The Physical Stability of Felodipine and Its Recrystallization from an Amorphous Solid Dispersion Studied by NMR Relaxometry.

The 1H nuclear magnetic resonance (NMR) relaxometry method was applied to investigate the physical stability of an active pharmaceutical ingredient (API) and, for the first time, its recrystallization process in an amorphous solid dispersion system (ASD). The ASD of felodipine and polyvinylpyrrolidone (PVP) was prepared using the solvent evaporation method in a mass ratio of 50:50. In the first stage of the study (250 days), the sample was stored at 0% relative humidity (RH). The recovery of magnetization was described by one-exponential function. In the second stage (300 days in 75% relative humidity), the recrystallization process of felodipine was studied, showing in the sample three components of equilibrium magnetization related to (i) crystalline felodipine, (ii) water, and (iii) felodipine and PVP remaining in the ASD. The study shows that the 1H NMR relaxometry method is a very useful tool for analysing the composition of a three-phase system mixed at the molecular level and for the investigation of recrystallization process of API in amorphous solid dispersion system.

NMR relaxometry in an investigation of the kinetics of the recrystallization of a three-phase system.

The method of 1H Nuclear Magnetic Resonance (NMR) relaxometry is applied to investigate the kinetics of the recrystallization of an active pharmaceutical ingredient (felodipine) from the amorphous phase of its physical mixture with a polymer (polyvinylpyrrolidone, PVP). Comparison of the recrystallization results obtained for amorphous felodipine and its mixtures with PVP shows that the recrystallization process of API is faster in the mixtures and depends on the content of water in the system. The free induction decay (FID) for protons that were detected are composed of three components, and the loss of water from PVP strongly influences the part characterized by the longest spin-spin lattice relaxation time. Analysis of the FID of the physical mixture indicates that the content of water does not change during the recrystalization process. The study shows that the T11H NMR relaxometry method is very useful for analysing the composition of a three-phase mixture and the recrystallization process.

Exploring the molecular reorientations in amorphous rosuvastatin calcium.

Molecular reorientations in rosuvastatin calcium, a drug that is widely used to prevent cardiovascular disease, were explored thoroughly by means of solid state nuclear magnetic resonance (1H and 13C NMR) combined with calculations of steric hindrances. The experimental results reveal rich internal reorientational dynamics. All relaxation processes were tested in a broad range of temperatures and described in terms of their type and the associated energy barriers. The internal molecular mobility of rosuvastatin calcium can be associated with the reorientational dynamics of four methyl groups, accompanied by reorientation of the isopropyl group. The energy barriers of methyl and isopropyl group reorientation depended on the type of E/Z isomers, while the water content also had a strong influence on the dynamics of the isopropyl group. In the paper, a consistent picture of the molecular dynamics is provided, facilitating our understanding of molecular mobility in this important pharmaceutical solid.

Exploring molecular reorientations in amorphous and recrystallized felodipine at the microscopic level.

Molecular reorientations were studied in amorphous, partially and fully recrystallized felodipine (calcium channel blocker, a drug from the family of 1',4-dihydropyridine) using a set of experimental methods: high-resolution solid-state nuclear magnetic resonance (NMR), relaxometry NMR and quasielastic neutron scattering (QENS). The results were compared with molecular dynamics in crystalline felodipine previously investigated [A. Pajzderska, K. Druzbicki, M. A. Gonzalez, J. Jenczyk, J. Mielcarek, J. Wasicki, Diversity of Methyl Group Dynamics in Felodipine: a DFT Supported NMR and Neutron Scattering Study, CrystEngComm, 2018, 20, 7371-7385]. The kinetics of the recrystallization was also studied. The most stable sample was the sample stored in a closed ampoule (at room temperature, in 0% RH) and its complete recrystallization lasted 105 days. In the fully recrystallized sample, the same molecular reorientation identified in the crystalline form was detected, so reorientations of all methyl groups and the ethyl ester fragment. In the partially recrystallized sample, static disorder caused by the two positions of both side chains was revealed. In the amorphous sample the reorientation of all methyl groups was analyzed and the distribution of correlation times and energy barriers connected with the loss of long-range ordering and disorder of side chains were analyzed. Additionally, inhibition of reorientation in the ethyl ester fragment was observed.

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.

Phase diagram of water confined in MCM-41 up to 700 MPa.

