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Varying thermodynamic conditions as a new way to tune the molecular order in glassy itraconazole
Abstract
In this paper, comprehensive calorimetric, structural, inter- and intramolecular dynamics measurements with the use of Differential Scanning Calorimetry (DSC), X-ray diffraction (XRD), Broadband Dielectric and Fourier Transform Infrared (FTIR) spectroscopies have been applied to investigate properties of itraconazole (ITZ) glasses obtained via slow cooling (ordinary glass, OG), rapid quenching (quenched glass, QG) and fast compression (compressed glass, CG). Interestingly, XRD studies showed that consistently with a recent paper by Teerakapibal et al. [Phys. Rev. Lett. 120 (2018) 055502], we can significantly reduce the content of smectic order in the glassy state of this compound solely by varying the rate of cooling and pressurization. Thermograms registered for the studied samples revealed the presence of the two glass transition temperatures located below and above the T g of the OG. Since in the QG and CG a smectic phase has not been completely removed, two T g s were interpreted as a clear manifestation of vitrification of reorientational motions around long (α) and short (δ) axis of ITZ, occurring within nematic and smectic domains, coexisting at the same thermodynamic conditions. Finally, structural studies carried out on the quenched and compressed glasses indicated that the smectic order tends to reconstruct with time during storage at T = 298 K. These data were furthermore used to explain the unexpected shift of the β-process towards higher frequencies (shorter relaxation times) during aging experiments performed on CG and QG at room temperature. Results presented herein clearly show that the characteristic liquid crystalline ordering can be significantly affected not only by the temperature variation but also by the density changes.
... In turn, Gómez et al. [37] have demonstrated that the vapor deposition of ITZ particles, carried out at temperatures close to the T g , allows receiving API films with various tilt angles of smectic arrangement. Besides, in our recent paper [38], as well as in work by Teerakapibal et al. [39], it was shown that by the variation in the cooling and compression rates, one could reduce the degree of smectic order in the glassy ITZ. Finally, it is worth mentioning about the studies on binary systems composed of this API and high as well as low molecular weight compounds (polymers: hypromellose acetate succinate, poly(acrylic acid), methacrylic acid−ethyl acrylate copolymer and acetylated saccharides, respectively) [40,41], which revealed that the addition of both types of excipients results in suppressing the LC order in ITZ. ...
... Panels (b) and (d) present the same dependencies for neat ITZ, POS, KET, FLU, as well as ITZ-POS, ITZ-KET, ITZ-VOR, ITZ-FLU (7:1 m/m) binary systems. Data for neat ITZ were taken from Ref. [38] and [41]. ...
In this paper, thermal and structural properties, as well as molecular dynamics of co-amorphous binary mixtures composed of itraconazole (ITZ) and four other active pharmaceutical ingredients (APIs) with antifungal activity (posaconazole (POS), ketoconazole (KET), fluconazole (FLU), and voriconazole (VOR)), have been investigated. Calorimetric measurements indicated that with increasing concentration of each excipient (EXC), the glass transition temperature and phase transition temperatures, related to the formation of nematic and smectic order, are affected in the binary systems. Comprehensive analysis of the enthalpy of isotropic-nematic transition and the temperature dependence of the order parameter, calculated from infrared data for selected mixtures, supported by the results of X-ray diffraction investigations, enabled us to confirm the suppression of liquid crystalline (LC) ordering in ITZ by KET, FLU, and VOR. On the other hand, ITZ enforced the nematic-like molecular arrangement of POS. Further dielectric measurements revealed that the type of EXC and its content in the mixture have no impact on the ratio of α- and δ-relaxation times (τα and τδ, respectively) in ITZ. Moreover, it was shown that δ-process is more sensitive to the isotropic-nematic phase transition than the α-one, and the formation of the nematic phase in this API occurs at different τα and τδ, dependently on the type of EXC and its concentration in the mixture. Summarizing, the results of our studies are much different with respect to those reported previously by Kozyra et al. [Mol. Pharm. 15 (2018) 5192–5206] and by some of us [Kaminska et al. Eur. J. Pharm. Biopharm. 88 (2014) 1094–1104] for ITZ mixed with various polymers and acetylated maltose, respectively. This finding clearly indicates that there is a different impact of the low and high molecular weight excipients on the ability in the formation of LC phases in ITZ, which may have important implications for the further development of the formulations of this pharmaceutical.
Itraconazole (ITZ) is a thermotropic liquid crystal that exhibits isotropic, nematic, and smectic phases on cooling towards the glass transition upon melting. Over the years, new aspects regarding the liquid-crystalline ordering of this antifungal drug were systematically revealed. It has been shown recently that the temperature range of individual mesophases in ITZ can be modified by adding a small amount of glycerol (GLY). Moreover, above the critical concentration of 5% w/w, a smectic to nematic transition can be avoided. Here we go one step further, and we used broadband dielectric spectroscopy to investigate the new phase behavior of the ITZ-GLY mixture (5% w/w). To confirm the phase transformations of the ITZ-GLY mixture, differential scanning calorimetry was also employed. The analysis of molecular dynamics of the ITZ-GLY mixture in the glassy and isotropic phases revealed features similar to those observed for neat ITZ. Two relaxation processes were identified in the smectic-A phase, with similar temperature dependence, most likely related to the fast rotations around the long axis of a molecule. Additionally, the derivative analysis revealed another low-frequency process hidden under DC conductivity ascribed to the slow rotations about a short axis. We will show that the differences in the molecular organization in the smectic-A and isotropic phases leave a clear fingerprint on the temperature behavior of relaxation times and other dielectric parameters, such as DC conductivity and dielectric strength, for which a pretransition effect has been detected.
