Stability and Degradation Pathways of <i>N</i>-Nitroso-Hydrochlorothiazide and the Corresponding Aryl Diazonium Ion

Despite the fact that it was put on market more than 60 years ago, hydrochlorothiazide (HCT) is still one of most important antihypertensive drugs. Due to its chemical structure, which contains secondary aryl-alkyl-amino moiety, vulnerable formation N-nitrosamine drug substance-related impurity (NDSRI) N-nitroso-hydrochlorothiazide (NO-HCT). In our study, we reveal NO-HCT degrades rapidly at pH values 6 8. The main degradation products identified are formaldehyde, thiatriazine, and aminobenzenesulfonic acid derivative. Interestingly, from 5 1 significantly slower provides a different profile when compared generated between Specifically, 5, HCT observed as key in addition formaldehyde acid. Moreover, 1, derivative transformed corresponding diazonium salt approximately 3% yield with nitrosyl cation, released during decomposition HCT. This highly unstable above 5. To verify does not produce could be formed via metabolic activation NO-HCT, this hydrolytic reduction were synthesized used standards for identification species NO-HCT. enabled us confirm aryl salt, would obtained pathway. Our study also demonstrates stable only presence large excess strong mineral under anhydrous conditions. water, instantaneously converted an These findings suggest should considered typical compound belonging cohort concern.