Theoretical and Experimental Investigation of Autoxidation Propensity of Selected Drugs in Solution State

Abstract

The C−H bond dissociation energy (BDE) of drug molecules is often used to estimate their relative propensities to undergo autoxidation. BDE calculations based on electronic structures provide a convenient means to estimate the risk for a given compound to degrade via autoxidation. This study aimed to verify the utility of calculated C−H BDEs of a range of drug molecules in predicting their autoxidation propensities, in the solution state. For the autoxidation study, 2,2′-azobis (2methylpropionitrile) was employed as the solution state stressor, and the experimental reaction rate constants were determined employing ultraperformance liquid chromatographic (UPLC) methods. Reaction rates in the solution state were compared to the calculated C−H BDE values of the respective compounds. The results indicated a poor correlation for compounds in the solution state, and their relative stabilities could not be explained with C−H BDE. On the other hand, a favorable relationship was observed between the relative extent of ionization and the autoxidation rates of the selected compounds. In the solution state, factors such as the type and extent of drug ionization, degree and type of solvation have been shown to contribute to differences in reactivity. By applying the computational method involving the effect of H-atom abstraction and potential ionization sites in the molecule, the calculated C−H BDE should relate better to the experimental autoxidation rates.

Screening Autoxidation Propensities of Drugs in the Solid-State Using PVP and in the Solution State Using N-Methyl Pyrrolidone

“…Overall, the relationship of the calculated C–H BDE with the (surface area normalized) extent of autoxidation in solid state is more apparent here than that with the autoxidation of the same set of drugs in aqueous AIBN solution that we found previously [ 32 ]. For the latter case, we found experimentally that the ionized state plays a crucial role (pH−pKa); thus, the calculation of C–H BDE of ionized species might be necessary.…”

“…These findings suggest that autoxidation of drugs in solid state shows clearer trends with respect to their C–H BDE values (that were previously calculated for the unionized molecular species) upon the particle size/surface area normalization of solids. This is an encouraging finding as our precedent study reported that autoxidation kinetics and energetics of drugs in solution tend to show a poor correlation with their calculated C–H BDEs [ 32 ]. A parallel reaction under nitrogen pressure was performed to account for the contribution of pressure and temperature on the anaerobic reaction.…”

“… Chemical structure of NMP, PVP, and the selected drugs. Each drug’s H-atom with the lowest C–H BDE value is shown in red as reported in reference [ 32 ]. For PVP, n is the number of repeating monomer units.…”

Molecular Mechanisms Involved in the Chemical Instability of ONC201 and Methods to Counter Its Degradation in Solution

“…It is very likely, from a mechanistic point of view, that an abstraction of the hydrogens present in the alpha position of the two nitrogen atoms could be the cause of the structures formed. Calculations based on molecular modeling techniques such as density functional theory (DFT) could be reliably used to predict the formation of the most stable radicals from hydrogen abstraction [17,18] and, therefore, help to strengthen the hypotheses of ONC201 degradation product structures. Specifically, the evaluation of bond dissociation energy (BDE) has been recognized as a good means of predicting and/or supporting the hypothesis of a radical abstraction oxidation mechanism, in particular if the corresponding BDE values are around or below 90 kcal mol −1 [19].…”