Discharge of the Nanopore Confinement Effect on the Glass Transition Dynamics via Viscous Flow.

Using dielectric spectroscopy, we demonstrate that confinement-induced changes in the glass transition dynamics, as observed for polymethylphenylsiloxane in alumina nanopores, reveal a pronounced nonequilibrium nature. Our results indicate that glass formers confined to nanopores are able to recover their bulklike mobility. We found that the characteristic time constant of such an equilibration process correlates with an extremely slow viscous flow rate in cylindrical channels of nanometer size. Thus, all the way to equilibrium, confinement effects seen in faster segmental dynamics are released through the viscous flow which eventually helps to eliminate surplus volume gained by nanoconstrained polymers upon cooling.

Evidence of a one-dimensional thermodynamic phase diagram for simple glass-formers.

Glass formers show motional processes over an extremely broad range of timescales, covering more than ten orders of magnitude, meaning that a full understanding of the glass transition needs to comprise this tremendous range in timescales. Here we report simultaneous dielectric and neutron spectroscopy investigations of three glass-forming liquids, probing in a single experiment the full range of dynamics. For two van der Waals liquids, we locate in the pressure-temperature phase diagram lines of identical dynamics of the molecules on both second and picosecond timescales. This confirms predictions of the isomorph theory and effectively reduces the phase diagram from two to one dimension. The implication is that dynamics on widely different timescales are governed by the same underlying mechanisms.

Formation of new polymorphs and control of crystallization in molecular glass-formers by electric field.

Static electric fields were observed to modify the crystallization behavior in a simple supercooled liquid, leading to a new crystal polymorph that could not be obtained in the absence of a field, even under high-pressure conditions. Using different thermal protocols and field amplitudes in the range from 40 to 200 kV cm-1, changes in both nucleation and crystal growth rates of 4-vinyl-propylene carbonate (vinyl-PC) are revealed. Remarkably, all field-induced changes in the crystallization behaviour were found to be fully reversible and do not affect dynamics of the tested liquid. Because vinyl-PC is a simple polar molecule, these field induced features are expected to occur in many other materials having permanent dipole moments. Our results highlight the important role of an external electric field as an additional control variable to influence the crystallization tendency of molecular glass-formers, and provide new opportunities in pharmaceutical science or organic electronics.

Nonlinear dielectric features of highly polar glass formers: Derivatives of propylene carbonate.

We have measured the nonlinear dielectric behavior of several highly polar propylene carbonate (PC) derivatives in the vicinity of their glass transition temperatures. Focus is on the effects of a large static electric field on the frequency dependent permittivity and on the cubic susceptibility measured using sinusoidal fields of high amplitude. The case of vinyl-PC shows dielectric saturation as well as an electro-rheological effect, i.e., a field induced increase of dielectric relaxation times, whose magnitude changes linearly with the apparent activation energy. The extent of this shift of the loss profile caused by the field correlates strongly with the peak magnitude of the cubic susceptibility, |χ3|, underlining the notion of a link between the |χ3| "hump" and this electro-rheological behavior. Further support for this picture emerges from the observation that the most polar of these liquids, (S)-(-)-methoxy-PC with εs ≈ 250, lacks both the electro-rheological effect in ε″(ω) and the "hump" typically observed in |χ3(ω)|. The absence of any sensitivity of the dynamics to an electric field is contrary to the expectation that the electro-rheological effect correlates with the field induced entropy change, which is extraordinarily high for this liquid. The results suggest that the dependence of the relaxation time on the electric field is not directly linked to the entropy change.

Comparison of high pressure and nanoscale confinement effects on crystallization of the molecular glass-forming liquid, dimethyl phthalate.

