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Herein, we investigated the molecular dynamics as well as intramolecular interactions in two primary monohydroxy alcohols (MA), 2-ethyl-1-hexanol (2EHOH) and n-butanol (nBOH), by means of broad-band dielectric (BDS) and Fourier transform infrared (FTIR) spectroscopy. The modeling data obtained from dielectric studies within the Rubinstein approach [Macromolecules2013, 46, 7525−7541] originally developed to describe the dynamical properties of self-assembling macromolecules allowed us to calculate the energy barrier (Ea) of dissociation from the temperature dependences of relaxation times of Debye and structural processes. We found Ea∼ 19.4 ± 0.8 and 5.3 ± 0.4 kJ/mol for the former and latter systems, respectively. On the other hand, FTIR data analyzed within the van’t Hoff relationship yielded the energy barriers for dissociation Ea∼ 20.3 ± 2.1 and 12.4 ± 1.6 kJ/mol for 2EHOH and nBOH, respectively. Hence, there was almost a perfect agreement between the values of Eaestimated from dielectric and FTIR studies for the 2EHOH, while some notable discrepancy was noted for the second alcohol. A quite significant difference in the activation barrier of dissociation indicates that there are probably supramolecular clusters of varying geometry or a ring-chain-like equilibrium is strongly affected in both alcohols. Nevertheless, our analysis showed that the association/dissociation processes undergoing within nanoassociates are one of the main factors underlying the molecular origin of the Debye process, supporting the transient chain model.

In this paper the crystal growth of nifedipine from pure system and from binary mixtures composed of active substance (API) and two acetylated disaccharides, maltose and sucrose (NIF–acMAL, NIF–acSUC, 5:1 weight ratio), was investigated. Optical snapshots supported by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) measurements showed that mainly β and α forms of nifedipine grow up in all investigated samples. They also revealed that the morphology of growing crystals strongly depends on the presence of modified carbohydrates and temperature conditions. Interestingly, it was found that the activation barrier for the crystal growth of the β polymorph is not affected by acetylated saccharides while the one estimated for the α form changes significantly from 48.5 kJ/mol (pure API) up to 122 kJ/mol (NIF–acMAL system). Moreover, the relationship between the crystal growth rate and structural relaxation times for pure NIF and solid dispersions were analyzed. It turned out that there is a clear decoupling between the crystal growth rate and structural dynamics in both NIF–acMAL and NIF–acSUC binary mixtures. This is in line with recent reports indicating the decoupling phenomenon to be a universal feature of soft matter in the close vicinity of the glass transition temperature.

•Sensitive isotope dilution calibration HPLC-MS/MS method for 5 selected estrogens.•Preparation of representative whole water matrix samples for improved comparability.•Comparison of sorbents for solid phase extraction of estrogens.•New method combining solid phase extraction disk and molecularly imprinted polymer.

Molecular dynamics of pure nifedipine and its solid dispersions with modified carbohydrates as well as the crystallization kinetics of active pharmaceutical ingredient (API) above and below the glass transition temperature were studied in detail by means of broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction method. It was found that the activation barrier of crystallization increases in molecular dispersions composed of acetylated disaccharides, whereas it slightly decreases in those consisting of modified monocarbohydrates for the experiments carried out above the glass transition temperature. As shown by molecular dynamics simulations it can be related to the strength, character, and structure of intermolecular interactions between API and saccharides, which vary dependently on the excipient. Long-term physical stability studies showed that, in solid dispersions consisting of acetylated maltose and acetylated sucrose, the crystallization of nifedipine is dramatically slowed down, although it is still observable for a low concentration of excipients. With increasing content of modified carbohydrates, the crystallization of API becomes completely suppressed. This is most likely due to additional barriers relating to the intermolecular interactions and diffusion of nifedipine that must be overcome to trigger the crystallization process.

