Ultrasensitive Liquid Chromatography Triple Quadrupole Mass Spectrometry Detection and Quantification of N‐Nitroso‐Meglumine in Tafamidis Meglumine Capsules Using Electrospray Ionization

ABSTRACT

Nitrosamine impurities, especially nitrosamine drug substance‐related impurities (NDSRIs), are a growing concern due to their potential mutagenic and carcinogenic effects. To mitigate health risks, regulatory authorities have imposed strict guidelines for their identification and quantification in pharmaceuticals. N‐nitroso‐meglumine (NNM), an impurity associated with tafamidis meglumine, has been identified as a high‐risk NDSRI, leading the European Medicines Agency (EMA) to establish a daily intake limit of 1500 ng/day. This study introduces a highly sensitive and reliable liquid chromatography triple quadrupole mass spectrometry (LC‐TQ/MS) method for detecting and quantifying NNM in tafamidis meglumine drug substances and capsules. Chromatographic separation was achieved using a Teknokroma PFP column (250 × 4.6 mm, 5μ) with an isocratic mobile phase of 0.1% formic acid in water and methanol (70:30 v/v). A 20 µL injection volume was used, with a 0.6 mL/min flow rate over 10 min. Mass spectrometric analysis was performed on a triple quadrupole system with electrospray ionization (ESI) in multiple reaction monitoring mode. The method exhibited excellent linearity (correlation coefficient > 0.999) over a 100–300 ng/mL range, with high sensitivity (LOD: 0.5 ng/mL, LOQ: 1 ng/mL). This validated approach ensures accurate quantification of NNM, facilitating regulatory compliance and enhancing drug safety monitoring.