Calculated carbon-hydrogen bond dissociation enthalpies for predicting oxidative susceptibility of drug substance molecules

The carbon-hydrogen bond dissociation enthalpy (BDE) concept is evaluated as a potential computed indicator of stability of pharmaceutical drug substance candidates - specifically for oxidative stability of these molecules. Computational methods are discussed. Accuracy and validity of the methods are evaluated. BDEs are computed for several well-known molecules, for which stability and degradant identification information is known. Anecdotal correlations are noted between the lowest BDE energies of familiar molecules (sertraline, ezlopitant and related structures, ziprasidone, trovafloxacin, and varenicline), the sites of oxidative lability on these molecules and the identities of oxidative degradants. A low BDE may correlate in general with a reactive site on a molecule, not just an oxidatively susceptible one. (C) 2011 Elsevier B.V. All rights reserved.