On the molecular dynamics in long-acting calcium channel blocker lacidipine: solid-state NMR, neutron scattering and periodic DFT study

Abstract

Molecular and vibrational dynamics of a new-generation lipophilic calcium channel blocker lacidipine (LCDP) are thoroughly explored by combining solid-state nuclear magnetic resonance (NMR) with high-flux quasi-elastic (QENS) and inelastic neutron scattering (INS) experiments. Contrary to the dynamically averaged ¹³C CP/MAS NMR response, neutron vibrational spectroscopy confirms our previous findings on the thermodynamically stable structure. High-resolution low-wavenumber INS spectrum is reported and fully interpreted based on periodic density functional theory (DFT) calculations in the quasi-harmonic approximation, staying in excellent agreement with the experiment. The INS spectrum was found to be clearly dominated by CH₃ torsional features, widely spread over the range of 5–35 meV. ¹H NMR relaxation indicates a molecular reorientation with different correlation times. The NMR relaxometry was further combined with an extended QENS study, providing a quantitative description of the intramolecular motions in terms of their activation barriers and correlation times, while their assignment was fully supported by theoretical analysis. While the internal dynamics of side-chain methyl groups can be described by rotation about the threefold-axes, the high-resolution QENS measurements give evidence of rotational tunneling of 2,6-methyl groups at low temperature. The vibrational analysis suggests that strong coupling of methyl librations with lattice modes promotes such an intriguing quantum effect.