Aleksandra Pajzderska

Mesoporous drug carrier systems for enhanced delivery rate of poorly water-soluble drug: nimodipine

Two mesoporous silica materials: MCM-41 and SBA-15 were applied as potential nanocarriers for poorly soluble drug—nimodipine. Drug incorporation was performed using modified adsorption from the solution method and loaded samples before and after washing procedure were studied. The physical properties were verified by: differential scanning calorimetry, X-ray powder diffraction, electron microscopies (SEM/TEM) and Fourier-transform infrared spectroscopy (FT-IR). FT-IR results for bulk nimodipine were interpreted on the basis of first principles calculations (DFT). As a result of encapsulation process, in both matrices nimodipine appeared simultaneously in two forms: crystalline and amorphous, but the first one turned out to be easily removable during washing procedure. The in vitro dissolution and release tests were performed with ultra pure water under supersaturating conditions. The release rate of the amorphous nimodipine from mesoporous silica materials was at least 70 times higher than dissolution rate of bulk drug, thus revealed a potential usefulness of such carrier in future pharmaceutical applications in terms of delivery of poorly soluble drugs.

Ordered mesoporous silica material SBA-15: loading of new calcium channel blocker - lacidipine

Mesoporous material SBA-15 of hexagonal structure was synthesised and its usefulness as a carrier for a poorly soluble drug – lacidipine (LA) – was tested. The source of silica was tetraethyl orthosilicate (TEOS) and the structure ordering agent was non-ionic surfactant Pluronic P123. SBA-15 with encapsulated LA was characterised by X-ray diffraction (XRD), infrared spectroscopy (FTIR), thermogravimetry (TG), differential scanning calorimetry (DSC) and transmission electron microscopy (TEM). Adsorption of the therapeutically active substance was performed in anhydrous environment (chloroform). The content of the therapeutic substance in SBA-15 estimated from TG measurements reached 9%. The properties of the compound obtained were compared with those of a physical mixture of the components.

Quasielastic neutron scattering study of pyridinium cation reorientation in thiourea pyridinium nitrate inclusion compound.

The dynamics of the pyridinium cation in thiourea pyridinium nitrate inclusion compound has been studied using quasielastic neutron scattering in a wide temperature range (10-350 K). The elastic incoherent structure factor was determined from neutron backscattering and time-of-flight measurements and its analysis allows to describe in detail the geometry of the motions of the pyridinium cation. Our study reveals two types of motion having two different correlation times. The pyridinium cation reorients about the axis perpendicular to its molecular plane over inequivalent threefold potential energy barriers and also executes a faster out-of-plane motion about the axis passing through two opposite atoms of the ring.

Calorimetric, FTIR and 1H NMR measurements in combination with DFT calculations for monitoring solid‐state changes of dynamics of sibutramine hydrochloride

Two forms of sibutramine hydrochloride, monohydrate and anhydrous, have been investigated by calorimetric methods, Fourier transform infrared (FTIR) absorption and (1) H nuclear magnetic resonance (NMR) measurements as well as by density functional theory (DFT) of vibrational frequencies and infrared intensities, calculations of steric hindrances and Monte Carlo simulations. The results of FTIR spectra combined with DFT calculations permitted identification of the bands corresponding to the dynamics and vibrations of water molecules. NMR study and Monte Carlo simulations revealed the occurrence of reorientation jumps of the methyl groups in sibutramine cation and also revealed that the reorientation of isopropyl group is possible only in sibutramine monohydrate hydrochloride. The hydration of sibutramine hydrochloride causes a change in the conformation of sibutramine cation.

