PURPOSE: To show, using a model study, how electronic structure theory can be applied in combination with LC/UV/MS/MS for the prediction and identification of oxidative degradants. METHODS: The benzyloxazole 1, was used to represent an active pharmaceutical ingredient for oxidative forced degradation studies. Bond dissociation energies (BDEs) calculated at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level with isodesmic corrections were used to predict sites of autoxidation. In addition, frontier molecular orbital (FMO) theory at the Hartree-Fock level was used to predict sites of peroxide oxidation and electron transfer. Compound 1 was then subjected to autoxidation and H2O2 forced degradation as well as formal stability conditions. Samples were analyzed by LC/UV/MS/MS and degradation products proposed. RESULTS: The computational BDEs and FMO analysis of 1 was consistent with the LC/UV/MS/MS data and allowed for structural proposals, which were confirmed by LC/MS/NMR. The autoxidation conditions yielded a number of degradants not observed under peroxide degradation while formal stability conditions gave both peroxide and autoxidation degradants. CONCLUSIONS: Electronic structure methods were successfully applied in combination with LC/UV/MS/MS to predict degradation pathways and assist in spectral identification. The degradation and excipient stability studies highlight the importance of including both peroxide and autoxidation conditions in forced degradation studies.
PURPOSE: To show, using a model study, how electronic structure theory can be applied in combination with LC/UV/MS/MS for the prediction and identification of oxidative degradants. METHODS: The benzyloxazole 1, was used to represent an active pharmaceutical ingredient for oxidative forced degradation studies. Bond dissociation energies (BDEs) calculated at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level with isodesmic corrections were used to predict sites of autoxidation. In addition, frontier molecular orbital (FMO) theory at the Hartree-Fock level was used to predict sites of peroxide oxidation and electron transfer. Compound 1 was then subjected to autoxidation and H2O2 forced degradation as well as formal stability conditions. Samples were analyzed by LC/UV/MS/MS and degradation products proposed. RESULTS: The computational BDEs and FMO analysis of 1 was consistent with the LC/UV/MS/MS data and allowed for structural proposals, which were confirmed by LC/MS/NMR. The autoxidation conditions yielded a number of degradants not observed under peroxide degradation while formal stability conditions gave both peroxide and autoxidation degradants. CONCLUSIONS: Electronic structure methods were successfully applied in combination with LC/UV/MS/MS to predict degradation pathways and assist in spectral identification. The degradation and excipient stability studies highlight the importance of including both peroxide and autoxidation conditions in forced degradation studies.
Authors: Kenneth C Waterman; Roger C Adami; Karen M Alsante; Jinyang Hong; Margaret S Landis; Franco Lombardo; Christopher J Roberts Journal: Pharm Dev Technol Date: 2002-01 Impact factor: 3.133
Authors: K G Liu; M H Lambert; A H Ayscue; B R Henke; L M Leesnitzer; W R Oliver; K D Plunket; H E Xu; D D Sternbach; T M Willson Journal: Bioorg Med Chem Lett Date: 2001-12-17 Impact factor: 2.823
Authors: Karen M Alsante; Kim C Huynh-Ba; Steven W Baertschi; Robert A Reed; Margaret S Landis; Scott Furness; Bernard Olsen; Mark Mowery; Karen Russo; Robert Iser; Gregory A Stephenson; Patrick Jansen Journal: AAPS PharmSciTech Date: 2013-12-21 Impact factor: 3.246