Relaxation dynamics and crystallization study of sildenafil in the liquid and glassy states.

In this paper, the physical stability and molecular dynamics of amorphous sildenafil are investigated in both the liquid and glassy states. We have established that the amorphous sildenafil is resistant to recrystallization at temperatures below the glass transition temperature Tg during the experimental period of its storage (i.e., above 6 months), however, it easily undergoes cold crystallization at T > Tg. To determine the crystallization mechanism, the isothermal and non-isothermal studies of the cold crystallization kinetics of the drug are performed by using the broadband dielectric spectroscopy (BDS) and the differential scanning calorimetry (DSC), respectively. The cold crystallization mechanism has been found to be similar in both the isothermal and non-isothermal cases. This mechanism has been analyzed from the point of view of the molecular mobility of sildenafil investigated in the supercooled liquid and glassy states by using the BDS measurements in the wide temperature range. This analysis has been enriched with a new approach based on a recently reported measure of dynamic heterogeneity given by a four-point dynamic susceptibility function. No tendency to recrystallization of glassy sildenafil at T < Tg is also discussed in relation to molecular dynamics of sildenafil in the glassy state. The relatively small molecular mobility reflected in one secondary relaxation as well as the predicted large time scale of structural relaxation of glassy sildenafil suggests that amorphous sildenafil should not recrystallize during its long-term storage at room temperature.

Mechanism of mutarotation in supercooled liquid phase: Studies on L-sorbose.

We have studied mutarotation in anhydrous supercooled L-sorbose by means of dielectric spectroscopy. The phenomenon observed in L-sorbose is much faster than in the structurally similar D-fructose. The kinetics of this process has been determined by applying 1st order kinetics model. Activation energy equal to 68 kJ/mol was obtained from temperature dependence of rate constants. To understand differences in mutarotation rate between D-fructose and L-sorbose, quantum mechanical calculations were performed to study mechanism of this phenomenon. The possible impact of water absorbed from air on the mutarotation in supercooled liquid state has been checked. It turned out that the process is probably intermolecular and the water molecules or other carbohydrate molecules assist in the proton transfer process. Finally we have shown that the rate constant can be alternatively determined from frequency of the maximum of peak, obtained by performing Fourier transform of kinetic curve.

Nanoscale domains with nematic order in supercooled vitamin-A acetate: molecular dynamics studies.

Vitamin-A acetate is one of the most versatile vitamins. It is applied in medicine because of its antioxidative properties, in tumor therapy because of its cytostatic activity, and in cosmetics because of its nutritional additives. Herein, using broadband dielectric spectroscopy, the molecular dynamics of supercooled and glassy vitamin-A acetate was investigated. It was shown that dielectric measurements carried out at ambient and elevated pressures reveal a number of relaxation processes associated with different types of molecular motions: α, δ, and ν processes-observed above the glass transition temperature and the next two modes: ß and γ identified in the glassy state. The occurrence of the δ mode in the dielectric spectrum may imply the existence of nanoscale domains with nematic order. This hypothesis is further checked by atomic force microscopy measurements. Finally, we have determined the value of the glass transition temperature (T(g)) as well as the steepness index (m(P)) at various T-P conditions.

Kinetic processes in supercooled monosaccharides upon melting: Application of dielectric spectroscopy in the mutarotation studies of D-ribose.

Dielectric spectroscopy has been recently used to monitor mutarotation in undercooled D-fructose. This method can be viewed as a universal method to study mutarotation phenomenon in the whole family of monosaccharides. In this paper, we studied kinetics of mutaration of anhydrous D-ribose at ambient pressure as well as pressure effect on the rate constant of this process. Ribose mutarotation behavior is compared to the one obtained for D-fructose. In addition, we attempted to determine the "direction" of mutarotation in undercooled monosaccharides after quenching the melted sample. To this end, analysis of dipole moments of different tautomers of D-fructose and D-ribose have been performed. Conformational analysis of studied carbohydrates was done with use of density functional theory. Geometry optimizations as well as calculations of dipole moments were done on the 6-311++G(d,p)/B3LYP level. Finally, it turned out that data obtained from the mutarotation experiment might be helpful in understanding the origin of gamma-process occurring in the whole family of carbohydrates.

Dielectric relaxation study on tramadol monohydrate and its hydrochloride salt.