Broadband dielectric and Raman spectroscopies combined with calorimetric measurements and DFT calculations have been used to investigate the molecular dynamics of the benzyl derivative of ibuprofen (Ben-IBU) incorporated into aluminum oxide (AAO) templates of various pore diameters (d=20 nm and d=80 nm). Time-dependent experiments on the material confined into pores of d=20 nm revealed the occurrence of the kinetic process of the low activation barrier, that was manifested as a variation in the integral intensities of some characteristic vibrations of carboxylic and benzene moieties as well as a shift of the structural relaxation process. Complementary DFT computations enabled us to identify its molecular nature as originating from cis to trans like conformational change. Our results clearly show that molecular rearrangements enforced by the interactions with the pore walls/substrate may affect the properties of the confined systems and consequently they must be taken into account to understand the dynamics and variation of the glass transition temperature in high (polymers) and low molecular glass formers subjected to spatial restrictions at the nanometer scale.
Glassy dynamics of polymethylphenylsiloxane (PMPS) is studied by broadband dielectric spec- troscopy in one-dimensional (1D) and two-dimensional (2D) nanometric confinement; the former is realized in thin polymer layers having thicknesses down to 5 nm, and the latter in unidirectional (thickness 50 μm) nanopores with diameters varying between 4 and 8 nm. Based on the dielectric measurements carried out in a broad spectral range at widely varying temperatures, glassy dynam- ics is analyzed in detail in 1D and in 2D confinements with the following results: (i) the segmental dynamics (dynamic glass transition) of PMPS in 1D confinement down to thicknesses of 5 nm is identical to the bulk in the mean relaxation rate and the width of the relaxation time distribution function; (ii) additionally a well separated surface induced relaxation is observed, being assigned to adsorption and desorption processes of polymer segments with the solid interface; (iii) in 2D confinement with native inner pore walls, the segmental dynamics shows a confinement effect, i.e., the smaller the pores are, the faster the segmental dynamics; on silanization, this dependence on the pore diameter vanishes, but the mean relaxation rate is still faster than in 1D confinement; (iv) in a 2D confinement, a pronounced surface induced relaxation process is found, the strength of which increases with the decreasing pore diameter; it can be fully removed by silanization of the inner pore walls; (v) the surface induced relaxation depends on its spectral position only negligibly on the pore diameter; (vi) comparing 1D and 2D confinements, the segmental dynamics in the latter is by about two orders of magnitude faster. All these findings can be comprehended by considering the density of the polymer; in 1D it is assumed to be the same as in the bulk, hence the dynamic glass transition is not altered; in 2D it is reduced due to a frustration of packaging resulting in a higher free volume, as proven by ortho-positronium annihilation lifetime spectroscopy. Published by AIP Publishing. [http://dx.doi.org/10.1063/1.4974767]
The impact of nanoparticles on phase transitions in liquid crystal (LC) - nanoparticles nanocollids is still poorly known. This contribution resume published and present new results in this area for dodecylcyanobiphenyl (12CB), pentylcyanobiphenyl (5CB) and hexyl isothiocyanatobiphenyl (6BT) as the LC host with the addition of BaTiO3 nanoparticles. The latter has a strong impact on the value of dielectric constant, relaxation time and the discontinuity of the isotropic – mesophase transitions. The first ever high pressure studies in such systems are also presented.
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 (dTg
/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 dTn
/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.
The static and complex permittivity of 4-n-octyl-4'-cyanobiphenyl (8CB) has been measured for the isotropic, nematic and smectic A phases as functions of temperature and pressure. The ranges of 297 - 361 K, 0.1 - 220 MPa, and 0.1 - 13 MHz, were covered. Only the parallel component of the complex permittivity, ε* (f) = ε′ (f) - iε″ (f), was measured. The relaxation times T∥(p, T) as well as Tis(p, T) were analysed at constant temperature, pressure and volume, yielding the activation volume, Δ≠V (T), activation enthalpy Δ≠H(p), and activation energy Δ≠U(V), respectively. All activation parameters calculated for the smectic A phase of 8CB are smaller than those obtained for the nematic phase. The activation energy constitutes approximately half of the activation enthalpy value in all three phases studied. The pressure study allowed to calculate the pressure dependence of the retardation factor g∥(p,T), from which the nematic potential q(p, T) can be derived. Using the relationships between g∥ and q / RT proposed by Kalmykov and Coffey, the order parameter <P2(p, T)> was calculated as a function of pressure.
Broadband Dielectric Spectroscopy (BDS) is used to study the molecular dynamics of thin layers of itraconazole – an active pharmaceutics ingredient with rod-like structure and whose Differential Scanning Calorimetry (DSC) scans reveal liquid crystalline-like phase transitions. It is found that (i) the structural relaxation process remains bulk like, within the limits of experimental accuracy, in its mean relaxation rate, while (ii) its shape is governed by two competing events: interfacial interactions, and crystalline ordering. Additionally, (iii) the dynamics of the -relaxation – assigned to the flip-flop rotation of the molecule about its short axis – deviates from bulk behaviour as the glass transition is approached for the confined material. These observations are rationalized within the framework of molecular dynamics as currently understood.
