Karolina Adrjanowicz

Broadband Dielectric Relaxation Study at Ambient and Elevated Pressure of Molecular Dynamics of Pharmaceutical: Indomethacin

Broadband dielectric measurements on the pharmaceutical indomethacin (IMC) were performed at ambient and elevated pressure. Data on molecular dynamics collected at ambient pressure are in good agreement with that published in the literature. In the glassy state, there is a well-resolved secondary relaxation with Arrhenius activation energy E(a) = 38 kJ/mol. This commonly observed relaxation process (labeled gamma) is of intramolecular origin because it is pressure-insensitive. Closer analysis of the ambient pressure dielectric spectra obtained in the vicinity of the T(g) indicated the presence of one more secondary relaxation (beta), which is slower than that commonly observed. Application of the CM predictions enabled us to classify it as a true JG relaxation. Pressure measurements confirmed our supposition concerning the origins of the two secondary relaxations in IMC. Moreover, we have found that IMC under pressure does not crystallize, even at very high temperatures of T > or = 372 K. This finding was discussed in the framework of the two-order parameter model proposed by Tanaka (Konishi, T.; Tanaka, H. Phys. Rev B 2007, 76, 220201), as well as the JG relaxation proposal by Oguni (Hikima T.; Hanaya M.; Oguni M. J. Mol Struct. 1999, 479, 245). We also showed that the shape of the alpha-relaxation loss peak is the same when comparing dielectric spectra with the same tau(alpha) but obtained at ambient and elevated pressure. Additionally, we found out that the fragility of IMC decreases with increasing pressure. In addition, the pressure coefficient of the glass transition temperature, dT(g)/dP, was determined, and it is 255 K/GPa. Finally, we discuss the possibility of preparation of the amorphous state with higher density than by cooling of the liquid.

Dielectric Relaxation and Crystallization Kinetics of Ibuprofen at Ambient and Elevated Pressure

Dielectric spectroscopy (DS) was used to investigate the relaxation dynamics of supercooled and glassy ibuprofen at various isobaric and isothermal conditions (pressure up to 1750 MPa). The ambient pressure data are in good agreement with that reported previously in the literature. Our high pressure measurements revealed validity of temperature-pressure superpositioning (TPS) for the alpha-peak. We also found that the value of the fragility index decreases with compression from m = 87 +/- 2 at atmospheric pressure to m = 72.5 +/- 3.5 at high pressure (p = 920 MPa). The drop of fragility observed in our experiment was discussed in the framework of the two-order-parameter (TOP) model. In addition, we have also studied crystallization kinetics in a liquid state of examined drug at ambient and high pressure. We found out that, for the same structural relaxation time/same viscosities, the samples prepared by compression of liquid at high temperatures have significantly elongated induction times as well as overall crystallization times (sample 2: t(0) approximately = 4 h, t(1/2) approximately = 37.5 h; sample 3: t(0) approximately = 5.6 h, t(1/2) approximately = 49 h) compared to that held at lower temperature and ambient pressure (sample 1: t(0) approximately = 1.2 h, t(1/2) approximately = 12.2 h). A possible explanation of this finding is also given.

Study of molecular dynamics of pharmaceutically important protic ionic liquid-verapamil hydrochloride. I. Test of thermodynamic scaling

Relaxation dynamics of verapamil hydrochloride (VH), which is a representative of ionic liquids, was studied under isobaric and isothermal conditions by using dielectric spectroscopy. In addition we also carried out pressure-temperature-volume (PVT) measurements. The obtained data enable us to examine the structural α-relaxation time τα as a function of temperature, pressure, and volume. Since the examined sample is a typical ionically conducting material, we employed the dielectric modulus formalism to gain information about α-relaxation process. It was found that application of pressure changes the shape of the modulus spectrum. The α-peak becomes narrower with compression. Consequently, it was also shown that the stretching parameter βKWW increases with pressure. Based on experimental data both the isobaric fragility (mp) at various pressures and isothermal fragility (mT) at various temperatures were calculated. Analyzing the effect of pressure on the dependences τα(T) as well as on the shape parameter...

Do Intermolecular Interactions Control Crystallization Abilities of Glass-Forming Liquids?

Broadband dielectric spectroscopy was used to investigate molecular dynamics of three very similar systems: D-glucose, α-pentaacetylglucose, and β-pentaacetylglucose in a wide range of temperatures. We found out that two latter systems (differing only in location of the acetyl group attached to the first carbon in the sugar ring) reveal completely opposite tendencies to crystallization. Therefore, the aim of this Article was to investigate in detail molecular dynamics of both pentaacetylglucoses to assess what are the underlying of different crystallization abilities of so closely related carbohydrates. To analyze the kinetics of crystallization, we used Avrami and Avramov approaches. Interestingly, we found out that both α-and β-pentaacetylglucose exhibit completely different crystallization mechanisms. In the first case, the value of Avrami exponent was estimated to be n = 2, whereas for the second carbohydrate this exponent was equaled to n = 5.5. Additionally, we have carried out isothermal time-dependent dielectric measurements on D-glucose to demonstrate that this saccharide is more stable than its acetyl derivatives. Results presented in this Article indicate that besides molecular mobility, the character of the intermolecular interactions might also be another important factor governing crystallization process. Surprisingly, this issue is not often addressed during studies on crystallization abilities of different glass-formers. Finally, additional optical measurements were carried out to get more detailed information about nucleation density, activation barrier for a crystal growth, and morphology of crystallization structures.

