Stability and degradation pathways of N-nitroso-hydrochlorothiazide and the corresponding aryl diazonium ion

Grahek, Rok (avtor), Drev, Miha (avtor), Zupančič, Borut (avtor), Hren, Jure (avtor), Ošlaj, Matej (avtor), Bastarda, Andrej (avtor), Kocijan, Andrej (avtor), Časar, Zdenko (avtor)

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

• Jezik: Angleški jezik
• Ključne besede: hydrochlorothiazide, N-nitrosamine, thiatriazine, diazonium, structure determination, degradation, reactivity, reaction mechanism
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2023
• Št. strani: Str. 1792–1811
• Številčenje: Vol. 27, iss. 10
• PID: 20.500.12556/RUL-152285
• UDK: 615
• ISSN pri članku: 1083-6160
• DOI: 10.1021/acs.oprd.3c00119
• COBISS.SI-ID: 169515523
• Datum objave v RUL: 16.11.2023

Gradivo je del revije

• Naslov: Organic process research & development
• Skrajšan naslov: Org. process res. dev.
• Založnik: American Chemical Society
• ISSN: 1083-6160
• COBISS.SI-ID: 3490842

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.