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.(15) 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).
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, Tg. 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 1.16Tg, where the dynamic glass transition (α relaxation) and the secondary β 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.
Results of studies of the dielectric permittivity and nonlinear dielectric effect NDE in the isotropic phase of n-hexyl-cyanobiphenyl are presented. The data reported cover both pressure and temperature dependence. Measurements under atmospheric pressure were carried out in a wide range, up to 100 K from the clearing temperature. The application of a weak measurement frequency (f 67 kHz) resulted in a negligible influence of relaxation processes on NDE results. For both temperature and pressure paths, the dielectric permittivity and the NDE exhibited strong pretransitional effects, described by ''critical'' exponents 10.5 and 1, respectively. Scaling expressions for the pretransitional behavior of the NDE and of the dielectric per-mittivity have been proposed. The relationship between pretransitional effects in the isotropic phase of nem-atogens and in critical solutions has also been discussed.
The pressure-temperature phase diagram of n-octyl-isothiocyanato-biphenyl (8BT) in the pressure range up to 250 MPa (2.5 kbar) and the temperature range 250-400 K was established with the aid of DTA. At 1 atm the substance exhibits exclusively CrE polymorphism. At pressures above 190 MPa, the clearing line splits showing an additional phase which is not yet identified. Dielectric relaxation measurements on the CrE phase of 8BT were performed in the pressure range 0.1-120 MPa and the temperature range 304-345 K. A Debye-type relaxation process was observed in the frequency range 100 Hz-1 MHz. The longitudinal relaxation time τ, characterizing the molecular reorientations around the short axis, was analysed with respect to the pressure and temperature, yielding the activation volume, Δ#V = RT(∂ ln τ/∂p)T, and activation enthalpy, Δ#H = R(∂ ln τ/∂ T-1)p, respectively. The results are compared with analogous data obtained recently for similar compounds having other liquid crystalline phases (N, SmA).
Molecular dynamics and orientational order of 4-heptyl-4'-isothiocyanatobiphenyl (7BT) in non-intersecting nano-pores of mean diameters from 4 nm to 10.5 nm are studied by a combination of Broadband Dielectric and Fourier-Transform Infrared Spectroscopy. The smectic E phase observed in bulk 7BT is replaced by short-range molecular order imposed by the surface potential within the pores. In contrast to bulk dielectric properties of 7BT, geometrical confinement leads to modification of the molecular dynamics. Two dielectric relaxation processes exhibiting Arrhenius-like thermal activation are detected for molecules in nanopores of mean diameters from 6 nm to 10.5 nm. The slower process is assigned to molecular reorientation around the short axis (delta-relaxation) whereas the faster dipolar relaxation process (beta-process) is attributed to librational motion of the molecules close to the pore-walls. Infrared Transition Moment Orientational Analysis reveals different molecular arrangement in pores of diameters 10.5 nm compared to the molecules in 4 nm and 6 nm pores.
Singular behavior of the static dielectric permittivity of n-alkyloxycyanobiphenyls (CnH2n+1O-Ph-Ph-C [triple bond] N, n=6, 7) was studied above and below the nematic clearing point (T(I-N)). On approaching the clearing point, the evolution of principal components of the nematic permittivity tensor, epsilon(parallel) and epsilon(perpendicular), is described by the order parameter exponent beta approximately 0.25. The mean value of the nematic permittivity epsilon(mean)=(epsilon(parallel)+2epsilon(perpendicular))/3 exhibits a singular behavior similar to that observed in the isotropic phase and that for the diameter of the coexistence curve in binary mixtures. The derivative of experimental data d(epsilon)iso(T)/dT and d(epsilon)mean(T)/dT shows the specific-heat-like behavior with universal exponents alpha=alpha' approximately 0.5. Results obtained confirm the hypothesis of the fluidlike, pseudospinodal, and tricritical behavior of the isotropic to nematic phase transition. [A. Drozd-Rzoska, Phys. Rev. E 59, 5556 (1999)].
The longitudinal relaxation time tau of a series of alkyl-isothiocyanato-biphenyls (nBT) liquid crystals in the smectic E phase was measured as a function of temperature T and pressure P using dielectric spectroscopy. This relaxation time was found to become essentially constant, independent of T and P, at both the clearing point and the lower temperature crystalline transition. tau(T,P) could also be superposed as a function of the product TV(gamma), where V is the specific volume and gamma is a material constant. It then follows from the invariance of the relaxation time at the transition that the exponent gamma superposing tau(T,V) can be identified with the thermodynamic ratio Gamma=- partial differential log(T(c)) partial differential log(V(c)), where the subscript c denotes the value at the phase transition. Analysis of literature data on other liquid crystals shows that they likewise exhibit a constant tau at their phase transitions. Thus, there is a surprising relationship between the thermodynamic conditions defining the stability limits of a liquid crystalline phase and the dynamic properties reflected in the magnitude of the longitudinal relaxation time.
