Ultra‐high‐speed liquid chromatography combined with mass spectrometry detection analytical methods for the determination of nitrosamine drug substance‐related impurities

Abstract

In the present study, five simple, feasible, and sensitive Ultra‐high‐speed liquid chromatography combined with mass spectrometry detection methods, using electrospray ionization are proposed. These methods were developed and validated for the determination of four different nitrosamine drug substance‐related impurities—N‐nitrosoacebutolol, N‐nitrosobisoprolol, N‐nitrosometoprolol, and N‐nitrososotalol—in five beta blockers active pharmaceutical ingredients—acebutolol HCl, bisoprolol fumarate, metoprolol tartrate, metoprolol succinate, and sotalol HCl. The proposed methods were validated as per regulatory guidelines. Acquity HSS T3 (3.0 × 100 mm, 1.8 μm) column and formic acid 0.1% in water combined with methanol or acetonitrile were used for chromatographic separation in all methods. The limit of detection and the limit of quantification were found to be in the range of 0.02–1.2 and 2–20 parts per billion, respectively. The accuracy and precision of the five methods have been demonstrated in the working range of each one, giving values of recovery within the range of 64.1%–113.3%, and the regression coefficients (R) were found to be in the range of 0.9978–0.9999. These methods could be used for controlling nitrosamine drug substance‐related impurities content for beta blockers drug substances batches manufactured at Moehs group.