High pressure and nanoscopic confinement are two different strategies commonly employed to modify the physicochemical properties of various materials. Both strategies act mostly by changing the molecular packing. In this work, we performed a comparative study on the effect of compression and confined geometry on crystallization of a molecular liquid. Dielectric spectroscopy was employed to investigate the crystallization of the van der Waals liquid, dimethyl phthalate, in nanoporous alumina of different pore sizes as well as on increased pressure (up to 200 MPa). The analysis of the crystallization kinetics under varying thermodynamic conditions revealed that both strategies affect the crystallization behavior of the sample in very distinct ways. Compression shifts the maximum crystallization rate towards a higher temperature and broadens it. As a result, it is more challenging to avoid crystallization upon cooling the liquid at high pressure. In contrast, when the same material is incorporated into nanopores, crystallization significantly slows down and the maximum rate shifts towards a lower temperature with decreasing pore size. Finally, we show that crystallization in nanoporous alumina is accompanied by pre-crystallization effects upon which a shift of the α-relaxation peak is observed. An equilibration process prior to the initiation of crystallization was detected for the confined material both above and below the glass transition temperature of the interfacial layer, while not in the bulk.

The effect of hydrogen bonding propensity and enantiomeric composition on the dynamics of supercooled ketoprofen - dielectric, rheological and NMR studies.

The aim of this work is to analyze in detail the effect of small hydrogen bonding (HB) structures and enantiomeric composition on the dynamics of glass-forming liquid ketoprofen. For that purpose dielectric relaxation, rheological and NMR studies were performed. Investigated samples are racemic ketoprofen, a single enantiomer of ketoprofen and a racemic ketoprofen methyl ester with no tendency to form HB dimers. The combination of complementary experimental techniques enables us to show that macroscopic viscosity η and α-relaxation time τα have nearly the same temperature dependencies, whereas the relation between the viscosity (or molecular reorientation) and the translational self-diffusion coefficient violates Stokes-Einstein law already at high temperature. Additionally, based on dielectric relaxation studies performed on increased pressure we were able to identify similarities and key differences in the supercooled liquid dynamics of investigated materials affected by their tendency to form intermolecular hydrogen bonds. This includes the effect of pressure on the glass transition temperature Tg, changes in the fragility parameter m and activation volume ΔV, the role of thermal energy and density fluctuations in governing the viscous liquid dynamics (Ev/Ep ratio). Finally, we have also demonstrated that the dynamic behaviour of a single enantiomer and the racemic mixture of the same compound are very much alike. Nevertheless, some slight differences were observed, particularly in the τα(T) dependencies measured in the vicinity of glass transition both at ambient and elevated pressure.

Communication: Slow supramolecular mode in amine and thiol derivatives of 2-ethyl-1-hexanol revealed by combined dielectric and shear-mechanical studies.

In this paper, we present results of dielectric and shear-mechanical studies for amine (2-ethyl-1-hexylamine) and thiol (2-ethyl-1-hexanethiol) derivatives of the monohydroxy alcohol, 2-ethyl-1-hexanol. The amine and thiol can form hydrogen bonds weaker in strength than those of the alcohol. The combination of dielectric and shear-mechanical data enables us to reveal the presence of a relaxation mode slower than the α-relaxation. This mode is analogous to the Debye mode seen in monohydroxy alcohols and demonstrates that supramolecular structures are present for systems with lower hydrogen bonding strength. We report some key features accompanying the decrease in the strength of the hydrogen bonding interactions on the relaxation dynamics close to the glass-transition. This includes changes (i) in the amplitude of the Debye and α-relaxations and (ii) the separation between primary and secondary modes.

Thermodynamic scaling of molecular dynamics in supercooled liquid state of pharmaceuticals: Itraconazole and ketoconazole.