Dielectric relaxation measurements as well as differential scanning calorimetry and X-ray diffraction investigations were performed on tramadol monohydrate and its hydrochloride salt. Examined samples do not crystallize during cooling and in consequence they reach the glassy state. In the case of the hydrochloride tramadol we are able to monitor alpha-relaxation process despite large contribution of dc conductivity to the loss spectra. It is the first such study on the salt of the drug. Up to now the dielectric spectroscopy has been regarded as useless in measuring such kind of API (active pharmaceutical ingredient). In this paper we also made some suggestions about the nature of the secondary relaxations in the amorphous tramadol monohydrate and its salt. The knowledge about the molecular mechanisms, which govern the observed secondary relaxations seems to be the key in predicting the stability of the amorphous form of the examined API. Finally additional dissolving measurements on the amorphous and crystal tramadol hydrochloride were performed. As a result we understood that dissolution properties of the amorphous form of the considered drug are comparable to those of crystalline one. However, we have found out that amorphous tramadol hydrochloride has greater ability to form tablets than its crystalline equivalent. This finding shows that amorphous drugs can be alternative even for the freely solved pharmaceuticals such as tramadol hydrochloride, because the former one has better ability to form tablets. It implies that during tabletting of the amorphous drugs there is no need to use any excipients and chemicals improving compaction properties of the API.

Identification of the slower secondary relaxation's nature in maltose by means of theoretical and dielectric studies.

Dielectric relaxation measurements on maltose were performed at ambient and increasing pressure. The loss spectra collected below glass transition of this disaccharide revealed presence of two well separated secondary relaxations. Activation energies determined for both modes are E(a)=73 kJ/mol and 47 kJ/mol for the slower (beta) and faster (gamma) relaxation, respectively. From high pressure measurements activation volume DeltaV=15.6 ml/mol for the slower secondary relaxation was estimated. Both quantities: activation energy and activation volume for alpha-process derived from dielectric data, were compared to those obtained from the conformational calculations with use of density functional theory (DFT). We found out satisfactory agreement between both quantities for the molecular motion related to the rotation of the two monosaccharide units around glycosidic linkage in this disaccharide.

Mutarotation in D-fructose melt monitored by dielectric spectroscopy.

Broadband dielectric spectroscopy was employed to investigate the kinetics of the mutarotation of D-fructose. In this article, D-fructose tautomerization behavior in pure melt is revealed. By monitoring structural relaxation time shift, we were able to determine speed in temperature range 303-333 K and the activation energy for this phenomenon. It is equal to 107 kJ/mol, which is very high in comparison to the solvated system. We have also shown the influence of this process to the gamma-relaxation (secondary relaxation process). Dielectric spectroscopy derived complex information about mutarotational dynamics.

On the pressure dependence of the fragility of glycerol.

This work was motivated by ostensibly contradictory results from different groups regarding the effect of pressure on the fragility of glycerol. We present new experimental data for an intermediate pressure regime showing that the fragility increases with pressure up to about 1.8 GPa, becoming invariant at higher pressures. There is no discrepancy among the various literature data taken in toto. The behavior of glycerol is quite distinct from that of normal liquids, a result of its substantial hydrogen bonding.

High pressure study on molecular mobility of leucrose.

Broadband dielectric measurements on leucrose were performed under ambient and high pressure. We showed that in this disaccharide, there are two secondary relaxation modes, a slower one sensitive to pressure and a faster one that is not. This finding clearly indicates that the faster secondary relaxation originates from the intramolecular motion. This conclusion contradicted previous interpretations of this mode observed for trehalose and maltitol, systems very closely related to leucrose. In addition, pressure sensitivity of the slower relaxation confirms our recent interpretation about the character of this process. Furthermore, we discovered that unlike the faster relaxation, the slower secondary relaxation is sensitive to the thermodynamic history of measurements. Finally, monitoring the changes in maximum loss of the slower secondary relaxation measured at the same pressure and temperature conditions for glasses obtained via different thermodynamic routes enabled us to draw a conclusion about the density of the formed glasses. Our observations may be helpful in establishing a new method of suppressing crystallization of amorphous drugs.

Dielectric studies on mobility of the glycosidic linkage in seven disaccharides.

Isobaric dielectric relaxation measurements were performed on seven chosen disaccharides. For five of them, i.e., sucrose, maltose, trehalose, lactulose, and leucrose, we were able to observe the temperature evolution of the structural relaxation process. In the case of the other disaccharides studied (lactose and cellobiose), it was impossible to obtain such information because of the large contribution of the dc conductivity and polarization of the capacitor plates to the imaginary and real part of the complex permittivity, respectively. On the other hand, in the glassy state, two secondary relaxations have been identified in the dielectric spectra of all investigated carbohydrates. The faster one (gamma) is a common characteristic feature of the entire sugar family (mono-, di-, oligo-, and polysaccharide). The molecular origin of this process is still not unambiguously identified but is expected to involve intramolecular degrees of freedom as inferred from insensitivity of its relaxation time to pressure found in some monosaccharides (fructose and ribose). The slower one (labeled beta) was recently identified to be intermolecular in origin (i.e., a Johari-Goldstein (JG) beta-relaxation), involving twisting motion of the monosugar rings around the glycosidic bond. The activation energies and dielectric strengths for the beta-relaxation determined herein provide us valuable information about the flexibility of the glycosidic bond and the mobility of this particular linkage in the disaccharides studied. In turn, this information is essential for the control of the diffusivity of drugs or water entrapped in the sugar matrix.

