group of fluoroquinolones and quinolones is used as an antibacterial agent in clinics
Method development Chromatographic separation Column selection and chromatographic parameters optimization was carried out using GC with Gas chromatography tandem mass spectrometry (MS) as a detector
Rtx-624 column was chosen for conducting further experiments
Summary
A broad group of fluoroquinolones and quinolones is used as an antibacterial agent in clinics. Alalevonadifloxacin (ALA, WCK 2349) is a mesylate salt of L-alanine ester pro-drug of levonadifloxacin. It is S-(-)-9-fluoro-8-(4-L-alaninyloxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H, 5Hbenzo-[i, j]-quinolizine-2-carboxylic acid methane sulfonic acid salt (Patel et al 2012). Possibility of undesired reactions between the methane sulfonic acid and the alcohols exists resulting in the formation of AMs (Andrew et al 2010; Snodin and Teasdale 2015; Snodin 2019). These impurities are deoxyribo nucleic acid (DNA) reactive substances that have the potential to directly cause DNA damage, thereby leading to genetic mutations causing cancer. These impurities induce genetic mutations or chromosomal abnormalities in bacterial and mammalian cell systems, as well as in vitro salmonella reverse mutation (Ames) and micronucleus
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