Abstract

Zaltoprofen, a selective cyclooxygenase-2 (COX-2) inhibitor and a member of the nonsteroidal anti-inflammatory drugs, has been associated with the formation of nitrosamine impurities under specific conditions involving secondary or tertiary amines and nitrite salts, particularly in acidic environments. This research presents a detailed, exacting, and structured analytical approach for quantifying nine nitrosamine impurities (N-Nitroso dimethyl amine, N-Nitroso- N-methyl-4-aminobutyric acid, N-Nitroso diethyl amine, N-Nitroso morpholine, N-Nitrosoethylisopropylamine, N-Nitroso diisopropylamine, N-Nitrosomethylphenylamine, N-Nitroso dibutyl amine, and 1-Methyl-4- Nitrosopiperazine) utilizing the Acquity UPLC HSS T3 (100 x 3.0 mm, 1.8μ) column on the Waters UHPLC-MS/ MS Acquity H-Class platform. The method established a gradient program utilizing 0.1% formic acid and methanol as mobile phases A and B, respectively, at a flow rate of 0.5 ml/minutes, with ionization performed using atmospheric pressure chemical ionization in positive mode. Quantification was performed utilizing multiple reaction monitoring mode, achieving sensitivity at the parts per million (ppm) level. The validation of the proposed analytical method adhered to the guidelines established by the International Council for Harmonisation Q2, incorporating parameters such as system precision, specificity, linearity (R² > 0.990 from limit of quantification (LOQ) to 200%), accuracy, method precision, intermediate precision, limit of detection (0.0014 ppm), and LOQ (0.0041 ppm) for the nine nitrosamine impurities. The method further assesses environmental sustainability through the Analytical GREEnness and Analytical Eco-Scale evaluations, which validated the method’s commendable eco-friendliness. This thorough approach highlights the essential requirement for the oversight of nitrosamine impurities in active pharmaceutical ingredients to uphold safety and conformity with regulatory standards.

Key words: Zaltoprofen, NDMA, NDEA, NEIPA, NMOR, MENP, NDIPA, NMPA, NMBA, NDBA, Green Analytical Chemistry, UHPLC-MS/MS.