Development of a Sensitive Headspace Gas Chromatography-Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients

Wisut Wichitnithad; Orawan Sudtanon; Pawadee Srisunak; Kamonrak Cheewatanakornkool; Siriwan Nantaphol; Pornchai Rojsitthisak

doi:10.1021/acsomega.1c00982

Development of a Sensitive Headspace Gas Chromatography-Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients

ACS Omega. 2021 Apr 16;6(16):11048-11058. doi: 10.1021/acsomega.1c00982. eCollection 2021 Apr 27.

Authors

Wisut Wichitnithad^{1

2}, Orawan Sudtanon¹, Pawadee Srisunak¹, Kamonrak Cheewatanakornkool¹, Siriwan Nantaphol², Pornchai Rojsitthisak^{3

4}

Affiliations

¹ Department of Analytical Development, Pharma Nueva Co., Ltd., Vibhavadi Rangsit Road, Bangkok 10900, Thailand.
² Department of Clinical Development, Pharma Nueva Co., Ltd., Vibhavadi Rangsit Road, Bangkok 10900, Thailand.
³ Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Phayathai, Bangkok 10330, Thailand.
⁴ Natural Products for Ageing and Chronic Diseases Research Unit, Chulalongkorn University, Phayathai, Bangkok 10330, Thailand.

Abstract

Nitrosamine impurities in angiotensin II receptor antagonists (sartans) containing a tetrazole group represent an urgent concern for active pharmaceutical ingredient (API) manufacturers and global regulators. Regarding safety, API manufacturers must develop methods to monitor the levels of each nitrosamine impurity before individual batch release. In this study, we developed and validated a sensitive, selective, and high-throughput method based on headspace gas chromatography-mass spectrometry (HS-GC-MS) for the simultaneous determination of four nitrosamines in losartan potassium API with simple sample preparation. N-Nitrosodimethylamine (NDMA, m/z 74), N-nitrosodiethylamine (NDEA, m/z 102), N-nitrosoethylisopropylamine (EIPNA, m/z 116), and N-nitrosodiisopropylamine (DIPNA, m/z 130) levels were quantified using an electron impact, single quadrupole mass spectrometer under a selected-ion-monitoring acquisition method. The method was validated according to the Q2(R1) ICH guidelines. The calibration curves of the assay ranged from 25 to 5000 ng/mL with limits of quantitation of 25 ppb for NDMA and NDEA and 50 ppb for DIPNA and EIPNA. The accuracy of the developed method ranged from -7.04% to 7.25%, and the precision %CV was ≤11.5. Other validation parameters, including specificity, stability, carryover, and robustness, met the validation criteria. In conclusion, the developed method was successfully applied for the determination of nitrosamines in losartan potassium APIs.