Kilogram-Scale Process Development of Formoterol Fumarate: Synthesis, Identification, and LC–MS/MS Method Development for Trace-Level Quantification of N -Nitroso Impurity

Formoterol fumarate is a long-acting, selective β 2 -adrenergic agonist with a rapid onset of action, widely used in the treatment of bronchospastic disorders. An improved, kilogram-scale synthetic route to formoterol fumarate was developed, featuring an enhanced chiral resolution of a key intermediate using l -(+)-tartaric acid followed by a selective formylation step. The optimized process demonstrated consistent performance under batch manufacturing conditions and improved the overall yield up to 60%. Moreover, a sensitive and selective liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for trace-level quantification of the N -nitroso impurity associated with formoterol. The validated method exhibited stringent linearity and enabled reliable quantification of N -nitroso-formoterol in the range of 3.60–15.50 ppb. This sensitivity and reliability ensured effective monitoring and control of the N -nitroso-formoterol throughout the process development and commercial API manufacturing.