AC versus DC field effects on the crystallization behavior of a molecular liquid, vinyl ethylene carbonate (VEC).

Using electric fields to control crystallization processes shows a strong potential for improving pharmaceuticals, but these field effects are not yet fully explored nor understood. This study investigates how the application of alternating high electric fields can influence the crystallization kinetics as well as the final crystal product, with a focus on the possible difference between alternating (ac) and static (dc) type fields applied to vinyl ethylene carbonate (VEC), a molecular system with field-induced polymorphism. Relative to ac fields, static electric fields lead to more severe accumulation of impurity ions near the electrodes, possibly affecting the crystallization behavior. By tuning the amplitude and frequency of the electric field, the crystallization rate can be modified, and the crystallization outcome can be guided to form one or the other polymorph with high purity, analogous to the findings derived from dc field experiments. Additionally, it is found that low-frequency ac fields reduce the induction time, promote nucleation near Tg, and affect crystallization rates as in the dc case. Consistency is also observed for the Avrami parameters n derived from ac and dc field experiments. Therefore, it appears safe to conclude that ac fields can replicate the effects seen using dc fields, which is advantageous for samples with mobile charges and the resulting conductivity.

Effect of Surface Chemistry on the Glass-Transition Dynamics of Poly(phenyl methyl siloxane) Confined in Alumina Nanopores.

Broadband dielectric spectroscopy (BDS) and differential scanning calorimetry (DSC) are combined to study the effect of changes in the surface chemistry on the segmental dynamics of glass-forming polymer, poly(methylphenylsiloxane) (PMPS), confined in anodized aluminum oxide (AAO) nanopores. Measurements were carried for native and silanized nanopores of the same pore sizes. Nanopore surfaces are modified with the use of two silanizing agents, chlorotrimethylsilane (ClTMS) and (3-aminopropyl)trimethoxysilane (APTMOS), of much different properties. The results of the dielectric studies have demonstrated that for the studied polymer located in 55 nm pores, changes in the surface chemistry and thermal treatment allows the confinement effect seen in temperature evolution of the segmental relaxation time, τα(T) to be removed. The bulk-like evolution of the segmental relaxation time can also be restored upon long-time annealing. Interestingly, the time scale of such equilibration process was found to be independent of the surface conditions. The calorimetric measurements reveal the presence of two glass-transition events in DSC thermograms of all considered systems, implying that the changes in the interfacial interactions introduced by silanization are not strong enough to inhibit the formation of the interfacial layer. Although DSC traces confirmed the two-glass-transition scenario, there is no clear evidence that vitrification of the interfacial layer affects τα(T) for nanopore-confined polymer.

Density scaling of structure and dynamics of an ionic liquid.

Room temperature ionic liquids are salts with low melting points achieved by employing bulky and asymmetrical ions. The molecular design leads to apolar and polar parts as well as the presence of competing Coulomb and van der Waals interactions giving rise to nano-scale structure, e.g. charge ordering. In this paper we address the question of how these nano-scale structures influence transport properties and dynamics on different timescales. We apply pressure and temperature as control parameters and investigate the structure factor, charge transport, microscopic alpha relaxation and phonon dynamics in the phase diagram of an ionic liquid. Including viscosity and self diffusion data from literature we find that all the dynamic and transport variables studied follow the same density scaling, i.e. they all depend on the scaling variable Γ = ργ/T, with γ = 2.8. The molecular nearest neighbor structure is found to follow a density scaling identical to that of the dynamics, while this is not the case for the charge ordering, indicating that the charge ordering has little influence on the investigated dynamics.

Crystallization of supercooled fenofibrate studied at ambient and elevated pressures.

