Tonglei Li, Ph.D.

Through electronic calculations and molecular modeling, we have found that 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.

5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, or ROY, is the “most polymorphic” organic compound and a prime example of a molecule that exhibits conformational polymorphism . ROY has been crystallized in ten polymorphs with seven being solved. ROY possesses three areas of torsional flexibility, a fundamental influence of conformational change in molecules possibly resulting in extensive variations of crystal packing motifs.

Still, the diversity of molecular conformation alone cannot explain the large number of polymorphs as seen of ROY. What we have found by analyzing electronic structures of the crystals is that different packing motifs among molecules may contribute significantly to the polymorphism. The electronic Fukui functions allow us to examine intermolecular interactions with regard to the local chemistry.