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

Nefliu, Marcela; Zelesky, Todd; Jansen, Patrick J.; Sluggett, Gregory W.; Foti, C.; Baertschi, Steven W.; Harmon, Paul A.

doi:10.1002/jps.24667

Cited by 8 publications

(13 citation statements)

References 22 publications

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“…At basic pH, hydrogen cyanide (pK a = 9.4 91 ) is converted into cyanide anion, which is believed to contribute, along with formaldehyde, to artifact generation in the degradation products of APIs. 13 Cyanide anion facilitates the Strecker reaction, which yields α-aminonitrile, containing primary or secondary amine motifs. At the conditions studied here, the concentration of hydrogen cyanide reaches ∼1 mM (Figure 6).…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, the presence of methanol induces byproducts such as formaldehyde, which was reported to facilitate the Strecker reaction (amine conversion into aminonitrile) in this system. 13 A representative AIBN/H 2 O/CH 3 OH stress-testing system is considered in the present work. The exact radical chemistry of this important system is complicated and not well understood.…”

Section: Introductionmentioning

confidence: 99%

“…Three types of oxidative stress testing are commonly used: (1) using hydrogen peroxide to cover nucleophilic-electrophilic (2-electron) oxidations, (2) using azoalkanes to cover free-radical oxidation, and (3) using transition metals to cover single electron transfer oxidations. Free radical oxidative pathways are better discovered by the use of radical initiators such as 2,2′-azobis(2-methylpropionitrile) (azobis(isobutyronitrile), or AIBN), rather than using hydrogen peroxide or through regulation of temperature and oxygen levels. , A radical initiator can be used to generate known fluxes of peroxyl radicals since its decomposition rate is often known. , While several azoalkanes are used for stress testing, usage of AIBN as a radical initiator is relatively common. − …”

Section: Introductionmentioning

confidence: 99%

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

Dana

Ranasinghe

et al. 2021

Mol. Pharmaceutics

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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)

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Dana

Ranasinghe

et al. 2021

Mol. Pharmaceutics

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“…At basic pH, hydrogen cyanide (pK a = 9.4 [90]) is converted into cyanide anion, which is believed to contribute, along with formaldehyde, to artifact generation in the degradation products of APIs. [13] Cyanide anion facilitates the Strecker reaction, which yields α-aminonitrile, containing primary or secondary amine motifs. At the conditions studied here, the concentration of hydrogen cyanide reaches ∼ 1 mM (Fig.…”

Section: Modelingmentioning

confidence: 99%

“…[7,8] While several azoalkanes are used for stress testing, [9] usage of AIBN as a radical initiator is relatively common. [9,10,11,12,13,14,15,16] Upon homolysis, AIBN, a symmetrical azo-compound, yields two cyanoisopropyl radicals which quickly produce cyanoisopropyl peroxyl radicals in the presence of molecular oxygen. Peroxyl radicals are considered the primary reactive oxygen species involved in free radical oxidative processes of an API.…”

Section: Introductionmentioning

confidence: 99%

Kinetic Modeling of API Oxidation: 1. The AIBN/H2O/CH3OH Radical "Soup"

Dana

Wu²,

Ranasinghe³

et al. 2021

Preprint

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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)/H2O/CH3OH 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.

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