Pressure-Volume-Temperature (PVT) measurements and broadband dielectric spectroscopy were carried out to investigate molecular dynamics and to test the validity of thermodynamic scaling of two homologous compounds of pharmaceutical activity: itraconazole and ketoconazole in the wide range of thermodynamic conditions. The pressure coefficients of the glass transition temperature (dT(g)/dp) for itraconazole and ketoconazole were determined to be equal to 183 and 228 K/GPa, respectively. However, for itraconazole, the additional transition to the nematic phase was observed and characterized by the pressure coefficient dT(n)/dp = 258 K/GPa. From PVT and dielectric data, we obtained that the liquid-nematic phase transition is governed by the relaxation time since it occurred at constant τ(α) = 10(-5) s. Furthermore, we plotted the obtained relaxation times as a function of T(-1)v(-γ), which has revealed that the validity of thermodynamic scaling with the γ exponent equals to 3.69 ± 0.04 and 3.64 ± 0.03 for itraconazole and ketoconazole, respectively. Further analysis of the scaling parameter in itraconazole revealed that it unexpectedly decreases with increasing relaxation time, which resulted in dramatic change of the shape of the thermodynamic scaling master curve. While in the case of ketoconazole, it remained the same within entire range of data (within experimental uncertainty). We suppose that in case of itraconazole, this peculiar behavior is related to the liquid crystals' properties of itraconazole molecule.

Negative Pressure Vitrification of the Isochorically Confined Liquid in Nanopores.

Dielectric relaxation studies for model glass-forming liquids confined to nanoporous alumina matrices were examined together with high-pressure results. For confined liquids which show the deviation from bulk dynamics upon approaching the glass transition (the change from the Vogel-Fulcher-Tammann to the Arrhenius law), we have observed a striking agreement between the temperature dependence of the α-relaxation time in the Arrhenius-like region and the isochoric relaxation times extrapolated from the positive range of pressure to the negative pressure domain. Our finding provides strong evidence that glass-forming liquid confined to native nanopores enters the isochoric conditions once the mobility of the interfacial layer becomes frozen in. This results in the negative pressure effects on cooling. We also demonstrate that differences in the sensitivity of various glass-forming liquids to the "confinement effects" can be rationalized by considering the relative importance of thermal energy and density contributions in controlling the α-relaxation dynamics (the E(v)/E(p) ratio).

Impact of low molecular weight excipient octaacetylmaltose on the liquid crystalline ordering and molecular dynamics in the supercooled liquid and glassy state of itraconazole.

Different experimental and theoretical techniques were applied to investigate basic physical properties of very stable and homogeneous solid dispersions formed by itraconazole and octaacetylmaltose. Differential scanning calorimetry as well as semi-empirical calculations have indicated that liquid crystalline ordering in itraconazole was completely suppressed in the binary mixtures. Molecular dynamics studies with the use of broadband dielectric spectroscopy have shown that the width of the structural relaxation process becomes smaller and fragility drops in solid dispersions with respect to the pure itraconazole. Moreover, the dynamics of secondary relaxation processes was affected by acetylated maltose. As demonstrated, ß- and γ-secondary modes shift to higher and lower frequencies, respectively. On the other hand, aging experiments revealed that isostructural relaxation times in the glassy state become systematically longer with the addition of modified carbohydrate. This is a very important finding in the context of the current discussion on the factors affecting physical stability of easily crystallizing APIs. It seems that beside intermolecular interactions and local reorientation, the global mobility might control the crystallization of amorphous solid dispersions. Finally, we have demonstrated that itraconazole in binary mixtures dissolves faster and to greater extent with respect to the crystalline and amorphous form of this API.

Impact of inter- and intramolecular interactions on the physical stability of indomethacin dispersed in acetylated saccharides.

Differential scanning calorimetry (DSC), broadband dielectric (BDS), and Fourier transform infrared (FTIR) spectroscopies as well as theoretical computations were applied to investigate inter- and intramolecular interactions between the active pharmaceutical ingredient (API) indomethacin (IMC) and a series of acetylated saccharides. It was found that solid dispersions formed by modified glucose and IMC are the least physically stable of all studied samples. Dielectric measurements showed that this finding is related to neither the global nor local mobility, as the two were fairly similar. On the other hand, combined studies with the use of density functional theory (DFT) and FTIR methods indicated that, in contrast to acetylated glucose, modified disaccharides (maltose and sucrose) interact strongly with indomethacin. As a result, internal H-bonds between IMC molecules become very weak or are eventually broken. Simultaneously, strong H-bonds between the matrix and API are formed. This observation was used to explain the physical stability of the investigated solid dispersions. Finally, solubility measurements revealed that the solubility of IMC can be enhanced by the use of acetylated carbohydrates, although the observed improvement is marginal due to strong interactions.

