Development of an Eco‐Friendly, Ultra‐Sensitive Liquid Chromatography Triple Quadrupole Mass Spectrometric Method for Simultaneous Quantification of Bupropion N‐Nitrosamine Impurities in Bupropion Drug Substance

ABSTRACT

Bupropion is an antidepressant widely used for the treatment of major depressive disorder, seasonal affective disorder, and as an aid in smoking cessation. The presence of nitrosamine drug substance‐related impurities in Bupropion drug substance raises potential safety concerns due to their carcinogenic nature. In this study, Bupropion‐associated two N‐nitrosamine impurities were identified and evaluated. Acceptable intake limits were established using the carcinogenic potency categorization approach, classifying the impurities under potency Category 5. A sensitive and selective liquid chromatography triple quadrupole mass spectrometric method was developed and optimized in agreement with International Council for Harmonisation Guideline Q14 procedures for the trace‐level quantification of Bupropion nitrosamine drug substance‐related impurities. Chromatographic separation was achieved using an Agilent Poroshell 120 Ethylene Crosslinked C18 column (150 mm × 2.1 mm, 2.7 µm) with gradient elution, employing 0.1% formic acid in water and acetonitrile as mobile phases at a flow rate of 0.4 mL/min and column temperature of 40°C. The method was designed based on an Analytical Target Profile, incorporating risk assessment and structured reporting. Method validation and robustness were carried out following International Council for Harmonisation Guideline Q2(R2) guidelines, demonstrating acceptable specificity, accuracy, precision, and sensitivity. The environmental sustainability of the method was evaluated using the Analytical GREEnness metric approach, the Modified Green Analytical Procedure Index, and the Blue Applicability Grade Index tools, confirming its green and sustainable nature. This study supports the United Nations Sustainable Development Goals, Goal 3: Good Health and Well‐Being, and Goal 9: Industry, Innovation, and Infrastructure by ensuring pharmaceutical safety through advanced impurity analysis and promoting environmentally sustainable analytical practices.