Solving the Computational Puzzle: Toward a Pragmatic Pathway for Modeling Low-Energy Vibrational Modes of Pharmaceutical Crystals

Five pharmaceutically
relevant compounds with increasing molecular
complexity, benzoic acid, diphenylacetic acid, l-tyrosine,
celecoxib (form III), and carvedilol (form II), were investigated
using a combination of low-frequency Raman (LFR) spectroscopy measurements
and theoretical solid-state density functional theory (DFT) calculations. l-Tyrosine, specifically, was investigated in more detail to
evaluate the effect and rationale for using specific computational
parameters. The experimental data were used to validate the DFT simulations
by probing the spectral dynamics of the low-energy vibrational modes
in a broad temperature range. Principal component analysis (PCA) and
individual peak analysis were also used to further elucidate temperature-induced
changes. Given the nature of the conducted theoretical calculations,
LFR measurements in a cold environment proved especially useful to
accurately assess their quality due to complex, temperature-induced
spectral dynamics for most of the investigated compounds (especially, l-tyrosine).