Investigation of (1R,2S)‐(−)‐Ephedrine by Cryogenic Terahertz Spectroscopy and Solid‐State Density Functional Theory

Abstract

The terahertz (THz) spectrum of the pharmaceutical (1R,2S)-(-)-ephedrine from 8.0 to 100.0 cm(-1) is investigated at liquid-nitrogen (78.4 K) temperature. The spectrum exhibits several distinct features in this range that are characteristic of the crystal form of the compound. A complete structural analysis and vibrational assignment of the experimental spectrum is performed using solid-state density functional theory (DFT) and cryogenic single-crystal X-ray diffraction. Theoretical modeling of the compound includes an array of density functionals and basis sets with the final assignment of the THz spectrum performed at a PW91/6-311G(d,p) level of theory, which provides excellent solid-state simulation agreement with experiment. The solid-state analysis indicates that the seven experimental spectral features observed at low temperature consist of 13 IR-active vibrational modes. Of these modes, nine are external crystal vibrations and provide approximately 57% of the predicted spectral intensity. This study demonstrates that the THz spectra of complex pharmaceuticals may be well reproduced by solid-state DFT calculations and that inclusion of the crystalline environment is necessary for realistic and accurate simulations.

First principles investigation of L-alanine in terahertz region

“…A possible explanation may be due to the overestimation the energies of the mode at 3.74 THz. It is worth noting that the same phenomenon can be found in many solid-state calculations [8,[33][34][35].…”

“…However, advances over the last decade in lasers and semiconductors have opened up tremendous opportunities in this region. In recent years, THz time-domain spectroscopy (THz-TDS) based on femtosecond laser technology has been considered as a competitive tool for medical diagnosis [3][4][5], pharmaceutical characterization [6][7][8], and security applications [9,11] because THz-TDS is strikingly sensitive not only to the biological molecule itself but also to its surrounding environment.…”

Understanding the Terahertz Spectra of Crystalline Pharmaceuticals: Terahertz Spectroscopy and Solid-State Density Functional Theory Study of (S)-(+)-Ibuprofen and (RS)-Ibuprofen

“…The influence of the shorter unit cell dimensions on THz vibrational frequencies is the shift of the observed frequencies to higher energies, as observed in previous THz studies. 7,13,30 Constricting unit cell dimensions effectively places the nuclear charges of neighboring molecules into closer proximity, thus creating steeper potential energy surfaces describing the lattice vibrational motions, ultimately leading to higher frequency vibrations.…”

“…29,30 Although rigid molecule approaches do provide useful information concerning the observed THz vibrational modes, they do not offer an accurate representation of lattice vibrations involving considerable mixing of both internal and external atomic motions whereas isolated molecule calculations neglect all intermolecular interactions primarily responsible for the THz spectral absorptions. Force field methods are commonly used for large systems, as these methods are computationally less demanding than DFT while accurately treating conformational energies and nonbonding interaction potentials.…”

Terahertz Vibrations and Hydrogen-Bonded Networks in Crystals

“…Extremely accurate calculations are necessary to clear up uncertainties with regard to the assignment of the complicated THz spectrum. The PBE functional is frequently selected for use, as the functional has been shown consistently to produce high-quality simulation of the solid-state structure and THz spectrum [140]. The kinetic energy cutoff, to which the valence electron wave function is expanded, is desired to be as large as possible.…”