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Dielectric relaxation studies on disaccharides lactose and octa-O-acetyl-lactose are reported. The latter is a hydrogen bonded system while the former is a van der Waals glass former. The transformation between them was arranged by substituting hydrogen atoms in lactose by acetyl groups. Hereby the influence of differences in bounding on dynamics of both systems is discussed. We showed that the faster secondary relaxation (labeled γ) in octa-O-acetyl-lactose has much lower amplitude than that of lactose. The relaxation time and activation energy remain unchanged in comparison to the γ- relaxation of lactose. We did not observe the slow secondary relaxation (labeled β), clearly visible in lactose, in its acethyl derivative. Detailed analysis of the dielectric spectra measured for octa-O-acetyl-lactose in its glassy state (not standard change in the shape of the γ- peak with lowering temperature) enabled us to provide probable explanation of our finding. No credible comparative analysis of the α- relaxation process of the lactose and octa-O-acetyl-lactose are presented, because loss spectra of the former carbohydrate were affected by the huge contribution of the dc conductivity. Notwithstanding, one can expect that octa-O-acetyl-lactose has lower glass transition temperature and steepness index than lactose.

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 Tor = 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 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 α-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. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:94–106, 2010

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.

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.

Some examples of recent advances in experiment and theory that have impact on solution of the glass transition problem are briefly discussed. The fundamental importance of a special class of secondary relaxations called the Johari-Goldstein beta-relaxations becomes clear from the recent advances. The main part of the paper addresses a recent research problem, which is the purported anomalous temperature dependence of the relaxation time of another secondary (gamma) relaxation found by fitting dielectric relaxation data in several glass-formers. We show the anomalous T-dependence of this faster gamma-relaxation is caused by the influence exerted by the slower Johari-Goldstein beta-relaxation in the vicinity. (C) 2008 Elsevier B.V. All rights reserved.

The aim of this study was to examine the ability of extracts from root of Rhodiola rosea (RR) and Rhodiola kirilowii (RK) to inhibit the development of acute ethanol tolerance. The ethanol-water (1:1) extracts were standardized on phenylpropanoids (rosavin, rosin, rosarin) and phenylethanoids (salidroside, p-tyrosol) contents. The experiments were performed …

We report dielectric relaxation measurements of the mixture 25% w/w cyclohexane in decahydroisoquinoline. Cyclohexane is a nonpolar liquid that acts as an external parameter influencing relaxation dynamics of pure decahydroisoquinoline. Two different secondary relaxation processes dominate the relaxation dynamics below the glass transition temperature, as previously observed in the pure decahydroisoquinoline. Based on the coupling model analysis we identified the fastest secondary process as the genuine secondary Johari Goldstein process, reflecting the motion of the whole molecule. On the other hand, the microscopic origin of the slowest secondary process still remains unknown. (c) 2006 Elsevier B.V. All riehts reserved.

Broadband dielectric spectroscopy was employed to study the relaxation dynamics of glass‐forming isoeugenol. Above Tg, the dielectric spectra exhibit an excess wing on the high‐frequency side of the primary α‐relaxation as well as an additional faster (γ) process. As the temperature is lowered below Tg, the excess wing is transformed into a distinctly resolved β‐peak. Analysis of the spectra using the Coupling Model confirms that the β‐peak and its parent excess wing is the genuine Johari‐Goldstein relaxation of isoeugenol.

