E. Kaminska

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.

Correlation between primary and secondary Johari-Goldstein relaxations in supercooled liquids: invariance to changes in thermodynamic conditions.

The primary alpha and the secondary Johari-Goldstein (JG) beta relaxations of supercooled glass-forming neat epoxy resin and 2-picoline in mixture with tristyrene are monitored by broadband dielectric relaxation spectroscopy at ambient pressure and elevated pressures. For different combinations of pressure and temperature that maintain the alpha-relaxation time constant, the frequency dispersion of the alpha relaxation is unchanged, as previously found in other glass-formers, but remarkably the JG beta-relaxation time remains constant. This is more clear evidence of a strong connection between the alpha- and JG beta-relaxation times, a fact that should be taken into account in the construction of a viable theory of glass transition.

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.

Two secondary modes in decahydroisoquinoline: which one is the true Johari Goldstein process?

Broadband dielectric measurements were carried out at isobaric and isothermal conditions up to 1.75 GPa for reconsidering the relaxation dynamics of decahydroisoquinoline, previously investigated by Richert et al. [R. Richert, K. Duvvuri, and L.-T. Duong, J. Chem. Phys. 118, 1828 (2003)] at atmospheric pressure. The relaxation time of the intense secondary relaxation tau(beta) seems to be insensitive to applied pressure, contrary to the alpha-relaxation times tau(alpha). Moreover, the separation of the alpha- and beta-relaxation times lacks correlation between shapes of the alpha-process and beta-relaxation times, predicted by the coupling model [see for example, K. L. Ngai, J. Phys.: Condens. Matter 15, S1107 (2003)], suggesting that the beta process is not a true Johari-Goldstein (JG) relaxation. From the other side, by performing measurements under favorable conditions, we are able to reveal a new secondary relaxation process, otherwise suppressed by the intense beta process, and to determine the temperature dependence of its relaxation times, which is in agreement with that of the JG relaxation.

Identification of the Molecular Motions Responsible for the Slower Secondary (β) 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.

Identifying the Origins of Two Secondary Relaxations in Polysaccharides

The main goal of this paper is to identify the molecular origins of two secondary relaxations observed in mechanical as well as in dielectric spectra in polysaccharides, including cellulose, and starches, such as pullulan and dextran. This issue has been actively pursued by many research groups, but consensus has not been reached. By comparing experimental data of monosaccharides, disaccharides, and polysaccharides, we are able to make conclusions on the origins of two secondary relaxations in polysaccharides. The faster secondary relaxations of polysaccharides are similar to the faster secondary relaxations of mono-, di-, and oligosaccharides. These include comparable relaxation times and activation energies in the glassy states, and also all the faster secondary relaxations have larger dielectric strengths than the slower secondary relaxation. The similarities indicate that the faster secondary relaxations in the polysaccharides have the same origin as that in mono-, di-, and oligosaccharides. Furthermore, since the relaxation time of the faster secondary relaxation in several mono- and disaccharides was found to be insensitive to applied pressure, the faster secondary relaxations of the polysaccharides are identified as internal motions within their monomeric units. The slower secondary relaxations in polysaccharides also have similar characteristics to those of the slower secondary relaxations of the disaccharides (maltose, cellobiose, sucrose, and trehalose), which indicates the analogous motions govern the slower process in these two groups of carbohydrates. Earlier we have shown in disaccharides that the rotation of the monomeric units around the glycosidic bond is responsible for this process. The same motion can occur in polysaccharides in the form of a local chain rotation. These motions involve the whole molecule in disaccharides and a local segment in polysaccharides. It is intermolecular in nature (with relaxation time pressure dependent, as found before in a disaccharide), and hence, it is the precursor of the structural alpha-relaxation. These results lead us to identify the slower secondary relaxation of the polysaccharides as the Johari-Goldstein beta-relaxation, which is supposedly a universal and fundamental process in all glass-forming substances.

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.

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.

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

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