Early Prediction of Pharmaceutical Oxidation Pathways by Computational Chemistry and Forced Degradation

Abstract

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.

Weathering of Compounded Products

“…622 Photodegradation rate is nearly linear with iron concentration. 623 Frontier molecular orbital theory and bond dissociation energies were used in model studies. The proposed mechanism suggests that hydroxyl radicals are generated during degradation.…”

The Use Of N-Methylpyrrolidone as a Cosolvent and Oxidant in Pharmaceutical Stress Testing

“…6 Perhaps this diversity is best exemplified by the variety of conditions used for oxidation. Some of the conditions and reagents recommended for oxidative stress testing include oxygen headspace, 7 peroxides, 8 free radical initiators, 9 metals, 10 electrooxidation, 11 potassium permanganate (KMnO 4 ), 12 Tween 80/Fe(III), 13 glyme/Fe(II), 14 and singlet oxygen. 15 This diversity stems in part from the variety of mechanisms 16 by which a drug molecule may oxidize in a formulation: free radical autoxidation, electron transfer, photooxidation, reactions with singlet oxygen, reactions with peroxides, and so on.…”

A Novel Accelerated Oxidative Stability Screening Method for Pharmaceutical Solids

“…Oxidation has been a major degradation route for pharmaceuticals, second only to hydrolysis. 1,2 The following primary oxidative degradation mechanisms have been known: autoxidation (free radical mediated), nucleophilic/ electrophilic (peroxide mediated), electron transfer (transition metal catalysis), and photochemicallyinduced oxidation. [3][4][5][6][7] A variety of oxidative stress degradation studies have been designed accordingly to probe the susceptibility of the active pharmaceutical ingredients to these mechanisms, which is usually conducted during the transition period from discovery to early development in the pharmaceutical industry.…”