On the basis of measurements of NMR signal intensity and T1 and T2(*) relaxation times as a function of temperature (290 K-170 K) and pressure (0.1 MPa-700 MPa), the p-T phase diagram was made for the sample containing water inside and outside MCM-41 pores of 1.81 nm in radius. The temperature of nucleation of water confined in nanopores under normal pressure was 230 K. With increasing pressure this temperature decreased to 200 K under 300 MPa, but with further increase in pressure it did not change.

Complex and mixture of ß-cyclodextrin with diazepam characterised by ¹H NMR and atom-atom potential methods.

Inclusion complex of ß-cyclodextrin with diazepam and a physical mixture of these components were studied by solid-state (1)H NMR. The activation barrier for reorientation of the methyl group in the diazepam molecule was found not changed by complex formation with ß-cyclodextrin. The complex formation resulted in a decrease in the number of water molecules and affected the relaxation time of ß-cyclodextrin. By the atom-atom potential method the most probable configuration of the diazepam molecule inside ß-cyclodextrin cavity was proposed.

Dynamics in molecular and molecular-ionic crystals: a combined experimental and molecular simulation study of reorientational motions in benzene, pyridinium iodide, and pyridinium nitrate.

Molecular dynamics (MD) simulations for crystalline benzene (C(6)H(6)), pyridinium iodide [C(5)NH(6)](+)I(-), and pyridinium nitrate [C(5)NH(6)](+)NO(3)(-) have been performed as a function of temperature and pressure. Despite the similar shape of the benzene molecule and the pyridinium cation, the experimental and simulated data have showed clear differences in their dynamics. Therefore, the rotational dynamics have been explored in detail by comparing thoroughly the existing experimental results together with new quasielastic neutron scattering (QENS) data obtained for (PyH)NO(3) and molecular dynamics simulations. The correlation times, activation energy, geometry of motion of benzene molecule and pyridinium cation, isothermal compressibility, and activation volume obtained from the simulations are compared with the experimental results obtained by nuclear magnetic resonance and QENS methods. MD simulations have also revealed that reorientation of the pyridinium cation in pyridinium nitrate between two inequivalent positions is strongly affected by the hydrogen bond N-H···O between the cation and the anion and the influence of temperature on strength of the hydrogen bond is much more important than that of the pressure.

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.

In-plane pyridinium cation reorientation in bis-thiourea chloride, bromide and iodide: quasielastic neutron scattering combined with molecular dynamics simulations.

We have studied the dynamics of bis-thiourea pyridinium chloride and bromide by means of quasielastic neutron scattering (QENS). The QENS data allow describing the geometry of the in-plane motion of the pyridinium cation and reveal that it is similar to the motion previously observed in bis-thiourea pyridinium iodide. Molecular dynamics (MD) simulations have been performed to investigate the cation dynamics on the high temperature phase of the full series of compounds: bis-thiourea pyridinium chloride, bromide and iodide. Three different models of intermolecular potential have been tested and the agreement between the simulated and experimental elastic incoherent structure factors (EISFs) is used to select the more realistic one. The detailed analysis of the MD results indicates that Coulombic interactions together with the formation of hydrogen bonds between the pyridinium cation and the host sublattice influence strongly the geometry of the in-plane cation reorientation.

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.

A study of out-of-plane cation dynamics in a bis-thiourea pyridinium chloride inclusion compound.

The out-of-plane motion of the pyridinium cation in the bis-thiourea pyridinium chloride inclusion compound has been studied in a wide temperature range using (1)H NMR, dielectric spectroscopy and quasielastic neutron scattering. The geometry of this motion is obtained from the Q-dependence of the elastic incoherent structure factor determined from the quasielastic neutron scattering measurements. We find that the pyridinium cation performs out-of-plane reorientations around the axis passing through two opposite atoms of the ring. The correlation times as a function of temperature were measured in the three known crystallographic phases, finding a good agreement between the three techniques employed. The activation energy for this motion changes from 5 ± 1 kJ mol(-1) in the low-temperature phase to 1.2 ± 0.2 kJ mol(-1) in the intermediate and high-temperature phases.

1H NMR study of rehydration/dehydration and water mobility in ß-cyclodextrin.

