Jacek Jenczyk

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

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.

Experimental and solid-state computational study of structural and dynamic properties in the equilibrium form of temazepam.

Structural properties and rotational dynamics of methyl groups in the most stable form of temazepam were investigated by means of (13)C CP MAS NMR, quasielastic neutron scattering (QENS), and (1)H NMR spin-lattice relaxation methods. The QENS and (1)H NMR studies reveal the inequivalency of methyl groups, delivering their activation parameters. The structural properties of the system were explored in frame of periodic density functional theory (DFT) computations, giving insight into the reorientational barriers and providing understanding of the solid-state NMR results. The theoretical computations are shedding light on the intermolecular interactions along their relation with particular asymmetric structural units.

Molecular Dynamics Study of Polystyrene-b-poly(ethylene oxide) Asymmetric Diblock Copolymer Systems

Two polystyrene-b-poly(ethylene oxide) (PS-b-PEO) diblock copolymers differing in molecular mass (49 and 78 kDa) but possessing the same PEO cylindrical morphology are examined to elucidate their molecular dynamics. Of particular interest here is the molecular motion of the PEO blocks involved in the rigid amorphous fraction (RAF). An analysis of complementary thermal calorimetry and X-ray scattering data confirms the presence of microphase-separated morphology as well as semicrystalline structure in each copolymer. Molecular motion within the copolymer systems is monitored by dielectric and nuclear magnetic resonance spectroscopies. The results reported herein reveal the existence of two local Arrhenius-type processes attributed to the noncooperative local motion of PEO segments involved in fully amorphous and rigid amorphous PEO microphases. In both systems, two structural relaxations governed by glass-transition phenomena are identified and assigned to cooperative segmental motion in the fully amorphous phase (the α process) and the RAF (the αc process). We measure the temperature dependence of the dynamics associated with all of the processes mentioned above and propose that these local processes are associated with corresponding cooperative segmental motion in both copolymer systems. In marked contrast to the thermal activation of the α process as discerned in both copolymers, the αc process appears to be a sensitive probe of the copolymer nanostructure. That is, the copolymer with shorter PEO blocks exhibits more highly restricted cooperative dynamics of PEO segments in the RAF, which can be explained in terms of the greater constraint imposed by the glassy PS matrix on the PEO blocks comprising smaller cylindrical microdomains.

Molecular and Vibrational Dynamics in the Cholesterol-Lowering Agent Lovastatin: Solid-State NMR, Inelastic Neutron Scattering, and Periodic DFT Study

Molecular and vibrational dynamics of a widely used cholesterol-lowering agent, lovastatin, have been studied by combining nuclear magnetic resonance relaxation experiments (1H NMR) with inelastic neutron scattering (INS) and periodic density functional theory modeling (plane-wave DFT). According to a complementary experimental study, lovastatin shows no phase transitions down to cryogenic conditions, while a progressive, stepwise activation of several molecular motions is observed below room temperature. The molecular packing and intermolecular forces were analyzed theoretically, supported by a 13C NMR study and further correlated with observed molecular dynamics. The NMR relaxation experiments combined with theoretical calculations disclose that molecular dynamics in solid lovastatin is related to methyl group motions and conformational disorder in the methylbutanoate fragment. This is precisely assigned and analyzed quantitatively from both experimental and theoretical perspectives. The neutron vibrational spectroscopy further corroborates that the methyl rotors have a classical nature. In addition to the intramolecular reorientations, the vibrational dynamics was analyzed with an emphasis on the low-wavenumber range. For the first time, the terahertz response of lovastatin was studied by confronting neutron and optical techniques and clearly illustrating their complementarity. The consistent picture of the molecular dynamics is provided, which may support further considerations on alternative drug formulations and the amorphization tendency in this important lipid-lowering drug.

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

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.