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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.

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... 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]. ...
Article
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.
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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.
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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.
Article
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.
Article
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).
Article
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.
Article
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.
Article
The glassy states of water are of common interest as the majority of H2O in space is in the glassy state and especially because a proper description of this phenomenon is considered to be the key to our understanding why liquid water shows exceptional properties, different from all other liquids. The occurrence of water's calorimetric glass transition of low-density amorphous ice at 136 K has been discussed controversially for many years because its calorimetric signature is very feeble. Here, we report that high-density amorphous ice at ambient pressure shows a distinct calorimetric glass transitions at 116 K and present evidence that this second glass transition involves liquid-like translational mobility of water molecules. This "double Tg scenario" is related to the coexistence of two liquid phases. The calorimetric signature of the second glass transition is much less feeble, with a heat capacity increase at Tg,2 about five times as large as at Tg,1. By using broadband-dielectric spectroscopy we resolve loss peaks yielding relaxation times near 100 s at 126 K for low-density amorphous ice and at 110 K for high-density amorphous ice as signatures of these two distinct glass transitions. Temperature-dependent dielectric data and heating-rate-dependent calorimetric data allow us to construct the relaxation map for the two distinct phases of water and to extract fragility indices m = 14 for the low-density and m = 20-25 for the high-density liquid. Thus, low-density liquid is classified as the strongest of all liquids known ("superstrong"), and also high-density liquid is classified as a strong liquid.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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
Article
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.
Article
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.
Article
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
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