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.

Development and Validation of LC-MS/MS Method for the Determination of 1-Methyl-4-Nitrosopiperazine (MNP) in Multicomponent Products with Rifampicin—Analytical Challenges and Degradation Studies

“…The sample treatment not only enables analyte preconcentration but also removes components of the matrix that may interfere with the analysis protocol. Five methods for the determination of MNP in medicinal products have been described in the literature using LC-MS/MS, SFC-MS/MS, and GC-MS/MS, and various extraction methods, including SALLE and LLE [28][29][30][31][32]. Gas chromatography coupled with mass spectrometry was used for the determination of MNP in cetirizine, amlodipine/bisoprolol, sunitinib, olmesartan and cilostazol [28,31].…”

“…Five methods for the determination of MNP in medicinal products have been described in the literature using LC-MS/MS, SFC-MS/MS, and GC-MS/MS, and various extraction methods, including SALLE and LLE [28][29][30][31][32]. Gas chromatography coupled with mass spectrometry was used for the determination of MNP in cetirizine, amlodipine/bisoprolol, sunitinib, olmesartan and cilostazol [28,31]. Rifampicin, according to the literature and our experimental data (on GC-MS/MS), decomposes at elevated temperatures to MNP, so it was impossible to use the GC-MS/MS method for determination of MNP in rifampicin products.…”

Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers Volume II

“…Since the worldwide crisis of contamination of medicinal products with nitrosamine, effective trace-level analysis of these contaminants is of continuing importance to the quality control of medicines. Witkowska et al [ 21 ] developed a novel GC-MS method with electron ionization and microextraction for the simultaneous determination of main carcinogenic nitrosamines in a range of representative active pharmaceutical ingredients. The method demonstrated good linearity and wide limits of detection.…”