Enhancement of the physical stability of amorphous indomethacin by mixing it with octaacetylmaltose. inter and intra molecular studies.

PURPOSE: To demonstrate a very effective and easy way of stabilization of amorphous indomethacin (IMC) by preparing binary mixtures with octaacetylmaltose (acMAL). In order to understand the origin of increased stability of amorphous system inter- and intramolecular interactions between IMC and acMAL were studied. METHODS: The amorphous IMC, acMAL and binary mixtures (IMC-acMAL) with different weight ratios were analyzed by using Dielectric Spectroscopy (DS), Differential Scanning Calorimetry (DSC), Raman Spectroscopy, X-ray Diffraction (XRD), Infrared Spectroscopy (FTIR) and Quantitative Structure-Activity Relationship (QSAR). RESULTS: Our studies have revealed that indomethacin mixed with acetylated saccharide forms homogeneous mixture. Interestingly, even a small amount of modified maltose prevents from recrystallization of amorphous indomethacin. FTIR measurements and QSAR calculations have shown that octaacetylmaltose significantly affects the concentration of indomethacin dimers. Moreover, with increasing the amount of acMAL in the amorphous solid dispersion molecular interactions between matrix and API become more dominant than IMC-IMC ones. Structural investigations with the use of X-ray diffraction technique have demonstrated that binary mixture of indomethacin with acMAL does not recrystallize upon storage at room temperature for more than 1.5 year. Finally, it was shown that acMAL can be used to improve solubility of IMC. CONCLUSIONS: Acetylated derivative of maltose might be very effective agent to improve physical stability of amorphous indomethacin as well as to enhance its solubility. Intermolecular interactions between modified carbohydrate and IMC are likely to be responsible for increased stability effect in the glassy state.

Molecular dynamics of itraconazole at ambient and high pressure.

Comprehensive molecular dynamics studies of vitrified and cryogrounded itraconazole (Itr) were performed at ambient and elevated pressure. DSC measurements yielded besides melting and glass transition observed during heating and cooling of both samples two further endothermic events at around T = 363 K and T = 346 K. The nature of these transitions was investigated using X-ray diffraction, broadband dielectric spectroscopy and Density Functional Theory calculations. The X-ray measurements indicated that extra ordering in itraconazole is likely to occur. Based on calculations and theory derived by Letz et al. the transition observed at T = 363 K was discussed in the context of formation of the nematic mesophase. In fact, additional FTIR measurements revealed that order parameter variation in Itr shows a typical sequence of liquid crystal phases with axially symmetric orientational order; i.e. a nematic phase in the temperature range 361.7 K to 346.5 K and a smectic A phase below 346.5. Moreover, dielectric measurements demonstrated that except for the structural relaxation process, there is also slower mode above the glass transition temperature in both vitrified and cryogrounded samples. We considered the origin of this mode taking into account DFT calculations, rod like shape of itraconazole and distribution of its dipole moment vectors. For the dielectric data collected at elevated pressure, evolution of the steepness index versus pressure was determined. Finally, the pressure coefficient of the glass transition temperature was evaluated to be equal to 190 K GPa(-1).

Molecular dynamics of the supercooled pharmaceutical agent posaconazole studied via differential scanning calorimetry and dielectric and mechanical spectroscopies.

