The polymorphism of indomethacin: an analysis by density functional theory calculations

Indomethacin exhibits conformational polymorphism. Crystal structures of two polymorphs have been solved bearing different molecular conformations. Herein, the conformational variance in the crystals was examined by density functional theory (DFT) calculations in order to understand the mutual influence between electronic structures and crystal packing.

Electronic structures of the two polymorphs and the single molecule of indomethacin were calculated with quantum mechanical methods. Electronic properties based upon conceptual density functional theory were thereby analyzed. A potential energy surface was generated with regard to the conformational flexibility, which was identified by the electronic analysis. Lattice energies of the two polymorphs were further calculated with an empirically augmented DFT method.

Electronic properties, including electronic and nuclear Fukui functions, provided a fundamental understanding of the energetic competition in the indomethacin molecule between delocalization of p-orbitals of two aromatic rings and steric repulsions. Two dihedral angles (the tau1 and tau2 in Fig. 1) were found playing a crucial role in affecting such competition and determining the variation of molecular conformations. The existing polymorphs, alpha- and gamma-forms, were located in local minima on the energy surface based on the two dihedral angles of their molecular conformations. Calculated lattice energies suggest the alpha-form is more stable than the gamma-form at the zero K.

The polymorphism of indomethacin lies in various meta-stable conformations of the molecule that are results of different orientations between the two aromatic indole and phenyl rings. The analysis of electronic and nuclear Fukui functions permits the revelation of local energy barriers that determine the conformational diversity and, for the case of indomethacin, the conformational polymorphism.