Different experimental techniques were applied to study thermal and structural properties, strength of H-bonds, possible keto-enol tautomerism and molecular dynamics at various thermodynamic conditions in the H-bonded active substance, curcumin (CRM). Dielectric measurements revealed dynamical features of examined compound that are uncharacteristic for the associated systems. This includes enormously large pressure coefficient of the glass transition temperature and prominent drop of the fragility with compression. Simultaneously, the shape of α-process slightly broadened at elevated pressures. Infrared investigations demonstrated that this effect is related to the variation in the population of H-bonds. Moreover, we studied the changes in the structural and dynamical properties of the glasses prepared upon cooling of the melt (ordinary glass, OG) and the one obtained after compression of CRM in the liquid phase and decompression at T = 293 K (dense glass, DG). Interestingly, during the aging of the latter sample, a clear shift of the β-relaxation towards higher frequencies was noted. This unexpected result indicated that the density of DG is probably getting smaller with time. Complementary X-ray diffraction experiments confirmed this supposition. Additionally, they showed that in DG there are traces of polymorph II of CRM that has a higher density than initial crystals (polymorph I). Finally, infrared studies demonstrated that H-bond pattern in DG is slightly different with respect to OG. Furthermore, Raman investigations suggested that probably keto-enol tautomerism might be shifted towards diketo form in the glass obtained at high compression. Our investigations are very interesting in the context of better understanding of the behavior of associated systems at high compression as well as provide a better insight into dynamics of higher density glasses produced at elevated pressures.
Herein, we tested the validity of the thermodynamic scaling of two (α and δ) relaxation processes observed in the isotropic and nematic phases of itraconazole, that is classified as a liquid crystal (LC). As illustrated, relaxation times of both processes obtained at various thermodynamic conditions can be successfully superposed over 1/TV^γ with different scaling exponents, γ, satisfying the thermodynamic scaling law. However, it was found that γ parameters determined in the isotropic phase are higher than those estimated for respective relaxation processes in the nematic state [J. Chem. Phys. 2015, 142, 224507]. It seems that differences in the arrangements of molecules within LC phases significantly affect the effective intermolecular potential resulting in the variation of scaling exponent and disagreement between γ and γEOS (estimated from the equation of state). The observed behavior suggests that both variables depend not only on the intermolecular potential but also on the degree of molecular ordering.
Liquid crystalline (LC) materials and their non-medical applications have been known for decades, especially in the production of displays, however the pharmaceutical implications of the LC state are inadequately appreciated and experimental data misunderstood leading to possible errors, especially in relation to physical stability of medicines. The aim of this work was to study LC phases of itraconazole (ITZ), an azole antifungal active molecule, and, for the first time, to generate full thermodynamic phase diagrams for ITZ/polymer systems taking into account isotropic and anisotropic phases that this drug can form. It was found that supercooled ITZ does not form an amorphous, but a vitrified smectic (vSm) phase with a glass transition temperature of 59.35 °C (determined using a 10°C/min heating rate), as evident from X-ray diffraction and thermomicroscopic (PLM) experiments. Two endothermic LC events with the onset temperature values for a smectic to nematic transition of 73.2±0.4 °C and a nematic to isotropic transformation at 90.4±0.35 °C and enthalpies of transition of 416±34 J/mol and 842±10 J/mol, respectively, were recorded. For the binary supercooled mixtures, PLM and differential scanning calorimetry showed a phase separation with birefringent vSm persistent over a wide polymer range, as noticed especially for the hypromellose acetate succinate (HAS) systems. Both, smectic and nematic, phases were detected for the supercooled ITZ/HAS and ITZ/methacrylic acid - ethyl acrylate copolymer (EUD) mixtures, while geometric restrictions inhibited the smectic formation in the ITZ/polyacrylic acid (CAR) systems. The Flory-Huggins lattice theory coupled with the Maier-Saupe-McMillan approach to model anisotropic ordering of molecules was successfully utilised to create phase diagrams for all ITZ/polymer mixtures. It was concluded that in a supercooled ITR/polymer mix, if ITZ is present in a liquid crystalline phase, immiscibility as a result of molecule anisotropy is afforded. This study shows that the LC nature of ITZ cannot be disregarded when designing stable formulations containing this molecule.
The inter- and intra-molecular interactions as they evolve in the course of glassy solidification are studied by broadband dielectric—and Fourier-transform infrared—spectroscopy for oligomeric derivatives of poly(ethylene glycol) derivatives, namely, poly(ethylene glycol) phenyl ether acrylate and poly(ethylene glycol) dibenzoate in the bulk and under confinement in nanoporous silica having mean pore diameters 4, 6, and 8 nm, with native and silanized inner surfaces. Analyzing the spectral positions and the oscillator strengths of specific IR absorption bands and their temperature dependencies enables one to trace the changes in the intra-molecular potentials and to compare it with the dielectrically determined primarily inter-molecular dynamics. Special emphasis is given to the calorimetric glass transition temperature Tg and Tαβ ≈ 1.25Tg, where characteristic changes in conformation appear, and the secondary β-relaxation merges with the dynamic glass transition (α-relaxation). Furthermore, the impact of main chain conformations, inter- and intra-molecular hydrogen bonding, and nanometric confinement on the dynamic glass transition is unraveled.
