pH control of nucleophilic/electrophilic oxidation

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Abstract

Finding formulations that prevent degradation of the active pharmaceutical ingredient is an essential part of drug development. One of the major mechanisms of degradation is oxidation. Oxidative degradation is complex, and can occur via different mechanisms, such as autoxidation, nucleophilic/electrophilic addition, and electron transfer reactions. This paper uses three model compounds and determines the mechanisms of oxidation and strategies to reduce degradation. The mechanism of oxidation was established by comparing the results of different forced degradation experiments (radical initiation and peroxide addition), computational chemistry to those of formulated drug product stability. The model compounds chosen contained both oxidizable amine and sulfide functional groups. Although, both oxidative forced degradation conditions showed different impurity profiles the peroxide results mirrored those of the actual stability results of the drug product. The major degradation pathway of all compounds tested was nucleophilic/electrophilic oxidation of the amine to form N-oxide. Strategies to prevent this oxidation were explored by performing forced degradation experiments of the active pharmaceutical ingredient (API) in solution, in slurries containing standard excipient mixtures, and in solid formulation blends prepared by wet granulation. The reaction was significantly influenced by pH in solvent and excipient slurries, with 100% degradation occurring at basic pH values (>pH 8) and no degradation occurring at pH 2 upon exposure to 0.3% peroxide. Wet granulated blends were also stabilized by lowering the pH during granulation through the addition of citric acid prior to the solution of peroxide, resulting in little (0.02% maximum) or no degradation for the four different blends after 6 week storage at 40 °C/75%RH.

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