This paper presents comprehensive studies on the molecular dynamics of a pharmaceutically important substance, posaconazole. In order to characterize relaxation dynamics in the supercooled liquid and glassy states, dielectric and mechanical spectroscopies were applied. Dielectric data have indicated multiple relaxation processes that appear above and below the glass transition temperature Tg (τα=100 s) of posaconazole. From the curvature of the dielectric log10(τα) versus inverse of temperature dependence, we determine so-called "fragility", being a very popular parameter for classifying the structural dynamics of supercooled liquids and polymers. From the calculations, we get m=150, which means that is one of the most fragile glass-forming liquids. In this paper, the relaxation dynamics of supercooled posaconazole extracted from the dielectric response function was also confronted with shear-mechanical relaxation. Finally, we have also presented a direct comparison of the fragility and the number of dynamically correlated molecules Nc determined from dynamic calorimetry curves and dielectric and mechanical spectroscopies, showing a clear deviation in the picture of glass-transition dynamics generated by calorimetric and spectroscopic techniques.

Communication: Synperiplanar to antiperiplanar conformation changes as underlying the mechanism of Debye process in supercooled ibuprofen.

In this Communication, we present experimental studies that put new insight into the puzzling nature of the Debye relaxation found in the supercooled liquid state of racemic ibuprofen. The appearance of D-relaxation in the loss spectra of non-hydrogen bonding methylated derivate of ibuprofen has proven that Debye relaxation is related solely with conformational changes of the carboxyl group, termed in this paper as synperiplanar-antiperiplanar. Our studies indicate that the presence of hydrogen bonding capabilities is not here the necessary condition to observe Debye process, however, their occurrence might strongly influence α- and D-relaxations dynamics. Interestingly, the activation energy of the D-process in ibuprofen methyl ester on approaching T(g) was found to be perfectly consistent with that reported for ibuprofen by Affouard and Correia [J. Phys. Chem. B 114, 11397-11402 (2010)] (~39 kJ/mol). Finally, IR measurements suggest that the equilibrium between conformers concentration depends on time and temperature, which might explain why the appearance of D-relaxation in supercooled ibuprofen depends on thermal history of the sample.

Mutarotation in biologically important pure L-fucose and its enantiomer.

The sugar specific mutarotation reaction in biologically important L-fucose and its enantiomer in the pure, anhydrous, supercooled liquid state has been studied. Kinetics measurements in the temperature range 313-328 K at ambient pressure have been performed by means of dielectric spectroscopy, a method widely used for studying the molecular dynamics of glass-forming liquids. The kinetic curves have been obtained by tracking the equilibration process in sugar melted and quenched to the desired temperature. Thereafter, an activation energy equal to Ea = 140 kJ mol(-1) for D-fucose and Ea = 123 kJ mol(-1) for L-fucose has been derived from the Arrhenius fit of temperature dependent rate constants. It was also shown that the kinetics curves at the lowest temperatures studied have sigmoidal shape, which was connected to the high concentration of furanosidic forms.

A new way of stabilization of furosemide upon cryogenic grinding by using acylated saccharides matrices. The role of hydrogen bonds in decomposition mechanism.

Recently it was reported that upon mechanical milling of pure furosemide significant chemical degradation occurs (Adrjanowicz et al. Pharm. Res.2011, 28, 3220-3236). In this paper, we present a novel way of chemical stabilization amorphous furosemide against decomposing that occur during mechanical treatment by preparing binary mixtures with acylated saccharides. To get some insight into the mechanism of chemical degradation of furosemide induced by cryomilling, experimental investigations supported by density functional theory (DFT) computations were carried out. This included detailed studies on molecular dynamics and physical properties of cryoground samples. The main thrust of our paper is that we have shown that furosemide cryomilled with acylated saccharides forms chemically and physically stable homogeneous mixtures with only one glass transition temperature, Tg. Finally, solubility measurements have demonstrated that furosemide cryomilled with acylated saccharides (glucose, maltose and sucrose) is much more soluble with respect to the crystalline form of this active pharmaceutical ingredient (API).

Impact of water on molecular dynamics of amorphous α-, ß-, and γ-cyclodextrins studied by dielectric spectroscopy.

