Determination of N-Nitroso-Nebivolol in Nebivolol Drug Substance by LCMS-2050

User Benefits

- A new method for the determination of NDSRI impurity in nebivolol raw material was established using LCMS-2050. - The method has high sensitivity, short analysis time and high accuracy, which can fully meet the FDA's AI limit for N-Nitroso-nebivolol.

Introduction

On September 4, 2024, the FDA issued the final guidance on the control of nitrosamine impurities in human drugs (Nitrosamine Guidance Version 2). The revised guidance describes two categories of nitrosamines: small-molecule nitrosamines and nitrosamine drug substance-related impurities (NDSRIs). Unlike small-molecule nitrosamine impurities that are structurally dissimilar to the active pharmaceutical ingredient (API), NDSRIs generally exhibit structural similarity to the API and may form through interactions between the API and nitrosating agents, such as nitrite impurities present in drug excipients. Nebivolol is a potent and selective third-generation β-blocker clinically used for the treatment of patients with moderate-to-severe hypertension, as well as angina pectoris and congestive heart failure, with a recommended daily dose of 5 mg. Due to its structural characteristics, the synthesis of nebivolol may involve nitrosation reactions, leading to the introduction of the NDSRI impurity N-nitroso-nebivolol. According to the FDA's nitrosamine guidance, based on the Carcinogenic Potency Categorization Approach (CPCA), the acceptable intake (AI) limit for N-nitroso-nebivolol, a potential NDSRI in nebivolol, is set at 1500 ng/day. This study established an LC-MS (LCMS-2050) method for the determination of N-nitroso-nebivolol in nebivolol drug substance. The method demonstrates high sensitivity, short analysis time, and accurate results, providing a reference for the detection of related nitrosamine impurities.

September 29, 2025 GMT