Identification of the molecular motions responsible for the slower secondary (beta) relaxation in sucrose.

Broad-band isothermal dielectric relaxation measurements of anhydrous sucrose were made at ambient pressure in its liquid and glassy states. We found a new secondary relaxation that is slower than the one commonly observed in sugars. Additionally, we carried out the dielectric measurements of the equimolar mixture of D-glucose and D-fructose in wide ranges of temperature and frequency. Comparison of the behavior of these two systems allowed us to make suggestions on the origin of the slower beta-relaxation in sucrose. Computer simulations and coupling model calculations were performed to support our interpretation of the kind of molecular motions responsible for the slower secondary relaxation in the disaccharide considered.

Reply to "Comment on 'Correlations between isobaric and isochoric fragilities and thermodynamical scaling exponent for glass-forming liquids' ".

Our recent paper [A. Grzybowski, K. Grzybowska, J. Ziolo, and M. Paluch, Phys. Rev. E 74, 041503 (2006)] tested the correlations between isobaric and isochoric fragilities, m_{P} and m_{V} , as well as the scaling exponent gamma under elevated pressure conditions. The preceding paper [R. Casalini and C. M. Roland, Phys. Rev. E 76, 013501 (2007)] is a Comment by the authors of the correlations originally determined for atmospheric pressure. In this Reply we present our point of view on criticisms contained in the Comment. We clarify and maintain our previously drawn conclusions.

Dielectric relaxation of alpha -tocopherol acetate (vitamin E).

Dielectric loss spectra are reported for alpha -tocopherol acetate (an isomer of vitamin E) in the supercooled and glassy states. The alpha -relaxation times, tau_{alpha} , measured over a 190 degrees range of temperatures, T , at pressures, P , up to 400MPa can be expressed as a single function of TV3.9 ( V is specific volume, measured herein as a function of T and P ). At ambient pressure, there is no dynamic crossover over eight decades of measured tau_{alpha} . The relaxation spectra above the glass transition temperature T_{g} show ionic conductivity and an excess wing on the high-frequency flank of the alpha -relaxation loss peak. Temperature-pressure superpositioning is valid for the alpha process; moreover, the peak shape is constant (stretch exponent equal to 0.65). However, application of pressure changes the shape of the dielectric spectrum at higher frequencies due to the shift of the excess wing to form a resolved peak. Additionally, another relaxation process, absent at atmospheric pressure, emerges on the high-frequency side of the alpha -process. We propose that this new peak reflects a more compact conformation of the alpha -tocopherol acetate molecule. Drawing on the coupling model, the experimentally determined relaxation times, activation energy, and activation volume for the Johari-Goldstein process are compared to values calculated from the properties of the alpha relaxation. The agreement is generally satisfactory, at least for T

The true Johari-Goldstein beta-relaxation of monosaccharides.

Broadband isothermal dielectric relaxation measurements of anhydrous fructose, glucose, galactose, sorbose, and ribose were made at ambient pressure in their liquidus and glassy states. We found a new secondary relaxation in fructose and glucose that is slower than those seen before by others. This new secondary relaxation also appears in the dielectric spectra of galactose, sorbose, and ribose, and hence it is a general feature of the relaxation dynamics of the monosaccharides. Dielectric measurements at elevated pressure of fructose and ribose show that the new secondary relaxation shifts to lower frequencies with applied pressures, mimicking the behavior of the alpha-relaxation. In contrast, the faster secondary relaxation remains stationary on applying pressure. These results together with other inferences indicate that the slower secondary relaxation bears relations to the alpha-relaxation, and hence, it is the true Johari-Goldstein secondary relaxation of the monosaccharides.

Correlations between isobaric and isochoric fragilities and thermodynamical scaling exponent for glass-forming liquids.

Two correlations concerning the isobaric and isochoric fragilities, m(P) and m(V), as well as the scaling exponent gamma reported by Casalini and Roland [Phys. Rev. E 72, 031503 (2005)] have been examined for several van der Waals and hydrogen-bonded glass formers. It has been pointed out that the correlations lead to some serious inconsistency with the exponent gamma, which is expected to be a constant dependent only on material, but varies also on pressure if experimentally found pressure dependences of m(P) are taken into account. This problem could be solved in the case of van der Waals liquids, but then at least one of the correlations becomes dependent on thermodynamic conditions, and consequently, loses its universality. However, some H-bonded systems, due to properties of hydrogen bonding, have been well argued not to be included to determine the correlations independently of thermodynamic conditions. Furthermore, it has been noticed that another correlation concerning the fragility, between m(P) and the structural relaxation peak breadth, yields discrepancies in comparison with results of experiments under elevated pressure.