I. INTRODUCTION
The effect of the chemical modification of poly(propylene glycol) (PPG) end groups on the molecular dynamics under 2D confinement and the polymer/matrix interactions (including interfacial energies) was investigated by a combination of differential scanning calorimetry (DSC), broadband dielectric spectroscopy (BDS), surface tension and contact angle measurements. The replacement of −OH groups in native PPG allowed to modify the interactions with the hydroxyl groups attached to the pore walls of nanoporous aluminum oxide (AAO) membranes of various pore diameter. It was found that the observed reduction in the glass transition temperature (Tg) of the core polymers correlates well with a general trend (the higher the solid–liquid interfacial tension, γSL, the lower Tg,confined) reported earlier. Moreover, we demonstrated that although the interfacial solid–liquid energy seems to be almost the same for each studied herein material, a clear change in the crossover temperature (Tc), related to the vitrification of the polymers adsorbed to the pore walls, is noted. Interestingly, the shift in Tc with respect to the glass transition temperature of the bulk polymer scales well according to the decreasing ability in the formation of H bonds in the order PPG–OH → PPG–NH2 → PPG–OCH3 for the constant γSL. One can add that no such effect is found for the glass transition of the core polymers, where a similar shift of the Tg was recorded. This finding has been discussed in the context of various sensitivity of the studied materials to the density fluctuations, equilibration phenomena occurring below Tc, etc. We believe that our finding will help in a better understanding of an interplay between interfacial and core molecules and contribute significantly to the discussion on the impact of interfacial interactions on the molecular dynamics of polymers under 2D confinement.
Type II clathrate hydrates (CHs) M•17 H2O, with M = tetrahydrofuran (THF) or 1,3 dioxolane, are known to collapse, or amorphize, on pressurization to ∼1.3 GPa in the temperature range 77-140 K. On heating at 1 GPa, these pressure-amorphized CH states show a weak, stretched sigmoid-shaped, heat-capacity increase because of a glass transition. Here we use thermal conductivity and heat capacity measurements to show that also type II CH with M = cyclobutanone (CB) collapses on isothermal pressurization and undergoes a similar, weak, glass transition upon heating at 1 GPa. Furthermore, we reveal for both THF CH and CB CH a second, much more pronounced, glass transition at temperatures above the thermally weak glass transition on heating in the 0.2-0.7 GPa range. This result suggests the general occurrence of two glass transitions in water rich (94 mol%) pressure-collapsed CHs. Because of large increase in dielectric permittivity concurrently as the weak heat capacity increase, the first glass transition must be due to kinetic unfreezing of water molecules. The thermal features of the second glass transition, measured on isobaric temperature cycling, are typical of a glass-liquid-glass transition, which suggests that pressure-amorphized CHs transform reversibly to liquids.
Liquid crystals (LCs) are known to undergo rapid ordering transitions with virtually no hysteresis. We report a remarkable counterexample, itraconazole, where the nematic to smectic transition is avoided at a cooling rate exceeding 20 K/s. The smectic order trapped in a glass is the order reached by the equilibrium liquid before the kinetic arrest of the end-over-end molecular rotation. This is attributed to the fact that smectic ordering requires orientational ordering and suggests a general condition for preparing organic glasses with tunable LC order for electronic applications.
In the present work, a detailed analysis of the glassy behavior and the relaxation dynamics of the liquid crystal dimer α-(4-cyanobiphenyl-4′-yloxy)-ω-(1-pyrenimine-benzylidene-4′-oxy) heptane (CBO7O.Py) throughout both nematic and smectic-A mesophases by means of broadband dielectric spectroscopy has been performed. CBO7O.Py shows three different dielectric relaxation modes and two glass transition (Tg) temperatures: The higher Tg is due to the freezing of the molecular motions responsible for the relaxation mode with the lowest frequency (μ1L); the lower Tg is due to the motions responsible for the two relaxation modes with highest frequencies (μ1H and μ2), which converge just at their corresponding Tg. It is shown how the three modes follow a critical-like description via the dynamic scaling model. The two modes with lowest frequencies (μ1L and μ1H) are cooperative in the whole range of the mesophases, whereas the highest frequency mode (μ2) is cooperative just below some crossover temperature. In terms of fragility, at the glass transition, the ensemble (μ1H+μ2) presents a value of the steepness index and μ1L a different one, meaning that fragility is a property intrinsic to the molecular motion itself. Finally, the steepness index seems to have a universal behavior with temperature for the dielectric relaxation modes of liquid crystal dimers, being almost constant at high temperatures and increasing drastically when cooling the compound down to the glass transition from a temperature about 34TNI.
The aim of this book is to give a unified and critical account of the fundamental aspects of liquid crystals. Preference is given to discussing the assumptions made in developing theories and analyzing experimental data rather than to attempting to compile all the latest results. The book has four parts. Part I is quite descriptive in character and gives a general overview of the various liquid crystalline phases. Part II deals with the macroscopic continuum theory of liquid crystals and gives a systematic development of the theory from a tensorial point of view thus emphasizing the relevant symmetries. Part III concentrates on experiments that provide microscopic information on the orientational behaviour of the molecules. Finally Part IV discusses the theory of the various phases and their attendant phase transitions from both a Landau and a molecular-statistical point of view. Simplifying the various models as far as possible, it critically examines the merits of a molecular-statistical approach.