The molecular structure of bis-5-hydroxypentylphthalate (BHPP) is like dihexyl phthalate but having appended to it two hydroxyl end groups, which contribute additional dipole moments and capacity for hydrogen-bond formation. In a previously published dielectric study of the primary and secondary relaxations of BHPP, it was found that all the dynamic properties are normal except for the anomalously large width of the primary relaxation loss peak. There are two secondary relaxations, the relaxation time of the slower one increases with increasing pressure, whereas that of the faster one is practically insensitive to pressure. Hence, the slower secondary relaxation is the "universal" Johari-Goldstein (JG) [J. Chem. Phys. 53, 2372 (1970); 55, 4245 (1971)] relaxation in BHPP. All is well except if the observed large width of the primary relaxation were an indication of a corresponding large coupling parameter n=0.45 in the coupling model. Then the predicted relations between the primary relaxation time tau(alpha) and the JG relaxation time tau(JG) found previously to hold in many glass formers would be violated. It was recognized that this singular behavior of BHPP is likely due to broadening of the primary loss peak by the overlapping contributions of two independent dipole moments present in BHPP, and the actual coupling parameter is smaller. However, at the time of publication of the previous work there were not enough data to support this explanation. By making broadband dielectric measurements of dibutyl phthalate (DBP) and dioctyl phthalate (DOP) that have chemical structures closely related to BHPP but with only one dipole moment, we show that all their dynamic properties are almost the same as BHPP but the widths of their primary relaxation loss peaks are significantly narrower corresponding to a smaller coupling parameter n=0.34. The new data presented here indicate that the coupling parameter of BHPP is about the same as DBP and DOP, and the predicted relations between tau(alpha) and tau(JG) of BHPP are brought back in agreement with the experimental data.

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.

Acamprosate (AC) is used as a drug for treating alcoholism. We evaluated the effect of AC on serum triacylglycerol hydrolysis (GEH, glycerol ester hydrolysis), triacylglycerol transacylation with cholesterol (GECAT, glycerol ester:cholesterol acyltransferase), and acylcholesterol hydrolysis (Cease, cholesterol ester hydrolysis) in an experimental model of alcoholism. Ethanol-preferring (PRF), non-preferring (NPF), and control (CR) male Wistar rats were treated with AC (500 mg/kg, p.o.) for 21 consecutive days. The beneficial effect of AC on lipid parameters of PRF rats included decreased triacylglycerol, total cholesterol, and LDL-cholesterol, and increased HDL-cholesterol levels. Acamprosate-compensated changes associated with ethanol consumption were observed. Acamprosate treatment decreased GECAT and increased Cease control rats, but increased GECAT and decreased CEase in PRF animals. In all groups of rats, AC treatment did not influence GEH. In conclusion, our results suggest that AC can influence triacylglycerol metabolism by its action on the balance between hydrolysis and transacylation in rats.

Aims: The purpose of this study was to assess the anxiolytic activity of ifenprodil in Warsaw high-preferring (WHP) and low-preferring (WLP) rats after chronic ethanol treatment. Methods: WHP and WLP animals, their paired-ethanol-naive groups and control Wistar rats were treated with ifenprodil (1.0 mg/kg, intraperitoneally) for 21 consecutive days. Anxiolytic activity was evaluated by using the two-compartment exploratory test. In addition, the locomotor activity paradigm was also assessed. Results: Ifenprodil did not affect this paradigm in all investigated groups. The ethanol treatment led to lowering of anxiolytic scores in WHP rats. Multiple ifenprodil administration showed an anxiogenic-like activity in both WHP- and WLP-ethanol-treated groups. Conclusions: Our results suggest that, under some conditions, the role of ifenprodil in the treatment of alcoholism may be insufficient to support its use.

The effect of 5-week voluntary ethanol (EtOH) intake on plasma and cerebrospinal fluid (CSF) leptin levels was determined in adult male Warsaw high EtOH preferring (WHP) and low preferring (WLP) rats. EtOH treatment led to a decrease in leptin CSF concentration in WHP rats when compared to EtOH-naive WHP and control Wistar rats. On the contrary, in EtOH-treated WLP rats, both plasma and CSF leptin levels were increased in comparison with EtOH-naive animals. It can be concluded that EtOH treatment led to different response expressed especially by CSF leptin levels in WHP and WLP animals and it may be related to their genetic predisposition.

The aim of this study was to evaluate the effect of treatment with single (1x) and multiple (10x) doses of the anti-craving compound acamprosate (AC, calcium acetyl homotaurinate) on working memory in rats, using in a three-panel runway test. We measured tasks after the animals were treated with AC (500 mg/kg/d, i.p.); scopolamine (SC, 0.5 mg/kg/d, i.p.), a cholinergic muscarinic receptor antagonist; or both drugs concomitantly (ACSC), either for 1 day (1x) or daily for 10 consecutive days (10x). Neither 1x not 10x AC alone had a significant effect on working memory task performance, whereas treatment with SC alone had a significantly negative effect on the ability of the rats to complete the tasks. Rats receiving ACSC performed better than those receiving SC alone, making fewer errors and displaying shorter latency, similar to the performance of the control group. These observations support the hypothesis of an indirect involvement of AC in the cholinergic system.

