Kinetic Modeling of API Oxidation: (1) The AIBN/H₂O/CH₃OH Radical “Soup”

Abstract

While different flavors of API stress testing systems have been used in experimental investigations for decades, the detailed kinetics of such systems as well as the chemical composition of prominent reactive species, specifically reactive oxygen species, are unknown.As a first step toward understanding and modeling API oxidation in stress testing, we investigated a typical radical "soup" solution an API is subject to during stress testing.Here we applied ab-initio electronic structure calculations to automatically generate and refine a detailed chemical kinetics model, taking a fresh look at API oxidation.We generated a detailed kinetic model for a representative azobisisobutyronitrile (AIBN)/H 2 O/CH 3 OH stress-testing system with varied co-solvent ratio (50%/50% --99.5%/0.5% vol. water/methanol) and for representative pH values (4--10) at 40oC stirred and open to the atmosphere.At acidic conditions hydroxymethyl alkoxyl is the dominant alkoxyl radical, and at basic conditions, for most studied initial methanol concentrations, cyanoisopropyl alkoxyl becomes the dominant alkoxyl radical, albeit at an overall lower concentration.At acidic conditions the levels of cyanoisopropyl peroxyl, hydroxymethyl peroxyl, and hydroperoxyl radicals are relatively high and comparable, while at both neutral and basic pH conditions, superoxide becomes the prominent radical in the system.The present work reveals the prominent species in a common model API stress testing system at various co-solvent and pH conditions, sets the stage for an in-depth quantitative API kinetic study, and demonstrates usage of novel software tools for automated chemical kinetic model generation and ab-initio refinement. File list (2) download file view on ChemRxiv 2021.04.01 a The Soup.pdf (5.01 MiB) download file view on ChemRxiv 2021.01.29 a Soup SI.pdf (1.02 MiB)

Kinetic Modeling of API Oxidation: (2) Imipramine Stress Testing

“…The AIBN-initiated oxidative degradation kinetics of imipramine were simulated using methods detailed in Section . The chemistry of the radical “soup,” was modeled in our previous work and served as a foundation for the present study. We modeled imipramine degradation at pH values of 6 and 11, consistent with our experimental conditions.…”

“…Generating first-principles kinetic models of API degradation requires a collection of computer programs (Figure , box 2b), as described in our previous work on modeling the stress testing system itself . An overview of the required software is given here, followed by subsections containing specific methodological details.…”

“…In the previous publication, we presented the detailed kinetic model of the AIBN/H 2 O/CH 3 OH stress testing system itself ( i.e. , the “soup”), which was generated by APIOxy.…”

“…This work is the second in a series describing the kinetic modeling of API oxidation . Here, we demonstrate the value and potential of ab initio kinetic modeling for API degradation via a case study of imipramine (Figure ), an API used in the treatment of depression, diabetic neuropathy, and panic disorder .…”

“…Imipramine is an ideal compound for initial studies that employ new technologies because its modest size is computationally tractable for high-level QM methods and its intrinsic susceptibility toward oxidative degradation is an active area of research. − The goal of the present work is to build a quantitative kinetic model for the radical-initiated oxidation ( i.e. , autoxidation) of imipramine in the azobis­(isobutyronitrile) (AIBN)/H 2 O/CH 3 OH “forced degradation” system . To validate our approach, we will compare the model’s predicted degradation products with both the predictions made using Zeneth and the observed products from experimental stress tests performed in the present work.…”