The impacts of nucleation site and temperature on the melt crystallization of itraconazole (ITZ) were investigated. ITZ recrystallized from melt into three distinct zones between two glass coverslips, as observed under a polarized light microscope. The first two corresponded to Forms I and II which are monotropically related, as determined by solubility and thermal analyses. The third zone differed from the other two in XRPD pattern, thermal properties, FTIR spectrum and dissolution rate, indicative of a new form (III) which has not been reported previously. Form III readily converted to the more stable Form II with the evolution of heat upon heating above 100°C or Form I upon dissolution in aqueous ethanol. At 70°C-150°C, Form II exhibited the fastest bulk crystal growth, followed successively by Form I and Form III. Analysis of the crystal growth data using the two-dimensional nucleation model afforded good data fitting with the model and revealed an inverse relationship between the bulk crystal growth rates and activation energies of individual polymorphs, reflecting the suitability of this model for describing the ITZ crystallization from melt. The polymorph selectivity of recrystallized ITZ appeared to be dictated by both the nucleation and crystal growth rates of individual polymorphs.
The freezing of the cooperative reorientational motions in orientationally disordered (OD) molecular crystals marks the so-called “glassy” transition, which may be considered a lower-dimensional version of the structural glass transition. Although structural glasses display both positional and orientational disorder, in orientational glasses, however, the disorder involves exclusively the orientational degrees of freedom of the constituent molecules, while the molecular centers of mass form an ordered lattice. We report here on a glass-forming system with even fewer degrees of freedom, namely, the OD phase of a dipolar benzene derivative, pentachloronitrobenzene (C6Cl5NO2). We probe the orientational dynamics of pentachloronitrobenzene as a function of temperature and pressure by means of dielectric spectroscopy (and high-pressure density measurements), and we show that, due to its anisotropy, the system exhibits a double primary relaxation feature associated with two distinct motions of the molecular dipole moment. This complex relaxation scenario shows a scaled dependence on the thermodynamic variables (P,T), with all relaxation times collapsing onto a single curve for each relaxation when plotted versus a specific-volume-dependent scaled variable TVγ. Our findings are in line with the recent prediction by Dyre and co-workers of the existence of a hidden-scale invariance also in van der Waals crystalline materials.
The dynamics and thermodynamics of confined triphenyl phosphite (TPP) were studied using broadband dielectric spectroscopy (BDS) and differential scanning calorimetry (DSC). Geometric confinement in channels having length scales commensurate with the molecular size of TPP causes bifurcation of the dynamics: two populations are observed, distinguished by their reorientational mobilities and glass transition temperatures. Upon cooling, significant changes in the relaxation process and temperature dependence occur due to the slow vitrification of the molecules in close proximity to the interface. Such a kinetic aspect of glass formation is unusual. This surface interaction alleviates constraints on the molecules, allowing their glass transition to shift to lower temperatures. Simultaneously, it was observed that the structural relaxation process shifts to lower frequencies, and the distribution of the relaxation times becomes narrower upon annealing. This effect is especially visible at lower frequencies, indicating the decreasing contribution of those molecules characterized by slower dynamics. In addition, it was found that structural relaxation times, as well as the glass transition temperatures, can be significantly modified by annealing samples over a particular range of temperatures. This work facilitated the understanding of the interplay between different kinds of mobility and its impact on changes in the glass transition temperature for two-dimensional confined materials.
The pressure-temperature phase diagram of n-octyl-isothiocyanato-biphenyl (8BT) in the pressure range up to 250 MPa (2.5 kbar) and the temperature range 250-400 K was established with the aid of DTA. At 1 atm the substance exhibits exclusively CrE polymorphism. At pressures above 190 MPa, the clearing line splits showing an additional phase which is not yet identified. Dielectric relaxation measurements on the CrE phase of 8BT were performed in the pressure range 0.1-120 MPa and the temperature range 304-345 K. A Debye-type relaxation process was observed in the frequency range 100 Hz-1 MHz. The longitudinal relaxation time tau, characterizing the molecular reorientations around the short axis, was analysed with respect to the pressure and temperature, yielding the activation volume, Delta V-#= RT(partial derivative 1n tau /p)(T), and activation enthalpy, Delta (#) H = R(partial derivative 1n tau/partial derivativeT(-1))(p), respectively. The results are compared with analogous data obtained recently for similar compounds having other liquid crystalline phases (N, SmA).
Recently, confinement of polymers with different geometries has become a research hotspot. Here, we report the dramatic deviation of glass transition behaviors of poly(methyl methacrylate) (PMMA) confined in cylindrical nanopores with diameter significantly larger than chain’s radius of gyration (Rg). Fast cooling a PMMA melt in the nanopores results in a glass with one single glass transition temperature (Tg). But two distinct Tgs are detected after slow cooling the melt. The deviation in Tg could be as large as 45 K. This phenomenon is interpreted by a two-layer model. During vitrification under slow cooling two distinct layers are formed: a strongly constrained interfacial layer showing an increased Tg as compared to that of the bulk polymer and a core with a decreased Tg. By thermal annealing experiments, we find that these two Tgs are inherently correlated. In addition, the deviation of Tg for PMMA confined in nanopores reveals a dependence on molecular weight.
