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

Artifacts Generated During Azoalkane Peroxy Radical Oxidative Stress Testing of Pharmaceuticals Containing Primary and Secondary Amines

“…The drug amine group reacts with formaldehyde to form the imine intermediate, which further reacts with cyanide (Scheme 5), explaining the incorporation of the nitrile and methylene groups observed during the labeling experiments. Previous reports showing formation of cyanide and acetone cyanohydrin during AIBN-initiated oxidation of benzene, 22 as well as formation of formaldehyde during the oxidative stress test carried out in the presence of methanol, 8 support the proposed mechanism. Table 2 shows our own measurements of cyanide levels generated during the thermal stress of AIBN in the absence of the test drug.…”

“…The role of AIBN peroxy radicals in generating artifactual degradation was first indicated by Nelson et al 8 and recently demonstrated by Watkins et al 14 The authors showed that addition of a small amount of methanol to the solvent system effectively prevented the alkoxy radicals from encountering and reacting with the dilute drug substance, by providing a sacrificial H atom donor. The use of methanol has been generally adopted in the recent years 12 and has greatly improved the correlation of the azoalkane stress test results with the actual, long term, drug product stability results.…”

“…The solution stress test involves peroxy radical formation via thermal decomposition of azo compounds and is designed to accelerate oxidative kinetics so as to induce in a short period of time an observable response for molecules susceptible to autoxidation induced by peroxy radical attack . Because of the complexity of the oxidative system, the test has historically suffered from some selectivity issues in creating the peroxy radical activity, allowing artifactual degradation to be observed . The current study represents another step in refining the test conditions and understanding its limitations.…”

“…7 Because of the complexity of the oxidative system, the test has historically suffered from some selectivity issues in creating the peroxy radical activity, allowing artifactual degradation to be observed. 8 The current study represents another step in refining the test conditions and understanding its limitations.…”

Realistic Prediction of Solid Pharmaceutical Oxidation Products by Using a Novel Forced Oxidation System

“…12,13 For this reason, oxidation is associated with a high risk of generating potentially genotoxic impurities. Many previous studies have described approaches for studying oxidative mechanisms, including autoxidation prediction using free radical initiators, [14][15][16][17] the use of N-methylpyrrolidone 18 and Tween80/Fe 3+ , 19 nucleophilic/ electrophilic oxidation prediction with peroxides, 3,4,20,21 electron transfer oxidation prediction with transition metals, 5 electro-oxidation prediction with voltammetry, 22 and prediction of photochemically induced oxidation with a photosensitizer. 6 Indeed, these approaches have been used in the pharmaceutical industry, often producing useful information relating to oxidation susceptibility that has been helpful in pharmaceutical development.…”