In this work, we have performed a detailed investigation on the crystallization tendency of the modeled glass-forming pharmaceutical compound, fenofibrate. To do this, we have employed four different experimental techniques allowing following of the crystallization process. This has included dielectric spectroscopy, optical microscopy, X-ray diffraction and differential scanning calorimetry. From the crystallization kinetic studies carried out at atmospheric pressure, we have determined the temperature dependence of the crystal growth rate and the overall crystallization rate. It was found that the time scale of the molecular motions responsible for α-relaxation correlates much better with the crystal growth rate than with the overall crystallization rate. Experiments carried out under varying thermodynamic conditions while remaining on the same timescale of α-relaxation have demonstrated that the crystallization tendency of the supercooled fenofibrate significantly slows down with increasing pressure. Lastly, we have also shown that the thermodynamic history of reaching crystallization conditions has a substantial impact on its overall progress.

The improvement of the dissolution rate of ziprasidone free base from solid oral formulations.

This work aims at increasing solubility and dissolution rate of ziprasidone free base-Biopharmaceutics Classifaction System (BCS) class II compound. The authors describe a practical approach to amorphization and highlight problems that may occur during the development of formulations containing amorphous ziprasidone, which was obtained by grinding in high-energy planetary ball mills or cryogenic mills. The release of ziprasidone free base from the developed formulations was compared to the reference drug product containing crystalline ziprasidone hydrochloride-Zeldox® hard gelatin capsules. All preparations were investigated using compendial tests (USP apparatuses II and IV) as well as novel, biorelevant dissolution tests. The novel test methods simulate additional elements of mechanical and hydrodynamic stresses, which have an impact on solid oral dosage forms, especially during gastric emptying. This step may prove to be particularly important for many formulations of BCS class II drugs that are often characterized by narrow absorption window, such as ziprasidone. The dissolution rate of the developed ziprasidone free base preparations was found to be comparable or even higher than in the case of the reference formulation containing ziprasidone hydrochloride, whose water solubility is about 400 times higher than its free base.

The kinetics of mutarotation in L-fucose as monitored by dielectric and infrared spectroscopy.

Fourier Transform Infrared Spectroscopy and Broadband Dielectric Spectroscopy are combined to trace kinetics of mutarotation in L-fucose. After quenching molten samples down to temperatures between T = 313 K and 328 K, the concentrations of two anomeric species change according to a simple exponential time dependence, as seen by an increase in absorbance of specific IR-vibrations. In contrast, the dielectric spectra reveal a slowing down of the structural (α-) relaxation process according to a stretched exponential time dependence (stretching exponent of 1.5 ± 0.2). The rates of change in the IR absorption for α- and ß-fucopyranose are (at T = 313 K) nearly one decade faster than that of the intermolecular interactions as measured by the shift of the α-relaxation. This reflects the fact that the α-relaxation monitors the equilibration at a mesoscopic length scale, resulting from fluctuations in the anomeric composition.

Glassy dynamics and physical aging in fucose saccharides as studied by infrared- and broadband dielectric spectroscopy.

Fourier Transform Infra Red (FTIR) and Broadband Dielectric Spectroscopy (BDS) are combined to study both the intra- and inter-molecular dynamics of two isomers of glass forming fucose, far below and above the calorimetric glass transition temperature, T(g). It is shown that the various IR-active vibrations exhibit in their spectral position and oscillator strength quite different temperature dependencies, proving their specific signature in the course of densification and glass formation. The coupling between intra- and inter molecular dynamics is exemplified by distinct changes in IR active ring vibrations far above the calorimetric glass transition temperature at about 1.16T(g), where the dynamic glass transition (α relaxation) and the secondary ß relaxation merge. For physically annealed samples it is demonstrated that upon aging the different moieties show characteristic features as well, proving the necessity of atomistic descriptions beyond coarse-grained models.

Stereoregulation, molecular weight, and dispersity control of PMMA synthesized via free-radical polymerization supported by the external high electric field.

We show the remarkable effect of using static (DC) and alternating (AC) electric fields to control the free-radical polymerization of methyl methacrylate (MMA). The magnitude and/or frequency of the applied electric field (up to 154 kV cm-1) were found to control the molecular weight, dispersity, and stereochemistry of the produced polymers.

