Abstract

Nitrosamine impurities in human medicines have raised concern among global health regulators because many of these compounds are known to be strong mutagens and carcinogens. N-nitrosodimethylamine (NDMA) is a nitrosamine that has been detected in several products, raising safety and quality concerns. The purpose of this study was to develop and validate a simple, reliable, and highly sensitive liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for detecting and quantifying trace levels of NDMA in Ibrutinib, a medicine used to treat certain cancers. The chromatographic separation was carried out on an XSelect CSH Phenyl-Hexyl column (150 × 4.6 mm, 3.5 μm) using gradient elution with 0.12% formic acid in water as mobile phase A and methanol as mobile phase B. Detection was performed using atmospheric pressure chemical ionisation (APCI) in positive mode, operating under multiple reaction monitoring (MRM) conditions at m/z 75 and 58 for NDMA. The method showed very good sensitivity with a limit of detection (LOD) of 0.005 ppm and a limit of quantitation (LOQ) of 0.01 ppm. The method was validated in accordance with the International Council for Harmonization (ICH) guidelines and demonstrated accuracy, precision, linearity, specificity, and robustness across the tested range. These validation results confirm that the method is suitable for the routine determination of NDMA impurity in Ibrutinib. In conclusion, the developed LC-MS/MS method provides a reliable and efficient tool for monitoring NDMA contamination at very low levels, supporting regulatory compliance and ensuring the safety and quality of pharmaceutical products. The method can also be adapted for the analysis of NDMA in other drug substances and formulations where similar contamination risks may exist.

Keywords: N-nitrosodimethylamine, NDMA, genotoxic impurity, Ibrutinib, UPLC-MS/MS

Article language: En