A Bayesian Approach to Kinetic Modeling of Accelerated Stability Studies and Shelf Life Determination.

Kinetic modeling of accelerated stability data serves an important purpose in the development of pharmaceutical products, providing support for shelf life claims and expediting the path to clinical implementation. In this context, a Bayesian kinetic modeling framework is considered, accommodating different types of nonlinear kinetics with temperature and humidity dependent rates of degradation and accounting for the humidity conditions within the packaging to predict the shelf life. In comparison to kinetic modeling based on nonlinear least-squares regression, the Bayesian approach allows for interpretable posterior inference, flexible error modeling and the opportunity to include prior information based on historical data or expert knowledge.

Solid State Kinetics of Nitrosation Using Native Sources of Nitrite.

While many reactive species are known to cause N-nitrosation, trace nitrite (NO), which may be present in several excipients, is a source of nitrosating agents in pharmaceutical formulations. In this study we have found that the salt form of NO can influence the favored nitrosation conditions and final amount of nitrosamine being formed. Using native levels of NO, most likely present as ammonium nitrite (NHNO), in microcrystalline cellulose, we have determined the kinetics of nitrosamine formation in solid state with dimethylamine substrate present in metformin, used as model compound.

Catalytic Aerobic Oxidation of C(sp )-H Bonds.

Oxidation reactions are a key technology to transform hydrocarbons from petroleum feedstock into chemicals of a higher oxidation state, allowing further chemical transformations. These bulk-scale oxidation processes usually employ molecular oxygen as the terminal oxidant as at this scale it is typically the only economically viable oxidant. The produced commodity chemicals possess limited functionality and usually show a high degree of symmetry thereby avoiding selectivity issues.

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen.

The methylene group of various substituted 2- and 4-benzylpyridines, benzyldiazines and benzyl(iso)quinolines was successfully oxidized to the corresponding benzylic ketones using a copper or iron catalyst and molecular oxygen as the stoichiometric oxidant. Application of the protocol in API synthesis is exemplified by the alternative synthesis of a precursor to the antimalarial drug Mefloquine. The oxidation method can also be used to prepare metabolites of APIs which is illustrated for the natural product papaverine.

Mechanism of the Cu-catalyzed benzylic oxygenation of (aryl)(heteroaryl)methanes with oxygen.

A mechanistic study of the copper-catalyzed oxidation of the methylene group of aryl(di)azinylmethanes was performed. Initial reaction rates were measured making use of IR reaction monitoring and a kinetic analysis of the reaction was executed. The reaction proved to be first order in oxygen concentration.