Journal of Pharmaceutical Sciences 2009-03-01

Solvent effects on the AIBN forced degradation of cumene: Implications for forced degradation practices.

Eric D Nelson, Gina M Thompson, Ye Yao, Holly M Flanagan, Paul A Harmon

Index: J. Pharm. Sci. 98(3) , 959-69, (2009)

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Abstract

Solvent effects on the AIBN and ACVA forced degradation of cumene are explored. The degradant formation rates of the three cumene oxidative degradants, cumene hydroperoxide, acetophenone, and 2-phenyl-2-propanol are reported. The relative abundance and ratios of these three degradants provide insight into the fate of the peroxy radical oxidants generated by the forced stress system, and suggest that alkoxy radicals are actually a significant source of the observed reactivity. The presence of even 1% methanol in the forced stress solvent significantly quenches this alkoxy radical reactivity, dramatically reducing the overall degradation rate and leaving cumene hydroperoxide as the major product of the oxidation reaction. The origin of this significant solvent effect on the oxidation product distribution is shown to be related to the preferential H-atom abstraction from methanol and its trace impurities by any alkoxy radicals present in the reaction solution. The implications for these observations are explored with the intent of producing more predictive oxidative forced stress experiments.(c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association