Origin of the Commonly Observed Secondary Relaxation Process in Saccharides

Broadband dielectric relaxation studies were performed on D-glucose and 1,6-anhydro-D-glucose. In the liquid phase of both systems, one can observe the cluster relaxation and structural relaxation. In the glassy state of D-glucose two secondary relaxations were recorded. The slower one, hardly detectable in the loss spectra, was identified as the Johari-Goldstein type (JG) relaxation. The faster one, the gamma-relaxation, is visible as a well pronounced peak. For the past few years the origin of this process has been a subject of hot debate. Different authors have speculated about the source of this relaxation, but no consensus was reached. Moreover, application of more sophisticated method, such as NMR and MD simulations have not resolved this problem yet. Comparison of the dielectric loss spectra measured for D-glucose and 1,6-anhydro-D-glucose, combined with other experimental findings described in detail in this paper, enabled us to certify unquestionably, that the rotation of hydroxymethyl group is the origin of gamma-relaxation in D-glucose as well as in the whole family of saccharides. Additionally, calculations of conformational changes with use of density functional theory (DFT) were performed to support our identification.

Molecular Dynamics in Supercooled Liquid and Glassy States of Antibiotics: Azithromycin, Clarithromycin and Roxithromycin Studied by Dielectric Spectroscopy. Advantages Given by the Amorphous State

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

Molecular Dynamics of the Cryomilled Base and Hydrochloride Ziprasidones by Means of Dielectric Spectroscopy

Cryomilling was applied to obtain amorphous forms of the base ziprasidone and its hydrochloride salt. Complete amorphization of both samples was confirmed by differential scanning calorimetry and X-ray measurements. As it turned out, cryogrinding is very effective way to obtain these drugs in the amorphous state, especially because melting of both ziprazidones accompanies significant chemical decomposition as revealed by ultra performance liquid chromatography examination. Consequently, the glassy state cannot be reached in conventional way, that is, by supercooling of melt. Broadband dielectric relaxation measurements were performed on both drugs to describe their molecular dynamics above as well as below their glass transition temperatures (T(g)). We found out that ziprasidone base and its hydrochloride salt differ in T(g) in the same way as it was previously reported for tramadol monohydrate and its hydrochloride. Moreover, our dielectric studies revealed that molecular mobility is not the main factor controlling kinetics of crystallization of both ziprasidones above their T(g) . Below the T(g) relaxation related to water as well as secondary relaxation process originating from the intermolecular interaction (Johari-Goldstein) were identified in the loss spectra of both materials. We have demonstrated that except of local mobility, water is the dominant factor moving both ziprasidones toward recrystallization process. Finally, we have also carried out solubility measurements to show that dissolution rate of the amorphous ziprasidones is much higher with respect to the crystalline samples.

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.

Confinement for More Space: A Larger Free Volume and Enhanced Glassy Dynamics of 2-Ethyl-1-hexanol in Nanopores

Broadband dielectric spectroscopy and positron annihilation lifetime spectroscopy are employed to study the molecular dynamics and effective free volume of 2-ethyl-1-hexanol (2E1H) in the bulk state and when confined in unidirectional nanopores with average diameters of 4, 6, and 8 nm. Enhanced α-relaxations with decreasing pore diameters closer to the calorimetric glass-transition temperature (T(g)) correlate with the increase in the effective free volume. This indicates that the glassy dynamics of 2D constrained 2E1H is mainly controlled by density variation.

Comprehensive studies on physical and chemical stability in liquid and glassy states of telmisartan (TEL): solubility advantages given by cryomilled and quenched material

To make full use of the advantages provided by amorphous pharmaceuticals it is necessary to understand the basic factors that determine their physical and chemical stability. Molecular mobility seems to be the most important one. Unfortunately, due to the exceedingly long time scale required for molecular motion in the glassy state, direct monitoring of the structural α-relaxation time ( ) in this temperature regime is rather difficult. A thorough investigation was carried out of the time scale of α-mobility in the glassy state of telmisartan (TEL). For this drug, global molecular mobility seems to be the most dominant factor responsible for its long-term stability. Based on some estimations obtained previously it was concluded that at room temperature, molecular mobility associated with the structural relaxation would exceed three years. To characterize the temperature behavior of structural relaxation below the glass transition temperature, T g, a modified Adam–Gibbs approach was used. Additionally, using results of dielectric measurements, a comparative analysis was performed of the molecular dynamics of amorphous TEL prepared by cryomilling as well as obtained by quench-cooling of the melt. An X-ray diffraction analysis was also carried out to confirm the long-term stability of amorphous TEL, whereas solubility studies revealed its markedly better solubility profile than that for the crystalline form. These findings have important implications for further handling of this drug.