Simulation and Assignment of the Terahertz Vibrational Spectra of Enalapril Maleate Cocrystal Polymorphs

Abstract

The identification of crystalline drug polymorphs using terahertz vibrational spectroscopy is a powerful approach for the nondestructive and noninvasive characterization of solid-state pharmaceuticals. However, a complete understanding of the terahertz spectra of molecular solids is challenging to obtain because of the complex nature of the low-frequency vibrational motions found in the sub-3 THz (sub-100 cm −1 ) range. Unambiguous assignments of the observed spectral features can be achieved through quantum mechanical solid-state simulations of crystal structures and lattice vibrations utilizing the periodic boundary condition approach. The terahertz spectra of two polymorphs of enalapril maleate are presented here to demonstrate that even large pharmaceuticals can be successfully modeled using solid-state density functional theory, including cocrystalline solids comprised of multiple distinct species. These simulations enable spectral assignments to be made, but also provide insights into the conformational and cohesion energies that contribute to the polymorph stabilities. The results reveal that the Form II polymorph of enalapril maleate is the more stable of the two under ambient conditions, and that this stability is driven by a greater intermolecular cohesion energy as compared to Form I.

Polymorphism of Carbamazepine Pharmaceutical Cocrystal: Structural Analysis and Solubility Performance

“…Most of the above-mentioned characteristic bands of the pure compounds appeared shifted in the Raman spectra of the cocrystal polymorphs, providing additional evidence for the formation of novel solid forms. Although the Raman spectra of form I and form II of [CBZ + MePRB] (1:1) in the mid-frequency range seem to be almost indistinguishable, indicating that the local environments of the molecules in these solid forms are similar, the polymorphs can be easily discriminated via the low-frequency spectral features ( Figure 3 ) that are mainly responsible for the lattice vibrations of molecular crystals [ 67 , 68 , 69 , 70 ]. In contrast, the [CBZ + MePRB] (1:0.25) form exhibits a distinct spectral pattern both in mid-frequency and low-frequency regions, highlighting the fact that the molecular content and packing arrangement of this form is different from those in the [CBZ + MePRB] (1:1) polymorphs.…”

Advances in Low-Frequency Vibrational Spectroscopy and Applications in Crystal Engineering

“…For example, the direct dependence of thermodynamic parameters on the vibrational energy levels implies that accurate reproduction of the low-frequency vibrational spectrum results in an equally accurate determination of thermodynamic values such as entropy and Gibbs/Helmholtz energies. This facet of the binary approach has been leveraged to uncover the stabilities of polymorphs on countless occasions, with a high degree of success. − …”

Vibrational spectroscopy and phonon‐related properties of monoclinic GABA, a non‐proteinogenic inhibitory neurotransmitter amino acid

“…However, with new developments toward a reliable DFT description of molecular crystals considering the impact of intermolecular interactions like hydrogen bonds and van der Waals interactions, [20][21][22][23][24][25][26] and increasing computer processing power at a reasonable cost, the simulation of the vibrational properties of molecular solids with trustable DFT-based vibrational mode assignment [27][28][29][30] has become feasible. One can mention here several important works of the research group associated to Prof. Timothy M. Korter, [31][32][33][34][35] that employed with success solid-state density functional theory to explain the low-wavenumber vibrations in molecular crystals observed through Terahertz spectroscopy, including an explanation of the anomalous behavior of the lowest-wavenumber lattice vibration in crystalline GABA with temperature, [33] being assigned to unexpected differences of strength between hydrogen bonds in the crystal. Besides, Silva et al [30] have calculated the IR and Raman spectral curves of the two lowest energy conformers of the L-aspartic molecule for the sake of comparison with DFT calculations for the crystal in an attempt to understand how electrostatic effects, hydrogen bonds, and dispersive interactions affect the lattice motions.…”