Elucidating Molecular Vibrations within the Cocrystal of a Nonsteroidal Anti-Inflammatory Drug and Amino Acid by Temperature-Dependent Terahertz Spectroscopy at 2–17 THz: A Case Study

Pharmaceutical cocrystals have attracted extensive interest to optimize the physicochemical properties of active pharmaceutical ingredients (APIs), which benefits nonsteroidal anti-inflammatory drugs (NSAIDs) by linking them with cocrystal formers (CCFs) via intermolecular interactions. The energy level matching between terahertz (THz) photons and intermolecular interactions makes THz spectroscopy sensitive to characterizing API-CCF cocrystals by spectral fingerprint. However, the limited frequency bandwidth and temperature range restrict the comprehensive understanding of spectral evolution and the molecular vibrational pattern. In this work, THz time-domain spectroscopy (THz-TDS) and synchrotron radiation-based broadband THz (SRBB-THz) are combined to extend the frequency range to 0.5-18 THz. A naproxen-proline (NAP-Pro) cocrystal is selected to conduct experiments from room temperature to 4.2 K. As the temperature decreases, the spectral evolution is characterized by peak sharpening, new peak appearance, peak shift, and peak splitting. The parameters of full width at half maximum (FWHM) and frequency shift are quantitatively fitted by a quadratic function and Bose-Einstein statistics, respectively. Quantum chemical calculations are further carried out to assign fingerprint frequencies to specific molecular vibrations, where collective vibrational modes govern low frequencies of 2-6 THz and individual modes dominate high frequencies of 6-17 THz. Based on oscillation theory, this is attributed to distinct force constants with respect to a specific vibrational mode. This study elucidates the evolutionary pattern of temperature-induced spectral features and molecular vibrational modes, which is insightful for investigating the pharmaceutical cocrystal system and systematically understanding the THz spectral characteristics.