pH control of nucleophilic/electrophilic oxidation

International Journal of Pharmaceutics
Anita L FreedCarol A Kingsmill

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, i...Continue Reading

Citations

Dec 27, 2011·Expert Opinion on Drug Delivery·Josias Hamman, Jan Steenekamp
Apr 24, 2014·Drug Development and Industrial Pharmacy·Kalle SigfridssonYudong Wang
Apr 1, 2011·Journal of Pharmaceutical Sciences·Changkang PanMichael Motto
Apr 15, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Nagsen GautamYazen Alnouti

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