In silico prediction of pharmaceutical degradation pathways: a benchmarking study.

Zeneth is a new software application capable of predicting degradation products derived from small molecule active pharmaceutical ingredients. This study was aimed at understanding the current status of Zeneth's predictive capabilities and assessing gaps in predictivity. Using data from 27 small molecule drug substances from five pharmaceutical companies, the evolution of Zeneth predictions through knowledge base development since 2009 was evaluated. The experimentally observed degradation products from forced degradation, accelerated, and long-term stability studies were compared to Zeneth predictions. Steady progress in predictive performance was observed as the knowledge bases grew and were refined. Over the course of the development covered within this evaluation, the ability of Zeneth to predict experimentally observed degradants increased from 31% to 54%. In particular, gaps in predictivity were noted in the areas of epimerizations, N-dealkylation of N-alkylheteroaromatic compounds, photochemical decarboxylations, and electrocyclic reactions. The results of this study show that knowledge base development efforts have increased the ability of Zeneth to predict relevant degradation products and aid pharmaceutical research. This study has also provided valuable information to help guide further improvements to Zeneth and its knowledge base.

The Degradation Chemistry of Farglitazar and Elucidation of the Oxidative Degradation Mechanisms.

The chemical degradation of farglitazar (1) was investigated using a series of controlled stress testing experiments. Farglitazar drug substance was stressed under acidic, natural pH, basic, and oxidative conditions in solution. In the solid state, the drug substance was stressed with heat, high humidity, and light. Farglitazar was found to be most labile toward oxidative stress. A series of mechanistic experiments are described in which the use of 18O-labelled oxygen demonstrated that oxidative degradation of farglitazar is caused primarily by singlet oxygen formed under thermal conditions. Major degradation products were isolated and fully characterized. Mechanisms for the formation of degradation products are proposed. Drug product tablets were also stressed in the solid state with heat, high humidity, and light. Stressed tablets afforded many of the same degradation products observed during drug substance stress testing, with oxidation again being the predominant degradation pathway. Evidence for the activity of singlet oxygen, formed during thermal stress testing of the solid oral dosage form, is presented. The degradation pathways observed during stress testing matched those observed during long-term stability trials of the drug product.

The use of N-methylpyrrolidone as a cosolvent and oxidant in pharmaceutical stress testing.

The use of N-methylpyrrolidone (NMP) as an oxidant and cosolvent in pharmaceutical stress testing (forced degradation) is examined. Various active pharmaceutical ingredients were heated in NMP-water solutions under nitrogen, air, and oxygen and then analyzed by high-performance liquid chromatography, usually with ultraviolet diode array detection and mass spectrometry detection. In some cases, degradation products were isolated and characterized by nuclear magnetic resonance. The NMP-water-air-heat system provided oxidative and hydrolytic degradation products. The observed oxidation products were consistent with products expected from free radical autoxidation, reactions with hydroperoxides, and possibly singlet oxygen. Oxidative and hydrolytic pathways could be distinguished by comparison of the reactions carried out under air/oxygen and nitrogen. In many cases, the oxidation products observed during stress testing were also observed during formal stability studies of drug products. The NMP-water-air-heat stress condition facilitates various oxidative degradation pathways, which are often relevant to drug product on stability. This approach facilitates stability-indicating method development and helps elucidate degradation pathways.