The present study examined the composition of lymphoid subsets in the peripheral blood of alcohol-preferring (PRF) and non-preferring (NPF) rats, in an experimental model of alcoholism involving the disruption of the circadian cycle. The absolute and relative number of lymphocytes in specific subsets (CD3, CD4, CD8, NK, CD45RA) were measured using the flow cytometry method. When control animals with a disrupted circadian cycle (KN) were compared with a normal diurnal cycle group (KD), it was noticed that this disruption led to an increase in the absolute number of lymphocytes T (CD3+, CD4+ and CD8+ cells) and lymphocytes B (CD45RA+). After the period of time when the alcohol preference was seen, there was a change in response — as measured by the numbers and the percentage of lymphoid subsets in NPF rats — involving a lowering of NK and CD45RA+ cells. It seems that these animals exhibit higher sensitivity towards prolonged ethanol intoxication. However, the PRF animals — for whom the analysed values were close to those of the control group (KN) — tolerated the toxic effects of ethanol better and this may be related to their genetic predisposition.

The aim of this study was to investigate possible interactions between the analgesic activity of ketamine (an N-methyl-D-aspartate antagonist), midazolam (a benzodiazepine derivative) and morphine using the tail-flick test in rats. Animals were treated s.c. with ketamine (1.0-10.0 mg/kg), midazolam (0.3 mg/kg), or morphine (0.6 mg/kg) alone. or in combination The strongest analgesic effect of ketamine was observed after 3.0 mg/kg. In higher doses no enhancement of ketamine activity were found. After morphine and ketamine (3.0 mg/kg) or morphine, midazolam and ketamine co-administration. higher antinociceptive effects compared to ketamine activity were found. Rats administered midazolam and ketamine (3.0 mg/kg) showed a decrease of the effect of ketamine analgesia, and the antinociceptive effect of the three-component mixture was lower than after co-injection of morphine and ketamine. The interaction of these two compounds with ketamine (5.0 mg/kg) occurred in a different manner, because midazolam led to a strong enhancement of ketamine analgesia. After morphine and ketamine (5.0 mg/kg) administration, very weak increase of ketamine analgesia was observed. The results of this study allow better understanding of the alteration of the analgesic effects of low doses of ketamine under the influence of morphine and midazolam.

Multiple (10x) treatment of zolpidem (1.0 or 2.0 mg/kg, orally, p.o.) led to different effects in chronically ethanol-treated and control rats. In control rats, after repeated zolpidem administration, a weaker, when compared to single administration, hypnotic effect of ethanol was observed, which may be the result of tolerance developed towards the inhibitory effect of zolpidem. However, in chronically ethanol-treated rats, the multiple zolpidem treatment led to prolongation of ethanol-induced sleep similar to the values observed in non-zolpidem-treated control animals. This suggests that zolpidem multiple administration may inhibit tolerance towards ethanol in chronically ethanol-treated rats. In the experiment with zolpidem, there were effects on performance in a memory test and the impairment of passive avoidance task after multiple drug treatment when compared to the effects after single administration in control rats. In contrast, in chronically ethanol-treated rats, amplification of latency (especially after 2.0 mg/kg) was observed. The possible relationship between ethanol-induced sedation and latency values would be consistent with a higher contribution of the inhibitory effect of zolpidem, than a direct influence on memory processes in chronically ethanol-treated rats.

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. 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).

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.

