Trace-level quantification of levofloxacin NDSRIs using LC-TQ-MS/MS: a multi-metric sustainability and integrated toxicological-analytical framework
Abstract
Nitrosamine drug substance-related impurities (NDSRIs) have emerged as a critical regulatory concern due to their potential genotoxicity at trace levels, necessitating highly sensitive and scientifically robust analytical methodologies. Despite the widespread use of levofloxacin (LOX), no validated analytical method has been reported for the simultaneous determination of LOX-specific NDSRIs. Although several LC-MS/MS methods have recently been reported for NDSRIs associated with other pharmaceutical compounds, these studies primarily focused on compound-specific impurity monitoring and did not address levofloxacin-derived NDSRIs. Furthermore, most reported methodologies emphasize analytical sensitivity without integrating toxicological risk assessment and sustainability evaluation. In this study, a highly sensitive and selective LC-TQ-MS/MS method was developed and validated for the simultaneous trace-level quantification of N-nitroso methyl piperazine (N-NMP) and N-nitroso desmethyl levofloxacin (N-NDLOX) in LOX drug substance and tablet formulations. A systematic risk-based analytical development strategy was employed to define the Analytical Target Profile (ATP) and guide method development and optimization. Structural confirmation of the synthesized NDSRIs was achieved using advanced spectroscopic techniques, including 1H-15N HMBC NMR. The developed method demonstrated excellent sensitivity, with limits of quantification of 0.6 ng mL⁻1 for N-NMP and 1.0 ng mL⁻1 for…
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