Development and validation of an analytical method for trace level quantification of genotoxic nitrosamine impurities in Losartan and Hydrochlorothiazide fixed dose combination tablets using UPLC‐TQ‐MS/MS

Since June of 2018, thousands of pharmaceuticals from all over the world have been recalled due to the unexpected presence of nitrosamines. Beginning with the class of pharmaceuticals known as sartans, subsequent lines of inquiry included antidiabetic medicines, antihistamines, and antibiotics. A critical review of FDA database reveals that the highest number of product recalls due to the presence of unacceptable levels of nitrosamines are belonging to Losartan potassium drug products and it’s co-formulated with other drug substances. The problem can be mainly ascribed to naively adopted approval revisions and the lack of sufficient current analytical technologies to detect those contaminants in time. In this work, we incorporated a specific, selective, accurate, precise, and robust UPLC-TQ-MS/MS method for the estimation of eight genotoxic nitrosamine impurities present in Losartan and Hydrochlorothiazide tablets which is the only fixed dosage combination approved by FDA for management of hypertension. The separation of all the nitrosamine impurities along with drug substances was achieved using Agilent Pursuit XRs Ultra Diphenyl (150 X 2.0 mm, 2.8μ) column with Mobile phase A (0.1% formic acid in water) and Mobile phase B (0.1 % formic acid in methanol) at flow rate 0.4 mL/min by using gradient elution program. The proposed method was validated as per ICH Q2 (R1) guidelines to ensure the method is fit for its intended purpose. LOD and LOQ were obtained in the range of 0.25 ng/mL to 0.5 ng/mL is very low compared to levels specified by USFDA, EMA, and other regulatory authorities that ensure the sensitivity of the method in its entire life cycle. The developed method could be incorporated into an official monograph and applied for routine quality control analysis of Losartan and Hydrochlorothiazide fixed dose combination tablets.