Identifying aspirin polymorphs from combined DFT-based crystal structure prediction and solid-state NMR

Abstract

A combined experimental and computational approach was used to distinguish between different polymorphs of the pharmaceutical drug aspirin. This method involves the use of ab initio random structure searching (AIRSS), a density functional theory (DFT)-based crystal structure prediction method for the high-accuracy prediction of polymorphic structures, with DFT calculations of nuclear magnetic resonance (NMR) parameters and solid-state NMR experiments at natural abundance. AIRSS was used to predict the crystal structures of form-I and form-II of aspirin. The root-mean-square deviation between experimental and calculated ¹ H chemical shifts was used to identify form-I as the polymorph present in the experimental sample, the selection being successful despite the large similarities between the molecular environments in the crystals of the two polymorphs.

Keywords: 1H NMR; NMR; NMR crystallography; ab initio random structure searching; crystal structure prediction; organic molecular crystals; pharmaceuticals; polymorphism; small molecules.