In search of the mutual relationship between the structure, solid-state spectroscopy and molecular dynamics in selected calcium channel blockers

Rok publikacji: 2016
Wydawca:  European Journal of Pharmaceutical Sciences, 2016, 85, 63-83
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K. Drużbicki, A. Pajzderska, A. Kiwilsza, J. Jenczyk, D. Chudoba, M. Jarek, J. Mielcarek, J. Wąsicki
Three isostructural 1,4-dihydropyridines (DHPs), namely, nifedipine, nitrendipine and nimodipine were selected to characterize their structure, intermolecular interactions and molecular dynamics. The studied samples were analyzed using powder X-ray diffraction (XRD), neutron (INS) and infrared spectroscopy (FT-IR) as well as solid-state nuclear magnetic resonance (NMR), where each technique was supported by the state-of-the-art theoretical calculations for solid-state. By combining multiple experimental techniques with advanced theoretical calculations we were able to shed light on the mutual relation between the structure, stabilizing intermolecular interactions and their spectral response. For the first time, unambiguous computationally-supported assignment of the most prominent spectral features in DHPs is presented to give a valuable support for polymorph screening and drug control. Molecular motions were interpreted in details, revealing that a dynamic reservoir of each compound is dominated by intra-molecular reorientations of methyl groups and large-amplitude oscillations in terminal chains. Our study successfully validates the realm of applicability of first-principles solid-state calculations in search of the mutual relation between the structure and spectroscopy in this important class of drugs. Such approach gives a first necessary step to gather combined structure-dynamics data on functionalized DHPs, which are of importance to better understand crystallization and binding tendency. The NMR relaxation experiments reveal that nitro groups significantly hinder the reorientation of methyl rotors and provide the first evidence of low-temperature methyl-group tunneling in DHPs, an intriguing quantum-effect which is to be further explored

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