Dielectric, calorimetric, and x-ray diffraction measurements were carried out on α-, ß-, and γ-cyclodextrins, which are cyclic saccharides built by, respectively, six, seven, and eight glucose units connected via glycosidic linkage. Differential scanning calorimetry measurements indicated that each carbohydrate has a melting temperature located much above the temperature at which thermal decomposition begins. Moreover, calorimetric data revealed that it is possible to completely dehydrate each cyclodextrin by annealing them above 413 K. Unfortunately, it is impossible to obtain amorphous forms of cyclodextrin by simple cooling of the melt. Thus, a solid state amorphization method has been applied. X-ray diffraction studies demonstrated that by ball milling at room temperature we are able to obtain completely amorphous cyclodextrins. Finally, dielectric measurements were carried out to probe molecular dynamics in the amorphous state of cyclodextrins. It was found that there is only one relaxation process in amorphous hydrated cyclodextrins, while in dried samples two secondary relaxations are present. Moreover, we have shown that water has an enormous effect on the dynamics of both relaxation modes, i.e., with increasing content of water, the activation energy of the slow mode decreases, while that evaluated for the fast mode increases. We were not able to follow the dynamics of the structural relaxation process, because glass transition temperatures of amorphous cyclodextrins were found to lie above thermal degradation points.

Study of dynamics and crystallization kinetics of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile at ambient and elevated pressure.

The organic liquid ROY, i.e., 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, has been a subject of detailed study in the last few years. One interest in ROY lies in its polymorph-dependent fast crystal growth mode below and above the glass transition temperature. This growth mode is not diffusion controlled, and the possibility that it is enabled by secondary relaxation had been suggested. However, a previous study by dielectric relaxation spectroscopy had not been able to find any resolved secondary relaxation. The present paper reports new dielectric measurements of ROY in the liquid and glassy states at ambient pressure and elevated pressure, which were performed to provide more insight into the molecular dynamics as well as the crystallization tendency of ROY. In the search of secondary relaxation, a special glassy state of ROY was prepared by applying high pressure to the liquid state, from which secondary relaxation was possibly resolved. Thus, the role of secondary relaxation in crystallization of ROY remains to be clarified. Notwithstanding, the secondary relaxation present is not necessarily the sole enabler of crystallization. In an effort to search for possible cause of crystallization other than secondary relaxation, we also performed crystallization kinetics studies of ROY at different T and P combinations while keeping the structural relaxation time constant. The results show that crystallization of ROY speeds up with pressure, opposite to the trend found in the crystallization of ibuprofen studied up to 1 GPa. The dielectric relaxation and thermodynamic properties of ROY with phenolphthalein dimethylether (PDE) are similar in many respects, but PDE does not crystallize. Taking all the above into account, besides the secondary relaxation, the specific chemical structure, molecular interactions and packing of the molecules are additional factors that could affect the kinetics of crystallization found in ROY.

Molecular dynamics in supercooled liquid and glassy states of antibiotics: azithromycin, clarithromycin and roxithromycin studied by dielectric spectroscopy. Advantages given by the amorphous state.

Antibiotics are chemical compounds of extremely important medical role. Their history can be traced back more than one hundred years. Despite the passing time and significant progress made in pharmacy and medicine, treatment of many bacterial infections without antibiotics would be completely impossible. This makes them particularly unique substances and explains the unflagging popularity of antibiotics within the medical community. Herein, using dielectric spectroscopy we have studied the molecular mobility in the supercooled liquid and glassy states of three well-known antibiotic agents: azithromycin, clarithromycin and roxithromycin. Dielectric studies revealed a number of relaxation processes of different molecular origin. Besides the primary α-relaxation, observed above the respective glass transition temperatures of antibiotics, two secondary relaxations in the glassy state were identified. Interestingly, the fragility index as well as activation energies of the secondary processes turned out to be practically the same for all three compounds, indicating probably much the same molecular dynamics. Long-term stability of amorphous antibiotics at room temperature was confirmed by X-ray diffraction technique, and calorimetric studies were performed to evaluate the basic thermodynamic parameters. Finally, we have also checked the experimental solubility advantages given by the amorphous form of the examined antibiotics.