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

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.