New Insights into the Crystallographic Disorder in the Polymorphic Forms of Aspirin from Low-Frequency Vibrational Analysis

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. 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 the 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, would be very useful to further
explore this perspective. Here, aspirin is a model system to show
how the additional insight from the low-frequency vibrational information
complements the structural data and allows for quantitative thermodynamic
information of pharmaceutical polymorphs to be extracted. The methodology
is directly applicable to other polymorphic systems.