Development, Validation, and Greenness Assessment of a Liquid Chromatography–Tandem Mass Spectrometry Method for Trace Determination of N‐ Nitrosodesbutyl Dronedarone in Dronedarone Hydrochloride

ABSTRACT

The increasing regulatory concern regarding nitrosamine drug substance‐related impurities necessitates the development of highly sensitive and selective analytical methods. This study presents a sensitive and environmentally sustainable liquid chromatography coupled with tandem mass spectrometry method for the determination of N‐ nitrosodesbutyl dronedarone impurity in dronedarone hydrochloride. To the best of our knowledge, this is the first validated analytical method reported for the trace‐level determination of this impurity. The analytical procedure employs a simplified sample preparation approach without derivatization using a water–methanol mixture containing 0.1% formic acid. The proposed method demonstrated excellent sensitivity, with a limit of detection of 0.0618 ppm and a limit of quantification of 0.1875 ppm, together with outstanding linearity (coefficient of determination ≥0.999). Accuracy, precision, and robustness were found to be compliant with the requirements of the International Council for Harmonization Guideline Q2(R2) for Validation of Analytical Procedures, confirming the suitability of the method for trace‐level impurity determination. The environmental sustainability of the method was systematically evaluated using the Analytical GREEnness metric approach, the Complex Green Analytical Procedure Index, and the Analytical Eco‐scale assessment tools, which indicated a favorable environmental profile. This is primarily attributed to minimal sample consumption, reduced solvent usage, elimination of derivatization, and a simplified analytical workflow. However, the use of organic solvents and energy‐intensive liquid chromatography–mass spectrometry instrumentation remains a limitation. Compared with previously reported liquid chromatography–mass spectrometry methods, the proposed method offers a shorter analysis time and a simplified analytical procedure. Overall, the developed analytical method provides an effective balance between analytical performance and environmental sustainability, making it suitable for routine pharmaceutical quality control applications while supporting the principles of Green Analytical Chemistry.