Development and Validation of a Highly Sensitive LC‐MS/MS Method for Quantification of Mutagenic <i>N</i> ‐Nitroso Desmethyl Citalopram in Drug Formulations

Abstract

Abstract The global pharmaceutical industry is presently apprehensive about nitrosamine impurities and nitrosamine drug substance‐related impurities (NDSRIs), which are known as human mutagens. Citalopram, a selective serotonin reuptake inhibitor, ranks among the most frequently prescribed antidepressants worldwide. It is a primary medicine utilized for the treatment of depression. Based on a theoretical assessment of the structure of Citalopram for the potential formation of an NDSRI, it was determined that it can indeed form an NDSRI, namely N ‐Nitroso Desmethyl Citalopram. The Carcinogenic Potency Category Assessment indicates that the impurity is classified as carcinogenic Category 1, with an acceptable intake limit of 26.5 ng per day (ng/day). Due to their elevated cancer risk, a very sensitive quantitative method is essential. An LC‐MS/MS method was established for quantification utilizing a Poroshell StableBond‐C18 column with dimensions of 150 (length) × 4.6 (internal diameter) mm and a particle size of 2.7 µm, with the column temperature maintained at 30°C. A 50 mM formic acid buffer and acetonitrile are employed in a 50:50 v/v ratio, with a flow rate of 0.5 mL/min in isocratic mode for peak elution. A multiple reaction monitoring program, MRM, was employed in mass spectrometry, utilizing three product ions at m / z 291.1 (quantifier), 138, and 263.1 (qualifier) with electrospray ionization mode. The LC‐MS/MS method was validated in accordance with regulatory criteria and deemed appropriate for its intended application. The employed approach is a highly sensitive analytical technology that will assist the scientific community by offering insights into the mutagenic impurity levels in citalopram drug formulations.

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