Crystallographic disorder in polymorphs of aspirin analysed by low-frequency vibrational analysis

Qi Li, a forth year PhD student from the group, is presenting some as yet unpublished results on using terahertz spectroscopy and solid state computational analysis into better understanding the fundaments behind the structures that the small organic drug molecule aspirin can form when it crystallises and how the molecular structure, its flexibility and the motion of the molecules relative to one another dictate what crystal structures form. Terahertz time-domain spectroscopy (THz-TDS) is applied to two polymorphs of acetylsalicylic acid (aspirin), and the experimental spectra are compared to lattice dynamical calculations using high accuracy density functional theory (DFT). The calculations confirm that forms I and II have very close energetic and thermodynamic properties, and also that they show similar spectral features in the far-infrared region, reflecting the high degree of similarity in their crystal structures. Unique vibrational modes are identified for each polymorph which allow them to be distinguished using THz-TDS measurements. The observation of spectral features attributable to both polymorphic forms in a single sample, however, provides further evidence to support the hypothesis that crystalline aspirin typically comprises intergrown domains of forms I and II. Differences observed in the baseline of the measured THz-TDS spectra indicate a greater degree of structural disorder in samples of form II. Calculated Gibbs free energy curves show a turning point at 75 K, inferring that form II is expected to be more stable than form I above this temperature, as a result of its greater vibrational entropy. The calculations do not account for any differences in configurational entropy that may arise from expected structural defects. Further computational work on these structures, such as ab initio molecular dynamics (AIMD), would be very useful to further explore this perspective. A preprint of the work is available on ChemRxiv at: Li Q, Bond AD, Korter TM, Zeitler JA. New Insights into the Crystallographic Disorder in the Polymorphic Forms of Aspirin from Low-frequency Vibrational Analysis . ChemRxiv. Cambridge: Cambridge Open Engage; 2021; https://doi.org/10.33774/chemrxiv-202... This content is a preprint and has not been peer-reviewed.