Efficacy of ultraviolet irradiation of pharmaceutical excipients in mitigating N-nitrosamine generation

The generation of N-nitrosamine compounds (NOCs) in drugs presents a critical regulatory challenge owing to their potential mutagenicity and exceptionally strict acceptable intake limits required for patient safety. These impurities arise primarily from the reaction between amine-containing active pharmaceutical ingredients and trace amounts of nitrosating agents (reactive NOx), which contribute to N-nitrosation. Reactive NOx species are frequently found in pharmaceutical excipients. Therefore, efficiently reducing reactive NOx is essential for robust management of the risk posed by NOCs. In this study, we employed ultraviolet (UV) irradiation of excipients as a novel preemptive strategy to reduce reactive NOx levels. Desloratadine was used as a secondary amine model to evaluate the generation of N-nitrosamine in physical mixtures with various excipients. The excipients were exposed to different UV wavelengths (248, 313, and 365 nm), and N-nitrosodesloratadine (NDLRT) generation was quantified after storage under stress conditions. We found that 365 nm UV irradiation was the most effective in reducing reactive NOx under all conditions. In a formulation study, 365 nm UV irradiation successfully reduced NDLRT generation in the tablet by 54-68% compared with the control. Overall, the novel strategy described herein should be useful for reducing NOCs without affecting the quality of drugs.