N-nitrosamine compounds have been recognized for their carcinogenic properties. Compounds containing secondary and tertiary amine moieties in their chemical structure, including drugs, intermediates, or solvents, are susceptible to the formation of nitrosamine impurities when they react with residual nitrite and nitrate reagents. Lidocaine (LDC) features a tertiary amine moiety, while lidocaine EP impurity E (LEE) includes a secondary amine moiety in its chemical structure. This structural characteristic makes it susceptible to the formation of N-nitroso-desethyl lidocaine (NDL) and N-nitroso lidocaine EP impurity E (NLE) during the synthesis of the LDC drug substance or the manufacturing of the LDC drug product. In this study, we developed and validated a triple quadrupole mass spectrometer (TQ-MS) method for the quantification of NDL and NLE in both the LDC drug substance and the LDC injectable formulation. This method employed a Zorbax Eclipse XDB-C18 column, utilizing an eluent composed of methanol and formic acid in water (0.1% v/v). This method enables the quantification of both NDL and NLE at a lower concentration of 0.0165 ng/mL. The method demonstrates a linear, precise, and accurate performance within the range of 0.0165 to 2.5 ng/mL for NDL and from 0.0165 to 5 ng/mL for NLE. Furthermore, the degradation pathways for both NDL and NEL impurities were discussed. In addition, the environmental impact from the TQ-MS approach using GAC tools like BAGI and AGREE was evaluated.
Batna et al. (Tue,) studied this question.