title: Calculated carbon-hydrogen bond dissociation enthalpies for predicting oxidative susceptibility of drug substance molecules.
abstract: 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.
authors.affiliation: Research Analytical, Pharmaceutical Sciences, Pfizer Global Research & Development, Groton, CT 06340, USA. tootalltom50@yahoo.com
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Sharp
mesh_terms: D003198:Computer Simulation; D004355:Drug Stability; D006358:Hot Temperature; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D015203:Reproducibility of Results; D013816:Thermodynamics
chemical_list: D004364:Pharmaceutical Preparations