The Structural Details of Aspirin Molecules and Crystals

Abstract

We revisit, in the key of structural chemistry, one of the most known and important drugs: the aspirin. Although apparently simple, the factors determining the molecular structure and supramolecular association in crystals are not trivial. We addressed the problem from experimental and theoretical sides, considering issues from X-ray measurements and results of first-principle reconstruction of molecule and lattices by ab initio calculations. Some puzzling problems can give headaches to specialists and intrigue the general public. Thus, the reported polymorphism of aspirin is disputed, a so-called form II being alleged as a result of misinterpretation. At the same time, were presented evidences that the structure of common form I can be disrupted by domains where the regular packing is changed to the pattern of form II. The problems appear even at the level of independent molecule: the most stable conformation computed by various techniques of electronic structure differs from those encountered in crystals. Because the energy difference between the related conformational isomers (computed as most stable vs. the experimental structure) is small, about 1 kcal/mol, comprised in the error bars of used methods, the unresting question is whether the modelling is imprecise, or the supramolecular factors are mutating the conformational preferences. By a detective following of the issue, the intermolecular effects were made responsible for the conformation of the molecule in crystal. The presented problems were gathered from literature results, debates, glued with modelling and analysis redone by ourselves, in order to secure the unitary view of the considered prototypic topic.

Keywords: Aspirin; computational modelling; intermolecular effects; molecular structure; polymorphism; supramolecular structure..