Vapor-Deposited Thin Films: Studying Crystallization and α-relaxation Dynamics of the Molecular Drug Celecoxib.

Crystallization is one of the major challenges in using glassy solids for technological applications. Considering pharmaceutical drugs, maintaining a stable amorphous form is highly desirable for improved solubility. Glasses prepared by the physical vapor deposition technique got attention because they possess very high stability, taking thousands of years for an ordinary glass to achieve. In this work, we have investigated the effect of reducing film thickness on the α-relaxation dynamics and crystallization tendency of vapor-deposited films of celecoxib (CXB), a pharmaceutical substance. We have scrutinized its crystallization behavior above and below the glass-transition temperature (Tg). Even though vapor deposition of CXB cannot inhibit crystallization completely, we found a significant decrease in the crystallization rate with decreasing film thickness. Finally, we have observed striking differences in relaxation dynamics of vapor-deposited thin films above the Tg compared to spin-coated counterparts of the same thickness.

Influence of Surface Roughness on the Dynamics and Crystallization of Vapor-Deposited Thin Films.

The substrate roughness is a very important parameter that can influence the properties of supported thin films. In this work, we investigate the effect of surface roughness on the properties of a vapor-deposited glass (celecoxib, CXB) both in its bulk and in confined states. Using dielectric spectroscopy, we provide experimental evidence depicting a profound influence of surface roughness on the α-relaxation dynamics and the isothermal crystallization of this vapor-deposited glass. Besides, we have verified the influence of film confinement on varying values of surface roughnesses as well. At a fixed surface roughness value, the confinement could alter both the dynamics and crystallization of vapor-deposited CXB.

Temperature and volume effect on the molecular dynamics of supercooled ibuprofen at ambient and elevated pressure.

In this paper we have studied the relative importance of thermal effects and volume in controlling structural relaxation of supercooled ibuprofen at ambient and elevated pressure. The relative contribution of both parameters on the structural relaxation times was estimated by means of the ratio E(V)/E(P) (i.e., the activation energy at constant volume to enthalpy of activation at constant pressure), which can be simply estimated from dielectric relaxation and pressure-volume-temperature (PVT) measurements. We found out that at ambient pressure the effect of thermal energy and molecular packing on structural relaxation dynamics is practically equaled. However, with increasing pressure the role of thermal effects in governing molecular dynamics becomes more prominent, leading to its complete domination in the pressure region of around 1 GPa. These results are discussed in the context of remarkably different behavior of supercooled ibuprofen crystallized at various thermodynamic conditions, as reported in our previous paper. The implication is that, when molecular mobility of supercooled ibuprofen is governed primarily by the thermal energy, significant slowing down of crystallization progress at isostructural relaxation conditions is observed.

Effect of cryogrinding on chemical stability of the sparingly water-soluble drug furosemide.

PURPOSE: To investigate the effect of cryogrinding on chemical stability of the diuretic agent furosemide and its mixtures with selected excipients. METHODS: Furosemide was ground at liquid nitrogen temperature for 30, 60, 120 and 180 min. Mixtures of furosemide-PVP and furosemide-inulin (1:1) were milled under cryogenic conditions. Materials were analyzed by XRD, UPLC, MS and NMR. RESULTS: Upon increasing the milling time, a significant build-up of an unidentified impurity 1, probably the main degradation product, was noticed. Cogrinding of furosemide with PVP and inulin worsened chemical stabilization of the pharmaceutical. The main degradation product formed upon cryomilling was subsequently identified as 4-chloro-5-sulfamoylanthranilic acid (CSA). Based on some theoretical considerations involving specific milling conditions, the milling intensity and an expected specific milling dose have been calculated. Results indicate that cryogenic grinding is capable to initiate mechanically induced decomposition of furosemide. CONCLUSIONS: Cryogenic grinding can activate and accelerate not only structural changes (solid state amorphization) but also chemical decomposition of pharmaceuticals. A cryogenic milling device should be considered as a chemical reactor, where under favourable conditions chemical reactions could be mechanically initiated.

