정초희 (중앙대학교)

한상범 (중앙대학교)

정초희 (중앙대학교)

한상범 (중앙대학교)

Nitrosamine drug-substance-related impurities (NDSRIs) present a major pharmaceutical liability, yet reference standards exist for <5% of regulatory targets. Although trace-level toxicity mandates sensitive MS detection, conventional synthesis requires harsh conditions, and electrochemistry necessitates supporting electrolytes that require tedious pre-treatment, hindering rapid analysis. To address this, an electrolyte- and acid-free electrochemical platform was developed utilizing tert-butyl nitrite (TBN) and electrons at room temperature. Anodic oxidation of TBN generates an  equivalent to mediate N-nitrosation, yielding electrolyte-free mixtures analyzed directly via dilute-and-shoot LC-Q-TOF-MS without any prior desalting or auxiliary purification steps. The platform successfully confirmed N-nitroso products for 17 APIs (mass accuracy ), yielding up to a 77-fold increase in formation over conventional assays. Furthermore, correlating LC-MS/MS yields with ORCA-computed DFT oxidative stability parameters successfully predicted substrate-dependent reactivity, establishing a robust toxicity assessment framework (= -0.955 for 8 calibrated APIs). This dual platform offers high potential for preparative scale-up to secure scarce NDSRI standards, advancing pharmaceutical risk assessment.