The processes of dehydration and rehydration of ß-cyclodextrin were studied by analysis of the (1)H NMR (nuclear magnetic resonance) line shape. Dehydration was carried in an open ampoule as a function of temperature and above 400 K total dehydration of ß-cyclodextrin was observed. This result was confirmed by the thermogravimetry (TG) measurements. Rehydration was studied as a function of time at room temperature. After 40 days, ß-cyclodextrin was found to absorb eight water molecules. The analysis of temperature changes in the shape of the (1)H NMR line of ß-cyclodextrin kept in a closed ampoule and its dielectric measurements provided information on the mobility of water molecules. The water molecules were found to perform complex molecular motions, that is, reorientational jumps below 200K and additionally, translational motion (diffusion) above 200K.

A hybrid method for estimation of molecular dynamics of diazepam-density functional theory combined with NMR and FT-IR spectroscopy.

Reorientation of the molecule of diazepam was investigated by calorimetric methods, IR absorption and NMR. The investigation of dynamics was complemented by density functional study (DFT) of vibrational frequencies and infrared intensities, calculations of steric hindrances and Monte Carlo simulations. The results indicated the occurrence of reorientation jumps of the CH(3) group and conformational motion of the benzodiazepine ring. The activation parameters of the methyl group reorientation were determined and the activation barrier obtained was in good agreement with the theoretically estimated value. The FT-IR spectra were assigned using results of DFT calculations.

Discovery of an intermediate phase in bis-thiourea pyridinium chloride inclusion compound.

This paper reports the occurrence of a new phase for bis-thiourea pyridinium chloride inclusion compound, which is intermediate to the high- and low-temperature ones already reported. The structure of the intermediate phase was determined by the x-ray diffraction and the following sequence of space groups was obtained: Cmcm-->(237 K)Cmc2(1)-->(206 K)Pbca. The triplication of the lattice a parameter in the intermediate phase was observed. Detailed investigations of its phase transitions were performed by differential scanning calorimetry, x-ray diffraction, and dielectric spectroscopy methods. The phase transition at T(1)=237 K is continuous while at T(2)=206 K is discontinuous. Both phase transitions have been classified as of order-disorder type. The high- and low-temperature phases are nonpolar in contrast to the intermediate phase, for which we could not found ferroelectric ordering.

NMR search for polymorphic phase transformations in chlorpropamide form-A at high pressures.

The high-pressure effects on chlorpropamide (C10H13ClN2O3S) form-A have been studied by 1H NMR spectroscopy at high pressures up to 800 MPa in the temperature range 90-300 K. A study of the NMR second moment and spin-lattice relaxation time has been completed by a calculation of the steric hindrances for molecular reorientations and simulations of the second moment of the NMR line by the Monte-Carlo method, which enabled a precise description of molecular dynamics in the compound studied. Reorientations of the methyl group, oscillations and reorientations of the chlorophenyl ring and reorientations of the propyl group have been revealed and respective activation parameters extracted. No phase transformation of the compound form-A has been detected.

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.

Redetermination of the structure and dielectric properties of bis(thiourea) pyridinium iodide--a new ferroelectric inclusion compound.

The crystal structure of bis(thiourea) pyridinium iodide (T(2)PyI) was previously determined at 295 and 110 K [Prout, Heyes, Dobson, McDaid, Maris, Mueller & Seaman (2000). Chem. Mater. 12, 3561-3569] and the two phases were described in the space groups Cmcm and P2(1)cn, respectively. Because differential scanning calorimetry revealed two phase transitions, at 161 and 141 K, a redetermination of the structure of T(2)pyI at 295, 155 and 110 K has been undertaken, and the following sequence of space groups obtained: Cmcm (I) --> C2cm (II) --> P2(1)cn (III). The high- (I) and low-temperature (III) phases confirmed the results reported in the previous study. In the new intermediate phase II, the mirror plane perpendicular to the x axis vanishes and the crystal structure loses the centre of symmetry. In phases I and II the pyridinium cations are strongly dynamically disordered, while in the low-temperature phase III the cations are well ordered. In all three phases the thiourea-iodine hydrogen-bonded sublattice is very well ordered. Dielectric measurements show that the intermediate and low-temperature phases are ferroelectric and that 161 K is the Curie point of a new ferroelectric crystal.

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.

Calculation of dipolar correlation function in solids with internal mobility.

A general equation for the dipolar correlation function, to be used to analyze various kinds of independent internal motions, described by some correlation times tau(cm) (m = 1,2 em...k), has been obtained. The obtained expression has been used to analyze the temperature dependencies of different NMR measured values: second moment: spin-lattice relaxation times; amplitude of solid echoes signals.