Development of a dynamic multiple reaction monitoring LC-APCI-MS/MS method for quantification of ten nitrosamines in ranitidine API with simple extraction approach

Abstract

Nitrosamines (NAs) are classified as probable or possible human carcinogens by the International Agency for Research on Cancer (IARC) and the presence of these impurities has resulted in numerous drug recalls from the market. In April 2020, ranitidine which is prescribed to reduce the amount of acid secreted by the stomach has been recalled owing to contamination with NAs. In this work, a simple and sensitive method for simultaneous determination of 10 NAs were developed, utilizing atmospheric pressure chemical ionisation source coupled liquid chromatography tandem mass spectrometer (LC-APCI-MS/MS). By performing dynamic multiple reaction monitoring (dMRM) mode, 10 NAs were separated on a Poroshell HPH C18 (4.6 x 150 mm, 2.7 µm) column with gradient elution implementing mobile phase A consisting of 0.2 % formic acid in water and mobile phase B consisting of methanol in 17 min. The proposed analytical method was successfully implemented in active pharmaceutic ingredient (API) of ranitidine with a water-based extraction procedure. Good linearity with a correlation coefficient (R2) ≥ 0.994 was accomplished over the concentration in range of 0.5–50 ng/mL. The limits of detection (LODs) ranged in 0.06–0.17 ng/mL and limits of quantitation (LOQs) ranged in 0.21-0.58 ng/mL of the method met thresholds of US Food and Drug Administration (US-FDA) and European Medicines Agency (EMA) for testing of NAs. The accuracy of the developed method ranged from 83.1% to 111.9 % and the percent relative standard deviation (%RSD) was ≤ 8.9.

Keywords

• Ranitidine
• Liquid chromatography
• Mass spectrometry
• Simultaneous determination
• N-nitrosamines

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