Polystyrene (PS)/o-terphenyl (oTP) solutions confined to nanometer scale
pores were studied by differential scanning calorimetry to investigate
size and confinement effects on the glass transition. We observed two
glass transitions Tg in all thermograms for materials
confined in the controlled pore glasses. One was at a lower temperature
than the bulk state Tg and the other was at a higher
temperature. The lower transition temperature decreases with decreasing
pore size, which is consistent with previous reports from this
laboratory on small molecule glass formers and some other reports in
similar systems. Although oTP and oTP/PS are not hydrogen bonding
materials, we interpret the higher temperature transition as due to the
existence of an interacting layer at the pore surface. A two-layer model
in which there exists a ``core'' liquid in the center surrounded by the
interacting layer at the pore surface is consistent with our
observations.
Significance
Water is not only the most important liquid for life on Earth, but also one of the most anomalous liquids. These anomalies become most evident in the supercooled state at subzero temperatures. We show from dielectric and calorimetric studies that water in the deeply supercooled regime, below –120 °C, can even exist as two distinct, ultraviscous liquids at ambient pressure, a low- (LDL, 0.92 g/cm ³ ) and high-density liquid (HDL, 1.15 g/cm ³ ), which can both remain in the metastable, equilibrium liquid state for many hours above their calorimetric glass transition temperatures of –137 °C (136 K) and –157 °C (116 K). LDL is identified as the strongest of all liquids, and also HDL is a strong liquid at record low temperature.
Results on the temperature dependence of orientational order at constant molar volume in the nematic liquid crystal p-azoxyanisole are reported for the first time. These results clearly indicate the failure of theories of the nematic phase which do not include both energetic and steric intermolecular interactions.
The molecular structure of itraconazole, C35H38Cl2N8O4, has been determined from single-crystal X-ray diffraction data. The two molecules in the asymmetric unit differ mainly in the conformation of the methoxyphenylpiperazine moiety. Apart from a 180 degrees rotation of the triazole ring, the geometry of the dichlorophenylethoxytriazole moiety is almost the same as the dichlorophenylethoxyimidazole geometry found in miconazole, econazole and ketoconazole.
The intra- and inter-molecular interactions of salol and polystyrene, as low molecular weight and polymeric glass-forming model systems, are studied by Fourier-transform infrared (FTIR) spectroscopy and Broadband Dielectric Spectroscopy (BDS). By analysing the temperature dependencies of specific IR absorption bands it is demonstrated that each molecular moiety in the glass-formers has its own signature in the course of the dynamic glass transition: while some do not show any change at the calorimetric glass transition temperature others exhibit a pronounced kink. The effects cannot be attributed solely to microscopic thermal expansion, but instead indicate gradual conformational changes. The ease of application of this approach to a variety of systems in different geometries and external conditions can assist the modelling of glasses and the understanding of the coupling between the glass transition and molecular-level dynamics.
Results are presented of temperature and pressure studies of the non-linear dielectric effect (NDE) in the isotropic phase of MBBA (N-4-methyoxybenzylidene-4′-n-butylaniline) and EBBA (N-4-ethoxybenzylidene-4′-n-butylaniline). In both nematogens the pretransitional increase of the NDE is described by the classical relation obtained on the basis of the Landau-de Gennes model. The value of the ratio of amplitudes describing the pretransitional effect of MBBA and EBBA shows a dependence on the measurement frequency of the NDE (a few MHz). In nematogens with a large positive anisotropy of the electric permittivity, change in the measurement frequency even leads to a change in sign of the NDE on approaching the clearing temperature.
The α-dispersion in many polymer systems is the process to be associated with the glass transition temperature where many physical properties undergo drastic changes. We have measured and analyzed the complex dielectric behavior of the α-dispersions for five polymers [i.e., polycarbonate and polyisophthalate esters of bisphenol A, isotactic poly-(methyl methacrylate), poly(methyl acrylate), and a copolymer of phenyl methacrylate and acrylonitrile] and have found that the usual methods of analysis cannot be used to represent the data. However, it is possible to represent the relaxation process as the sum of two dispersions but there is no evidence to support this contention. An empirical expression is proposed to represent the data. This expression which takes the form of
appears to be a general representation for the three known dispersions, i.e., Debye, circular arc, and skewed semicircle. The complex dielectric constants calculated with the aid of this expression and the parameters for each polymer system which was determined graphically were found to be in excellent agreement with the experimental complex dielectric constants. This method of representation was extended to sixteen α-dispersions reported in the literature always with excellent results.
The purpose of the present work is the elucidation of two endothermic transitions at 74 and 90°C, respectively, observed during differential scanning calorimetry of glassy itraconazole. Modulated temperature DSC (MTDSC), hot-stage microscopy (HSM), HPLC and high temperature X-ray diffraction (HT-X ray) were used to examine the thermal properties of glassy itraconazole. It was found that the preparation mode of the glass does not seem to influence the appearance of both endothermic transitions since they were present during heating of glassy itraconazole which was prepared by cooling the melt or by rapid solvent evaporation of an itraconazole solution. These observations suggest that the appearance of the two endothermic transitions require the liquid state prior to glass formation. The transitions are not due to impurities in the starting material, nor are they caused by thermal decomposition. This was further confirmed by HPLC-analysis. HSM showed structure formation following cooling of the melt, at approximately 87°C; cooling the product further showed a second change in optical contrast. HT-X ray confirmed and identified the formation of a nematic mesophase. The appearance of the two endothermic signals during scanning of glassy itraconazole points to the formation of a mesophase. Due to the nature of itraconazole, it appears as a chiral nematic phase of which the mobility is frozen into a glass upon cooling below 59°C thereby impeding further crystallization.