The dielectric loss spectra of two closely related monosaccharides, D-ribose and 2-deoxy-D-ribose, measured at ambient and elevated pressures are presented. 2-deoxy-D-ribose and D-ribose are respectively the building blocks of the backbone chains in the nucleic acids DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). Small differences in the structure between D-ribose and 2-deoxy-D-ribose result in changes of the glass transition temperature Tg, as well as the dielectric strength and activation enthalpy of the secondary relaxations. However, the frequency dispersion of the structural α-relaxation for the same relaxation time remains practically the same. Two secondary relaxations are present in both sugars. The slower secondary relaxation shifts to lower frequencies with increasing applied pressure, but not the faster one. This pressure dependence indicates that the slower secondary relaxation is the important and 'universal' Johari–Goldstein β-relaxation of both sugars according to one of the criteria set up to classify secondary relaxations. Additional confirmation of this conclusion comes from good agreement of the observed relaxation time of the slower secondary relaxation with the primitive relaxation time calculated from the coupling model. All the dynamic properties of D-ribose and 2-deoxy-D-ribose are similar to the other monosaccharides, glucose, fructose, galactose and sorbose, except for the much larger relaxation strength of the α-relaxation of the former compared to the latter. The difference may distinguish the chemical and biological functions of D-ribose and 2-deoxy-D-ribose from the other monosaccharides.

Dielectric loss spectra of two glass-forming isomers, eugenol and isoeugenol, measured at ambient and elevated pressures in the normal liquid, supercooled, and glassy states are presented. The isomeric chemical compounds studied differ only by the location of the double bond in the alkyl chain. Above the glass transition temperature T(g), the dielectric loss spectra of both isomers exhibit an excess wing on the high frequency flank of the loss peak of the alpha relaxation and an additional faster gamma process at the megahertz frequency range. By decreasing temperature below T(g) at ambient pressure or by elevating pressure above P(g), the glass transition pressure, at constant temperature, the excess wing of isoeugenol shifts to lower frequencies and is transformed into a secondary beta-loss peak, while in eugenol it becomes a shoulder. These spectral features enable the beta-relaxation time tau(beta) to be determined in the glassy state. These changes indicate that the excess wings in isoeugenol and eugenol are similar and both are secondary beta relaxations that are not resolved in the liquid state. While in both isoeugenol and eugenol the loss peak of the beta relaxation in the glassy state and the corresponding excess wing in the liquid state shifts to lower frequencies on elevating pressure, the locations of their gamma relaxation show little change with increasing pressure. The different pressure sensitivities of the excess wing and gamma relaxation are further demonstrated by the nearly perfect superposition of the alpha-loss peak together with excess wing from the data taken at ambient pressure and at elevated pressure (and higher temperature so as to have the same alpha-peak frequency), but not the gamma-loss peak in both isoeugenol and eugenol. On physical aging isoeugenol, the beta-loss peak shifts to lower frequencies, but not the gamma relaxation. Basing on these experimental facts, the faster gamma relaxation is a local intramolecular process involving a side group and the slower beta relaxation mimics the structural alpha relaxation in behavior, involves the entire molecule and satisfies the criteria for being the Johari-Goldstein beta relaxation. Analysis and interpretation of the spectra utilizing the coupling model further demonstrate that the excess wings seen in the equilibrium liquid states of these two isomers are their genuine Johari-Goldstein beta relaxation.

Aim of the study was to assess dihydrocodeine (DHC) and metabolites concentrations and their correlations with DHC analgesia in cancer patients with pain. Thirty opioid-naive patients with nociceptive pain intensity assessed by VAS (visual analogue scale) > 40 received controlled-release DHC as the first (15 patients, 7 days) or as the second opioid (15 patients, 7 days). Blood samples were taken on day 2, 4 and 7 at each study period. DHC and its metabolites were assayed by HPLC. DHC provided satisfactory analgesia when administered as the first or the second opioid superior to that of tramadol. When DHC was the first opioid administered, DHC and dihydrocodeine-6-glucuronide (DHC-6-G) concentrations increased in the second and the third comparing to the first assay. A trend of nordihydromorphine (NDHM) level fall between the first and the third assay was noted; trends of dihydromorphine (DHM) level increase in the second relative to the first determination and decrease in the third compared to the second assay were observed. When DHC followed tramadol treatment a trend of DHC concentration increase in the second relative to the first assay was noted. DHC-6-G level increased in the second and in the third comparing to the first determination; NDHM and DHM concentrations were stable. DHC and DHC-6-G concentrations increased similarly during both treatment periods which suggest their prominent role in DHC analgesia. Few significant correlations were found between DHC dose, DHC and metabolites serum concentrations with analgesia suggesting the individual DHC dose titration.