title: Photochemical stability of 4'-azido-2'-deoxy-2'-methylcytidine hydrochloride: structural elucidation of major degradation products by LC-MS and NMR analysis.
abstract: The photochemical stability of (1'R,2'S,3'S,4'R)-4'-azido-2'-deoxy-2'-methylcytidine hydrochloride, a new anti-HCV agent, was investigated. Aqueous solutions and bulk drug powder of the drug candidate were exposed to UV-visible light, complying with ICH requirements. The nucleoside analog decomposed via loss of nitrogen to yield products derived from a highly reactive azide intermediate. Major photolysis products were identified by LC-MS and NMR analysis, revealing three main photodegradation pathways. The first one led to the formation of a ring-expanded imidate ester. The other degradation pathways involved exocyclic or endocyclic bond cleavage with imine or imino lactone formation. The latter were prone to rapid hydrolysis, eventually resulting in the release of cytosine, 2-methyl malonaldehyde and (E)-cytosyl-2-methylpropenal.
authors: Pharmaceutical Development and Manufacturing Sciences, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. tom.huybrechts@sepspharma.com
authors: Tom
authors: T
authors: Huybrechts
authors: Maurice
authors: M
authors: Hermans
authors: Bart
authors: B
authors: Van Hoof
authors: Guy
authors: G
authors: Winderickx
authors: Carla
authors: C
authors: De Neef
authors: Steven
authors: S
authors: Hostyn
authors: Sara
authors: S
authors: Vrielynck
authors: Wim
authors: W
authors: Vermeulen
mesh_terms: D000998:Antiviral Agents / Q000032:analysis / Q000737:chemistry / Q000528:radiation effects*; D002851:Chromatography, High Pressure Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry / Q000528:radiation effects; D004355:Drug Stability; D004356:Drug Storage; D006868:Hydrolysis; D008027:Light; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010782:Photolysis; D011208:Powders; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D014466:Ultraviolet Rays
chemical_list: D000998:Antiviral Agents; D011208:Powders; D003841:Deoxycytidine; C578070:4'-azido-2'-deoxy-2'-methylcytidine