On the Segmental Dynamics and the Glass Transition Behavior of Poly(2-vinylpyridine) in One- and Two-Dimensional Nanometric Confinement.

Geometric nanoconfinement, in one and two dimensions, has a fundamental influence on the segmental dynamics of polymer glass-formers and can be markedly different from that observed in the bulk state. In this work, with the use of dielectric spectroscopy, we have investigated the glass transition behavior of poly(2-vinylpyridine) (P2VP) confined within alumina nanopores and prepared as a thin film supported on a silicon substrate. P2VP is known to exhibit strong, attractive interactions with confining surfaces due to the ability to form hydrogen bonds. Obtained results show no changes in the temperature evolution of the α-relaxation time in nanopores down to 20 nm size and 24 nm thin film. There is also no evidence of an out-of-equilibrium behavior observed for other glass-forming systems confined at the nanoscale. Nevertheless, in both cases, the confinement effect is seen as a substantial broadening of the α-relaxation time distribution. We discussed the results in terms of the importance of the interfacial energy between the polymer and various substrates, the sensitivity of the glass-transition temperature to density fluctuations, and the density scaling concept.

Pressure Dependence of the Crystallization Rate for the S-Enantiomer and a Racemic Mixture of Ibuprofen.

This paper examines the pressure effect on the crystallization rate of the pharmaceutically active enantiomerically pure S-enantiomer and the racemic mixture of the well-known drug ibuprofen. Performed experimental studies revealed that at ambient pressure S-ibuprofen crystallizes faster than the racemic mixture. When the pressure increases, the crystallization rate slows down for both systems, but interestingly it is more apparent in the case of the S-enantiomer. It is found that this experimentally observed trend can be understood based on the predictions of the classical nucleation theory. We suggest that the solid-liquid interfacial free energy is the main reason for the observed variations in S- and RS-ibuprofen's stability behaviors. Employing a special method of computational studies, i.e., the capillary fluctuation method, we show that the increase in pressure affects the solid-liquid interfacial free energy for S- and RS-ibuprofen in an entirely different way. Importantly, the detected differences correspond to the experimentally observed variations in the overall crystallization rates.

Pressure and Temperature Dependence of Local Structure and Dynamics in an Ionic Liquid.

A detailed understanding of the local dynamics in ionic liquids remains an important aspect in the design of new ionic liquids as advanced functional fluids. Here, we use small-angle X-ray scattering and quasi-elastic neutron spectroscopy to investigate the local structure and dynamics in a model ionic liquid as a function of temperature and pressure, with a particular focus on state points (P,T) where the macroscopic dynamics, i.e., conductivity, is the same. Our results suggest that the initial step of ion transport is a confined diffusion process, on the nanosecond timescale, where the motion is restricted by a cage of nearest neighbors. This process is invariant considering timescale, geometry, and the participation ratio, at state points of constant conductivity, i.e., state points of isoconductivity. The connection to the nearest-neighbor structure is underlined by the invariance of the peak in the structure factor corresponding to nearest-neighbor correlations. At shorter timescales, picoseconds, two localized relaxation processes of the cation can be observed, which are not directly linked to ion transport. However, these processes also show invariance at isoconductivity. This points to that the overall energy landscape in ionic liquids responds in the same way to density changes and is mainly governed by the nearest-neighbor interactions.

The role of the dipole moment orientations in the crystallization tendency of the van der Waals liquids - molecular dynamics simulations.

Computer simulations of model systems play a remarkable role in the contemporary studies of structural, dynamic and thermodynamic properties of supercooled liquids. However, the commonly employed model systems, i.e., simple-liquids, do not reflect the internal features of the real molecules, e.g., structural anisotropy and spatial distribution of charges, which might be crucial for the behavior of real materials. In this paper, we use the new model molecules of simple but anisotropic structure, to studies the effect of dipole moment orientation on the crystallization tendency. Our results indicate that proper orientation of the dipole moment could totally change the stability behavior of the system. Consequently, the exchange of a single atom within the molecule causing the change of dipole moment orientation might be crucial for controlling the crystallization tendency. Moreover, employing the classical nucleation theory, we explain the reason for this behavior.

