Time-dependent selected reaction monitoring-based GC-MS/MS method for estimation of genotoxic impurities in new antibact
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(2020) 11:22
Journal of Analytical Science and Technology
RESEARCH ARTICLE
Open Access
Time-dependent selected reaction monitoring-based GC-MS/MS method for estimation of genotoxic impurities in new antibacterial agent: alalevonadifloxacin mesylate Vinod K. Ahirrao* , Rajiv A. Jadhav, Vipul P. Rane, Harshal R. Bhamare and Ravindra D. Yeole
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%. Keywords: Alalevonadifloxacin, GC-MS/MS, Time-dependent SRM, Alkyl mesylates
Introduction 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. Chemically, 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). The chemical structure of ALA is shown in Fig. 1. ALA has completed phase I study in US (ClinicalTrials.gov Identifier: NCT02217930) and phase III study in India for the treatment of skin and skin structure infections (Chugh et al. 2015; Niu et al. 2015; Chugh et al. 2016; * Correspondence: [email protected] Wockhardt Research Centre, D-4, MIDC, Chikalthana, Aurangabad 431006, India
Rodvold et al. 2018; Mason et al. 2019). Very recently, a marketing approval has been issued by the Drug Controller General of India to commercialize this new drug in India. Synthesis of ALA involves use of methanol, ethanol, and isopropanol as solvents at various stages of synthesis and during purification. 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
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