Evaluation of Solution Oxygenation Requirements for Azonitrile-Based Oxidative Forced Degradation Studies of Pharmaceutical Compounds

Solvent Effects on the AIBN Forced Degradation of Cumene: Implications for Forced Degradation Practices

“…However, the use of even small amounts of methanol as a reaction additive prevents this effect. If one accepts the premise that the purpose of such stress solutions is to mimic peroxy radical chemistry,4–6 then it follows that it is prudent to select a solvent system that is not prone to this issue. We have found that acetonitrile/methanol/water systems serve this role well, and commonly use 5% methanol in control experiments to quench alkoxy radical activity of the AIBN forced degradation experiment.…”

“…Practices for oxidative forced degradation are particularly subject to interpretation 3. Recently, there has been a resurgence of interest in evaluating how the meaningfulness and predictive power of oxidative forced degradation can be increased and improved 4, 5. A survey of industry practices in 2003 suggested a wide variety of oxidation conditions, including a growing trend of the use of azonitrile radical initiators such as AIBN (2, 2′‐azobisisobutyronitrile) and ACVA (4,4′‐azobis‐4‐cyanovaleric acid) to purposefully induce peroxy radical oxidation of drug substance in solution 2…”

“…The implications of these observations for the general practice of oxidative forced degradation experiments are discussed. These observations are particularly relevant to drug‐sparing forced degradation experiments, as the disproportionation of the desired peroxy radical oxidizing species into alkoxy radicals are more likely when low drug concentrations are used 4…”

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

“…9 When heated, AIBN and ACVA generate two alkyl free radicals and a molecule of nitrogen. The alkyl free radicals react rapidly with oxygen to form peroxy radicals, which in turn may abstract labile hydrogen atoms on a drug molecule forming an API radical and a hydroperoxide.…”

“…Degradation products of API resulting from radical formation and reactions with peroxides are thus facilitated by these conditions. 9 Hence, free radical/oxygen conditions mimic autoxidation and can be predictive of autoxidation in drug products. One possible problem with use of AIBN is the formation of adducts with an API (e.g., Michael receptors).…”