Ultra‐Trace Level Quantification of N‐Nitroso Metoprolol Content in Metoprolol Tartrate and Hydrochlorothiazide Tablets Using LC‐MS/MS

ABSTRACT Hypertension is considered the most prevalent risk factor for cardiovascular diseases, affecting about 45% of adults. Metoprolol tartarate, a beta‐blocker drug, alone or in combination with other hypertensive drugs such as hydrochlorthiazide, is used in the management of hypertension as fixed‐dose combinations. Reports of unacceptable levels of Nitroso‐Drug Substance Related Impurities and subsequent recalls of FDCs have seen a surge in recent days. Various regulatory agencies have set up a limit of 1500 ng/day for N‐Nitrosometoprolol. A highly sensitive, rapid, and accurate LC‐MS/MS method for determining N‐Nitrosometoprolol in Metoprolol Tartrate and Hydrochlorothiazide tablet formulations is reported herewith. The separation was achieved on C18 Phenomenex Luna (5 µm × 150 × 4.6 mm) using a gradient mobile phase composition. The method was validated comprehensively as per ICH Q2 guidelines, demonstrating linearity from 0.084 to 3.375 ng/mL levels with a coefficient of determination ( R 2 ) at 0.99977. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 0.042 and 0.084 ng/mL, respectively. Recoveries for the range of 80%–120% for N‐Nitrosometoprolol was found satisfactory, and precision limits were less than 2%. Thus, the given method can be used for routine analysis of N‐Nitrosometoprolol content in Metoprolol Tartrate and Hydrochlorothiazide tablets.