Abstract
Recently, the focus of regulatory agencies has shifted to nitrosamine drug substance-related impurities (NDSRIs). Terazosin has two secondary amine impurities, impurity C and impurity N, that are potential precursors of nitrosamines, namely N-nitroso terazosin impurity C and N-nitroso terazosin impurity N, for which regulatory bodies have established acceptable intakes. To control the two potential N-nitrosamine impurities of terazosin in terazosin 5 mg tablets, we have, for the first time, developed two highly sensitive LC-MS/MS methods. Fast chromatographic separations were performed on an Atlantis Premier BEH C18 AX mixed-mode column. Gradient elution at acidic pH was used for N-nitroso terazosin impurity N with a run time of 10 min, and isocratic elution at neutral pH was applied for N-nitroso terazosin impurity C for 4 min. Both compounds were sensitively detected in positive electrospray ionization multiple reaction monitoring mode. The method for N-nitroso terazosin Impurity N was validated as a limit test with a limit of detection of 13.5 ppb. Full validation was carried out for the quantitation of N-nitroso terazosin Impurity C. The limits of detection and quantitation were 45 and 450 ppb, respectively. The method was linear over the 0.45–15 ppm range, with mean repeatability values ranging from 1.08% to 3.99%. The recoveries ranged from 94.0% to 103.9%. The eco-friendliness of both methods was evaluated using the modified green analytical procedure index (MoGAPI) and the analytical greenness (AGREE) metrics. The suitability of the proposed methods for confirmatory testing was demonstrated by determining the NDSRI content in 10 terazosin formulation batches.