Study of Crystal Packing on the Solid-State Reactivity of Indomethacin with Density Functional Theory

Abstract

Purpose Solid-state reactions are highly anisotropic. Different polymorphs of the same compound may have remarkably different chemical reactivities. It was reported that two polymorphs of indomethacin single crystals, α- and γ-forms, reacted with ammonia gas at dramatically different rates. In this study, the effect of crystal packing on their difference in chemical reactivity was investigated by examining the electronic structures and properties of the crystal forms. Methods Ab initio methods, including density functional theory, were used to calculate electronic structures of the α- and γ-forms of indomethacin. In particular, nuclear Fukui functions were obtained to elucidate how a molecule in a crystal may respond to an electronic perturbation that can be caused by a chemical reaction. Results Different conformers in the two polymorphs showed different electronic structures. The carboxylic group of one symmetrically different molecule in the α-form had significantly larger nuclear Fukui functions than those of other molecules of either the α- or γ-form, supporting the experimental observation that the α-form was much more reactive with ammonia than the γ-form. In addition, the large nuclear Fukui functions associated with atoms other than those from the carboxylic group were attributed to the tension of two dislodged aromatic rings. Conclusions Electronic calculations were able to provide insightful glimpses into the effect of crystal packing on the solid-state reaction of indomethacin. The nuclear Fukui function, which characterizes the physical stress on an atom due to perturbation in electron density, may provide a powerful means of studying the solid-state reactions of organic crystals at the electronic level.