title: Experimental and Quantum Chemical Evaluations of Pyridine Oxidation Under Drug Development Stress Test Conditions.
abstract: The oxidation reaction of pyridine by hydrogen peroxides in water media was investigated by combining quantum chemical calculations and laboratory experiments. Pyridine was selected as a model system for aromatic amines that frequently occurs in drug molecules. Several different reaction conditions, commonly used in stress testing of drug molecules during drug development, were investigated to increase mechanistic insight to this class of oxidation reactions. Of special interest is to note that small amounts of acetonitrile, a regularly used cosolvent to keep poorly soluble drug molecules in water solution, could catalyze the oxidation reaction in the presence of hydrogen peroxide. Consequently, attention needs to be taken when comparing data from different stress test studies of amine oxidation by hydrogen peroxides at different pH, and with and without acetonitrile. In particular, they need to be controlled when identifying the proper intrinsic stability of the drug molecule.
authors.affiliation: Pharmaceutical Development, AstraZeneca R&D Mölndal, Mölndal S-431 83, Sweden.
authors.forename: Carina
authors.initials: C
authors.lastname: Bäcktorp
authors.affiliation: Pharmaceutical Development, AstraZeneca R&D Mölndal, Mölndal S-431 83, Sweden.
authors.forename: Eivor
authors.initials: E
authors.lastname: Örnskov
authors.affiliation: Pharmaceutical Development, AstraZeneca R&D Mölndal, Mölndal S-431 83, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Ottosson
authors.affiliation: RIA innovative Medicines unit, AstraZeneca R&D Mölndal, Mölndal S-431 83, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Evertsson
authors.affiliation: Pharmaceutical Development, AstraZeneca R&D Mölndal, Mölndal S-431 83, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Remmelgas
authors.affiliation: Pharmaceutical Development, AstraZeneca R&D Mölndal, Mölndal S-431 83, Sweden. Electronic address: anders.broo@astrazeneca.com.
authors.forename: Anders
authors.initials: A
authors.lastname: Broo
mesh_terms: D000097:Acetonitriles / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D002384:Catalysis; D006861:Hydrogen Peroxide / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D010084:Oxidation-Reduction; D011725:Pyridines / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D000097:Acetonitriles; D000588:Amines; D011725:Pyridines; D014867:Water; D006861:Hydrogen Peroxide; C023666:pyridine; C032159:acetonitrile
keywords: CO2; H2O2; ab initio calculations; acetonitrile; amine; chemical stability; drug development; forced conditions; mechanism; oxidation