Development of a Sensitive Screening Method for Simultaneous Determination of Nine Genotoxic Nitrosamines in Active Pharmaceutical Ingredients by GC-MS

Abstract

A worldwide crisis with nitrosamine contamination in medical products began in 2018. Therefore, trace-level analysis of nitrosamines is becoming an emerging topic of interest in the field of quality control. A novel GC-MS method with electron ionization and microextraction was developed and validated for simultaneous determination of nine carcinogenic nitrosamines (NDMA, NMEA, NDEA, NDBA, NMOR, NPYR, NPIP, NDPA, and N-methyl-npz) in active pharmaceutical ingredients (APIs): cilostazol, sunitinib malate, and olmesartan medoxomil. The method was validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, demonstrating good linearity in the range of LOQ up to 21.6 ng/mL (120% of specification limit). The limits of detection for the nine nitrosamines were determined to be in the range 0.15–1.00 ng/mL. The developed trace level GC-MS method turned out to be specific, accurate, and precise. The accuracy of all the tested APIs ranged from 94.09% to 111.22% and the precision evaluated by repeatability, intermediate precision, and system precision was RSD ≤ 7.65%. Nitrosamines were not detected in cilostazol and sunitinib, whereas in olmesartan medoxomil NDEA was detected at the level of LOQ. The novel protocol was successfully applied for nitrosamines determination in selected APIs and can be used for the routine quality control of APIs under Good Manufacturing Practices rules, ensuring the safety and effectiveness of pharmaceutical products.