Photodegradation of aqueous argatroban investigated by LC/MSn: Photoproducts, transformation processes and potential implications.
Argatroban (ARGA), used as intravenous anticoagulant drug, has been reported to photodegrade under light exposure, requiring specific precautions at handling, storage and administration. Thus, for the first time, aqueous ARGA photodegradation under aerobic conditions has been described in terms of photoproducts, phototransformation processes and potential implications. ARGA significant photoproducts were successfully separated and characterized by gradient reversed-phase liquid chromatography coupled with high-resolution multistage mass spectrometry (LC/HR-MSn). Hitherto still not available in literature, ARGA in-depth fragmentation study was conducted so as to thoroughly sort out the main mechanisms specific to the molecule and therefore, to propose a fragmentation pattern relevant to the identification of ARGA related substances. Thereafter, in view of the structural characteristics of the photoproducts formed, ARGA photodegradation pathways could be worked out, showing that whether by direct photolysis or through photosensitization, the methyltetrahydroquinoline nitrogen and that of guanidine group would be mainly involved in photolysis initiation reactions, through one-electron oxidation along with proton loss. Desulfonation, cyclisation affording compounds of diazinane type, and/or rearrangements with transfer of the methyltetrahydroquinoline group toward the guanidine function were observed accordingly. Having a good insight into ARGA photodegradation pathways allows for consistent measures in view of mitigating or avoiding the drug decay and the related potential effects.
University of Paris-Sud, Department of Pharmacy, Laboratory "Matériaux et Santé" EA 401, 5 rue Jean Baptiste Clément, 92296 Châtenay-Malabry, France. Electronic address: philippe-henri.secretan@u-psud.fr.
Philippe-Henri
PH
Secrétan
University of Paris-Sud, Department of Pharmacy, Laboratory "Matériaux et Santé" EA 401, 5 rue Jean Baptiste Clément, 92296 Châtenay-Malabry, France; University of Monastir, Department of Pharmacy, Analytical Chemistry Laboratory, rue Ibn Sina, 5000 Monastir, Tunisie.
Maher
M
Karoui
University of Paris-Sud, Department of Pharmacy, Laboratory "Matériaux et Santé" EA 401, 5 rue Jean Baptiste Clément, 92296 Châtenay-Malabry, France; Assistance Publique-Hôpitaux de Paris, Agence Générale des Equipements et Produits de Santé, Quality Control and Analytical Development Laboratory, 7 rue du Fer à Moulin, 75005 Paris, France.
Mélisande
M
Bernard
University of Paris-Sud, Department of Pharmacy, CNRS UMR 8612 Institut Galien Paris-Sud, LabEx LERMIT, 5, rue Jean Baptiste Clément, 92296 Châtenay-Malabry, France.
Noureddine
N
Ghermani
University of Monastir, Department of Pharmacy, Analytical Chemistry Laboratory, rue Ibn Sina, 5000 Monastir, Tunisie.
Fathi
F
Safta
University of Paris-Sud, Department of Pharmacy, Laboratory "Matériaux et Santé" EA 401, 5 rue Jean Baptiste Clément, 92296 Châtenay-Malabry, France.
Najet
N
Yagoubi
University of Paris-Sud, Department of Pharmacy, Laboratory "Matériaux et Santé" EA 401, 5 rue Jean Baptiste Clément, 92296 Châtenay-Malabry, France; Assistance Publique-Hôpitaux de Paris, Groupe hospitalier Henri Mondor, Department of Pharmacy, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
Bernard
B
Do
D001120:Arginine / Q000031:analogs & derivatives; D056148:Chromatography, Reverse-Phase / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D010782:Photolysis; D010875:Pipecolic Acids / Q000032:analysis*; D013449:Sulfonamides
D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban
Argatroban; Drug degradation; Fragmentation pattern; LC–MS(n); Photodegradation pathways; Radical initiation sites