title: Evaluation of solution oxygenation requirements for azonitrile-based oxidative forced degradation studies of pharmaceutical compounds.
abstract: AIBN and ACVA oxidative forced degradation models are examined for two drug molecules whose predominant oxidation chemistries arise from different reaction mechanisms (i.e., free radical vs. nucleophilic). Stress was conducted under a variety of initiator concentrations, and under ambient and pressurized oxygen atmospheres. In each case examined, the azonitrile initiator solutions served as a good predictive model of the major oxidative degradation products observed in pharmaceutical formulations. At low to moderate inititator concentrations, the degradation product distributions and degree of reactivity were similar for samples stored in ambient and pressurized oxygen environments. These results are rationalized with reference to the oxygen consumption kinetics of AIBN and ACVA solutions as a function of initiator concentration. The data suggests that ambient air provides sufficient oxygen to enable chain propagation of peroxy radicals in azonitrile solutions of concentrations appropriate to the forced degradation of pharmaceutical compounds.
authors.affiliation: Pharmaceutical Research and Development, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. Eric_Nelson2@Merck.com
authors.forename: Eric D
authors.initials: ED
authors.lastname: Nelson
authors.forename: Paul A
authors.initials: PA
authors.lastname: Harmon
authors.forename: Renee C
authors.initials: RC
authors.lastname: Szymanik
authors.forename: Martin G
authors.initials: MG
authors.lastname: Teresk
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Randal A
authors.initials: RA
authors.lastname: Seburg
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reed
mesh_terms: D000097:Acetonitriles / Q000737:chemistry; D001391:Azo Compounds / Q000737:chemistry*; D009570:Nitriles / Q000737:chemistry*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000032:analysis / Q000737:chemistry*; D010545:Peroxides / Q000737:chemistry; D004364:Pharmaceutical Preparations; D014631:Valerates / Q000737:chemistry*
chemical_list: D000097:Acetonitriles; D001391:Azo Compounds; D009570:Nitriles; D010545:Peroxides; D004364:Pharmaceutical Preparations; D014631:Valerates; C091250:4,4'-azobis(4-cyanovaleric acid); C004526:azobis(isobutyronitrile); D010100:Oxygen; C032159:acetonitrile