Wednesday, 20 May 2015

Computationally Assisted (Solid-State Density Functional Theory) Structural (X-ray) and Vibrational Spectroscopy (FT-IR, FT-RS, TDs-THz) Characterization of the Cardiovascular Drug Lacidipine

Kacper Drużbicki, Jadwiga Mielcarek, Anna Kiwilsza, Loic Toupet, Eric Collet, Aleksandra Pajzderska, and Jan Wąsicki


Abstract


The structural properties of a second-generation dihydropyridine calcium antagonist, lacidipine, were explored by combining low-temperature X-ray diffraction with optical vibrational spectroscopy and periodic density functional theory (PBC DFT) calculations. Crystallographic analysis cannot discriminate between two possible molecular symmetries in crystals made of pure lacipidine: the space group Ama2, where the lacipidine molecule lies on mirror symmetry, or a Cc space group with distorted lacipidine molecules. Intermolecular interactions analysis reveals an infinite net of moderate-strength N–H···O hydrogen-bonds, which link the molecular units toward the crystallographic b-axis. Weak interactions were identified, revealing their role in stabilization of the crystal structure. The vibrational dynamics of lacidipine was thoroughly explored by combining infrared and Raman spectroscopy in the middle- and low-wavenumber range. The given interpretation was fully supported by state-of-the-art solid-state density functional theory calculations (plane-wave DFT), giving deep insight into the vibrational response and providing a complex assignment of spectral features. The vibrational analysis was extended onto the lattice-phonon range by employing time-domain terahertz spectroscopy. Analysis of the anisotropic displacement parameters suggests noticeable dynamics of the terminal (tert-butoxycarbonyl)vinyl moiety. The terahertz study provides direct experimental evidence of “crankshaft” type motions in the terminal chain. By combining low-wavenumber vibrational spectroscopy with the first-principles calculations, we were able to prove that the quoted thermodynamically stable phase corresponds to the monoclinic Cc space group.



This study was performed using TeraView's Spectra 3000 system. (TeraView, Cambridge, UK)