Turbidity measurements at high pressures were performed in the isotropic phases of MBBA, EBBA, and CBNA. In all cases an increase of the value of T//c - T* with pressure is observed. However, rather unusual behavior is found for the magnitude of the turbidity at the isotropic-nematic transition: in MBBA this magnitude decreases with increasing pressure, in the homologous neighbor EBBA it increases, and in CBNA it increases and then decreases. In conjunction with estimates of the volume discontinuity obtained from our previously reported PVT data, these turbidity data are used to calculate the values of the transition parameters, including in particular the order parameter Q//c. Comparison of these results with previous experimental data indicates that the validity of the mean field theory, which the authors have used to calculate these parameters, must be seriously questioned. Finally, the data show that the value of T//c - T* is somewhat larger along an isochoric trace than along the more conventional isobaric trace.
It has been shown that the temperature behavior of dielectric permittivity (ε) in the isotropic phase of nematogens can be described in the same way as in critical binary solutions. Hence, using a relation with the critical exponent phi=1-alpha=0.5+/-0.03 it was possible to portray the results of ε(T) measurements in the isotropic phase of 5-heptyl-2-(4'-cyanobiphenyl)-pyrimidine and 4,4-n-octylcyanobiphenyl. The influence of the position of the permanent dipole moment on the results was tested by additional measurements in n-(p-methoxybenzylidene)-p'-butylaniline. It also has been shown that a fluidlike analogy can be applied to the nonlinear dielectric effect (NDE), which describes changes of dielectric permittivity induced by a strong electric field. Measurements were conducted for the lowest frequency used in NDE studies (f=67 kHz), so the condition tauf
The objective of the present study was to estimate the molecular mobility of glassy itraconazole below the glass transition, in comparison with structural analogues (i.e. miconazole and ketoconazole).Glassy itraconazole and miconazole were prepared by cooling from the melt. The glassy state of the drug was investigated with modulated temperature DSC using the following conditions: amplitude +/-0.212 K, period 40 s, underlying heating rate 2 K/min. The glass transition was determined from the reversing heat flow and occurred at 332.4 (+/-0.5) K and 274.8 (+/-0.4) K for itraconazole and miconazole, respectively. The jump in heat capacity at the glass transition was 303.42 (+/-3.43) J/mol K for itraconazole and 179.35 (+/-0.89) J/mol K for miconazole. The influence of the experimental conditions on the position of the glass transition of itraconazole was investigated by varying the amplitude from +/-0.133 to +/-0.292 K and the period from 25 to 55 s, while the underlying heating rate was kept constant at 2 K/min. Glass transition temperature, T(g), was not significantly influenced by the frequency of the modulation nor by the cooling rate. However, the relaxation enthalpy at the glass transition increased with decreasing cooling rate indicating relaxation during the glass formation process. To estimate the molecular mobility of the glassy materials, annealing experiments were performed from T(g)--10 to T(g)--40 K for periods ranging from 15 min to 16 h. Fitting the extent of relaxation of glassy itraconazole to the Williams--Watts decay function and comparing the obtained values with those of amorphous miconazole and ketoconazole indicated that the molecular mobility is influenced by the complexity of the molecular structure. The more complex the structure, the more stable the amorphous state.
The low frequency relaxation times tau//, which characterize the flip-flop molecular motions in liquid crystalline phases, recently determined in high-pressure experiments for eight liquid crystalline substances, were reanalyzed considering a relation proposed for the glass-forming liquids [C. Dreyfus, Phys. Rev. E 68, 011204 (2003); R. Casalini and C. M. Roland, Phys. Rev. E 69, 062501 (2004)]. The data, measured at constant pressure, constant temperature, and constant molar volume, could be rescaled onto a master line in the ln tau// vs 1/(T V(gamma)m) plot, with gamma as an adjustable parameter (Vm=1/rho is the specific volume). The obtained gamma values are in good agreement with other estimations; here, the value of gamma parameter was determined for the crystal-like smectic- E phase.
Pressure-temperature-volume (pVT) measurements were carried out on 2-(4-hexyloxyphenyl)-5-octyl-pyrimidine, a substance exhibiting nematic and smectic A and C polymorphism. Analysis of the longitudinal relaxation times obtained recently for elevated pressures [Czub et al., Z. Naturforsch. A: Phys. Sci. 58, 333 (2003)] was performed for isobaric, isothermal, and isochoric conditions within the two smectic phases. Several relationships linking the dynamical and thermodynamical quantities, derived recently for isotropic glass formers [Roland et al. Rep. Prog. Phys. 68, 1405 (2005)], were found to hold for the liquid crystal, revealing a striking similarity of behaviors for these two types of materials. The parameter gamma characterizing the steepness of the interaction potential was derived in different ways. It is interesting that the liquid crystal gives relaxation time versus TV(-gamma) plots that are linear, unlike results for glass formers, implying that the dynamics of the former is thermally activated.
The effect of shape on the interaction of colloidal particles
- Onsager