“In-Silico Seeding”: Isostructurality and Pseudoisostructurality in a Family of Aspirin Derivatives

Novel crystal packings of the aspirin molecule and 17 molecules that are related to aspirin by substitution are studied using a computational approach. The packings are created by taking a crystal structure for which the crystal packing and molecular geometry have been determined experimentally and replacing the native molecule with a different one. The resulting crystal structures are optimized using molecular mechanics, followed by a quantum mechanical method based on density functional theory and including a correction for dispersive interactions. There are 21 known, experimental, crystal structures for the molecules considered, some of which are polymorphic. For any given molecule, the lowest, calculated lattice energy is always found to be that of a crystal structure which corresponds to experiment. For the three polymorphic molecules, the second lowest lattice energy is also found to correspond to an experimental structure. The agreement between the observation of a particular packing and its low rank in the list of possible packings is evidence of the accuracy of the method for calculating the lattice energy. Further analysis of the results shows patterns reflecting the underlying supramolecular constructs that are common to the different packings of these molecules. This leads to some speculation as to the possibilities of finding new polymorphs for some of these molecules.