Dielectric secondary relaxations in polypropylene glycols.

Broadband dielectric measurements of polypropylene glycol of molecular weight M(w)=400 g / mol (PPG 400) were carried out at ambient pressure over the wide temperature range from 123 to 353 K. Three relaxation processes were observed. Besides the structural alpha relaxation, two secondary relaxations, beta and gamma, were found. The beta process was identified as the true Johari-Goldstein relaxation by using a criterion based on the coupling model prediction. The faster gamma relaxation, well separated from the primary process, undoubtedly exhibits the anomalous behavior near the glass transition temperature (T(g)) which is reflected in the presence of a minimum of the temperature dependence of the gamma-relaxation time. We successfully applied the minimal model [Dyre and Olsen, Phys. Rev. Lett. 91, 155703 (2003)] to describe the entire temperature dependence of the gamma-relaxation time. The asymmetric double-well potential parameters obtained by Dyre and Olsen for the secondary relaxation of tripropylene glycol at ambient pressure were modified by fitting to the minimal model at lower temperatures. Moreover, we showed that the effect of the molecular weight of polypropylene glycol on the minimal model parameters is significantly larger than that of the high pressure. Such results can be explained by the smaller degree of hydrogen bonds formed by longer chain molecules of PPG at ambient pressure than that created by shorter chains of PPG at high pressure.

Pretransitional behavior in the isotropic phase of a nematic liquid crystal with the transverse permanent dipole moment.

The results presented give the evidence for the quasicritical, pretransitional behavior of dielectric properties in the isotropic phase of a rodlike nematic liquid crystal with the transverse permanent dipole moment. Studies were conducted in 2-cyano-4-pentylbiphenyl 4-(trans-4-pentylcyclohexyl) benzoate, focusing on the static-and ionic-dominated low-frequency (LF) regions. For the static dielectric permittivity [epsilon(')(T)] the application of the derivative analysis revealed the pretransitional anomaly associated with the specific heat exponent alpha approximately 0.5. For the LF domain the contribution to epsilon(')(T) from residual ionic impurities follows a linear temperature dependence on approaching the isotropic-nematic (I-N) transition. This dependence and pretransitional anomalies of electric conductivity and dielectric modulus can be associated with the influence of prenematic fluctuations. "Linear" dielectric studies were supported by the static nonlinear dielectric effect measurements, which delivered reliable estimations of the temperature of the hypothetical continuous phase transition T(*) and the discontinuity of the I-N transition DeltaT approximately 1.7 K.

Emergence of a new feature in the high pressure-high temperature relaxation spectrum of tri-propylene glycol.

We investigated dielectric relaxation of a tri-propylene glycol system under high compression. By increasing temperature and pressure we observed that a new relaxation process emerges from the low frequency tail of the structural peak. This new peak starts to be visible at about 0.5 GPa and becomes clearly evident at 1.7 GPa. However, this additional peak merges again with the structural one as the glass transition is approached, since it has a weaker temperature dependence. This finding enriches the relaxation scenario of molecular glass formers confirming that the application of very high hydrostatic pressure can favor the detection of new relaxation or otherwise unresolved processes in supercooled liquid systems.

Effect of pressure on dynamic heterogeneity in dendrimeric alkyd resin.

Broadband dielectric spectroscopy is employed to investigate the non-Debye relaxation behavior in a dendrimeric alkyd resin. From temperature-dependent measurements at ambient pressure, we found a very broad distribution of relaxation times. This is attributed to the complex geometrical topology of the molecule. However, compression significantly reduces the non-Debye character of the dielectric response; thus, pressure induces dynamic homogeneity in the dendrimeric alkyd resin.

Effect of large hydrostatic pressure on the dielectric loss spectrum of type- a glass formers.

New dielectric spectroscopy results are reported for propylene carbonate (PC), glycerol, and threitol, measured at very high (1.8 GPa) pressure. These glass formers all exhibit an excess wing in their dielectric spectrum above T(g). We show that the shape of the alpha peak and excess wing of PC are invariant to pressure and temperature, when compared at a fixed value of the alpha -relaxation time. However, for the hydrogen-bonded liquids, there is a marked breakdown of this temperature-pressure superpositioning, due to a change in chemical structure (i.e., concentration of hydrogen bonds) with change of temperature or pressure. For all these materials, we can conclude that the excess wing is merely a secondary relaxation, masked under ordinary conditions by the intense, overlapping alpha peak.