Frequency of the AC Electric Field Determines How a Molecular Liquid Crystallizes.

The ability to control crystallization is of central importance to many technologies and pharmaceutical materials. Electric fields have been shown to impact crystallization, but little is known about the mechanism of such effects. Here we report on our observations of how the frequency of an external electric (ac) field changes the crystallization rate and the partitioning into distinct polymorphs of vinylethylene carbonate. We find that the field effects are pronounced only for frequencies below a certain threshold, which is orders of magnitude below that characterizing molecular orientation but consistent with the reorientation of polar crystal nuclei of radius r < 3 nm. We conclude that the electric field opens an additional nucleation pathway by lowering the free-energy barrier to form a polymorph that melts at a temperature ∼20 K below that of the ordinary crystal. This lower melting polymorph is not obtained at zero electrical field.

Testing density scaling in nanopore-confinement for hydrogen-bonded liquid dipropylene glycol.

Recently, it has been demonstrated that the glassy dynamics of the molecular liquids and polymers confined at the nanoscale level might satisfy the density scaling law (ρ γ /T) with the same value of the scaling exponent, γ, as that determined from the high-pressure studies of the bulk material. In this work, we have tested the validity of this interesting experimental finding for strongly hydrogen-bonded molecular liquid, dipropylene glycol (DPG), which is known to violate the ρ γ /T scaling rule in the supercooled liquid bulk state. The results of the independent dielectric relaxation studies carried out on increased pressure and in nanopores, have led to an important finding that when the density change induced by geometrical confinement is not very large, DPG can still obey the density scaling law with the same value of the scaling exponent as that found for the bulk sample. In this way, we confirm that the information obtained from the universal density scaling approach applied to nanoscale confined systems is somehow consistent with the macroscopic ones and that in both cases the same fundamental rules governs the glass-transition dynamics.

Connecting 1D and 2D Confined Polymer Dynamics to Its Bulk Behavior via Density Scaling.

Under confinement, the properties of polymers can be much different from the bulk. Because of the potential applications in technology and hope to reveal fundamental problems related to the glass-transition, it is important to realize whether the nanoscale and macroscopic behavior of polymer glass-formers are related to each other in any simple way. In this work, we have addressed this issue by studying the segmental dynamics of poly(4-chlorostyrene) (P4ClS) in the bulk and upon geometrical confinement at the nanoscale level, in either one- (thin films on Al substrate) or two- (within alumina nanopores) dimensions. The results demonstrate that the segmental relaxation time, irrespective of the confinement size or its dimensionality, can be scaled onto a single curve when plotted versus ργ/T with the same single scaling exponent, γ = 3.1, obtained via measurements at high pressures in bulk. The implication is that the macro- and nanoscale confined polymer dynamics are intrinsically connected and governed by the same underlying rules.

High-pressure cell for simultaneous dielectric and neutron spectroscopy.

In this article, we report on the design, manufacture, and testing of a high-pressure cell for simultaneous dielectric and neutron spectroscopy. This cell is a unique tool for studying dynamics on different time scales, from kilo- to picoseconds, covering universal features such as the α relaxation and fast vibrations at the same time. The cell, constructed in cylindrical geometry, is made of a high-strength aluminum alloy and operates up to 500 MPa in a temperature range between roughly 2 and 320 K. In order to measure the scattered neutron intensity and the sample capacitance simultaneously, a cylindrical capacitor is positioned within the bore of the high-pressure container. The capacitor consists of two concentric electrodes separated by insulating spacers. The performance of this setup has been successfully verified by collecting simultaneous dielectric and neutron spectroscopy data on dipropylene glycol, using both backscattering and time-of-flight instruments. We have carried out the experiments at different combinations of temperature and pressure in both the supercooled liquid and glassy state.