Structural and dynamical aspects of the phase transition in the new thiourea thiazolium bromide inclusion compound

A new thiourea thiazolium bromide inclusion compound is presented here. Detailed investigations of its phase transition were performed by differential scanning calorimetry, x-ray diffraction, and dielectric and nuclear magnetic resonance spectroscopy methods, completed by calculation of the steric hindrances for molecular reorientations and simulations of the second moment of the nuclear magnetic resonance line by the Monte Carlo method. A second order ferrielectric structural phase transition has been detected at 190.5 K as thiazolium cations collectively reorient inside channels. The dynamics is discussed in terms of inequivalent energy barriers associated with cation rotation as the symmetry breaking occurs. Oscillations of thiourea molecules and NH(2) groups have been also observed.

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 simulation of cation dynamics in bis-thiourea pyridinium nitrate inclusion compound.

Molecular dynamics simulations have been performed on the high temperature phase of the bis-thiourea pyridinium nitrate inclusion compound. Three different potential models have been tested. In the three cases, the analysis of the centre of mass motion of pyridium cations indicates that they do not diffuse along the channels. However, only the potential including a specific hydrogen bonding interaction provides a description of the in-plane cation reorientation in reasonable agreement with the experimental results deduced from quasielastic neutron scattering (QENS) measurements. This model shows that the pyridinium cation reorients among three non-equivalent positions and gives reorientational correlation times comparable to those extracted from the QENS data. We conclude that the particular geometry of this reorientation is due to the formation of hydrogen bonds of different strength between the pyridinium cation of the guest sublattice and the host sublattice.

Analysis of the Distribution of Energy Barriers in Amorphous Diazepam on the Basis of Computationally Supported NMR Relaxation Data

Crystalline and amorphous diazepam, a psychoactive drug, were investigated by employing spin-lattice relaxation 1H NMR along with atom-atom calculations of the landscape of energy barriers. The activation barriers for reorientation of the methyl group in amorphous diazepam were found to be in the range of 1.9-12.7 kJ/mol. Atom-atom calculations permitted determination of the distribution of energy barriers for reorientations of methyl groups, which was in a good agreement with that obtained on the basis of experimental data. The NMR relaxation combined with calculations provided a quantitative description of the distribution of energy barriers including intra- and inter-molecular interactions.

On the relaxation dynamics in active pharmaceutical ingredients: solid-state 1H NMR, quasi-elastic neutron scattering and periodic DFT study of acebutolol hydrochloride

The molecular dynamics of a cardioselective beta-blocker with intrinsic sympathomimetic activity – acebutolol hydrochloride, was investigated by employing spin-lattice relaxation 1H nuclear magnetic resonance (NMR) and quasielastic neutron scattering (QENS) experiments along with periodic density functional theory (DFT) computations. The relaxation experiments reveal the presence of four dynamic processes, further assigned to the methyl groups reorientations. The analyzed motions were characterized in terms of their activation barriers and correlation times, while their assignment was supported by theoretical computations. The earlier reported crystallographic structure reveals intriguing features in the large-size unit-cell, defined by eight molecular units. By combining solid-state DFT calculations with the intermolecular interactions analysis (Hirshfeld Surface; Reduced Density Gradient), the nature of the stabilizing crystal forces has been revealed, emphasizing the role of moderate-strength (N–H⋯O; O–H⋯Cl; N–H⋯Cl) and weak (C–H⋯O) hydrogen-bond contacts. The theoretical computations provide clear support for the assignment of particular motions and interpretation of the experimental data as showing a competing influence of both internal-structure and intermolecular factors on their activation barriers. The highest energy barriers were assigned to the acetyl-related methyl rotors, the intermediate ones are due to the isopropyl part, while the most-dynamic methyl groups are assigned to the alkyl chain. Inclusion of crystallographic forces via calculations in periodic boundary conditions was found to be essential for a proper understanding of both the conformational and dynamic properties of the system under interest, as it could not be achieved with molecular modeling. Therefore, the performance of several semi-local exchange–correlation functional approximations was critically examined, revealing a clear tendency in favor of the ‘soft’ and dispersion-corrected schemes for estimation of the rotational barriers in pharmaceutical solids.