Differential scanning calorimetry (DSC), broadband dielectric (BDS), and Fourier transform infrared (FTIR) spectroscopies as well as theoretical computations were applied to investigate inter- and intramolecular interactions between the active pharmaceutical ingredient (API) indomethacin (IMC) and a series of acetylated saccharides. It was found that solid dispersions formed by modified glucose and IMC are the least physically stable of all studied samples. Dielectric measurements showed that this finding is related to neither the global nor local mobility, as the two were fairly similar. On the other hand, combined studies with the use of density functional theory (DFT) and FTIR methods indicated that, in contrast to acetylated glucose, modified disaccharides (maltose and sucrose) interact strongly with indomethacin. As a result, internal H-bonds between IMC molecules become very weak or are eventually broken. Simultaneously, strong H-bonds between the matrix and API are formed. This observation was used to explain the physical stability of the investigated solid dispersions. Finally, solubility measurements revealed that the solubility of IMC can be enhanced by the use of acetylated carbohydrates, although the observed improvement is marginal due to strong interactions.

This paper presents comprehensive studies on the molecular dynamics of a pharmaceutically important substance, posaconazole. In order to characterize relaxation dynamics in the supercooled liquid and glassy states, dielectric and mechanical spectroscopies were applied. Dielectric data have indicated multiple relaxation processes that appear above and below the glass transition temperature Tg(τα= 100 s) of posaconazole. From the curvature of the dielectric log10(τα) versus inverse of temperature dependence, we determine so-called “fragility”, being a very popular parameter for classifying the structural dynamics of supercooled liquids and polymers. From the calculations, we get m= 150, which means that is one of the most fragile glass-forming liquids. In this paper, the relaxation dynamics of supercooled posaconazole extracted from the dielectric response function was also confronted with shear-mechanical relaxation. Finally, we have also presented a direct comparison of the fragility and the number of dynamically correlated molecules Ncdetermined from dynamic calorimetry curves and dielectric and mechanical spectroscopies, showing a clear deviation in the picture of glass-transition dynamics generated by calorimetric and spectroscopic techniques.

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).

Broadband dielectric measurements were carried out in the supercooled as well as in the glassy state of two very important disaccharides: trehalose and sucrose. Multiple relaxation processes were observed. Above the glass transition temperatures of examined disaccharides structural relaxation of cooperative origin was detected, where in the glassy state more local motions (secondary modes) appeared. Our data were discussed in light of the findings reported by other groups. We pointed out that sample preparation might impact mobility and, thus, dielectric loss spectra in a significant way. Consequently, it may lead to misinterpretation of the dielectric relaxation processes. Moreover, impact of physical aging and pressure on dynamics of two secondary relaxation processes observed in the glassy state of trehalose and sucrose has been investigated. Additionally, we have demonstrated that, in contrast to the calorimetric measurements (DSC), activation energies of the β- and γ-relaxation processes observed in the glassy state of sucrose and trehalose do not change as a result of physical aging. Finally, we found out that the β-relaxation process slows down as pressure increases. We interpreted this fact in view of increasing rigidity of the structures of disaccharides.

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.

In this paper, we present a novel way of stabilization of amorphous celecoxib (CEL) against recrystallization by preparing binary amorphous celecoxib–octaacetylmaltose (CEL–acMAL) systems by quench-cooling of the molten phase. As far as we know this is the first application of carbohydrate derivatives with acetate groups to enhance the stability of an amorphous drug. We found that CEL in the amorphous mixture with acMAL is characterized by a much better solubility than pure CEL. We report very promising results of the long-term measurements of stability of the CEL–acMAL binary amorphous system with small amount of stabilizer during its storage at room temperature. Moreover, we examined the effect of adding acMAL on molecular dynamics of CEL in the wide temperature range in both the supercooled liquid and glassy states. We found that the molecular mobility of the mixture of CEL with 10 wt % acMAL in the glassy state is much more limited than that in the case of pure CEL, which correlates with the better stability of the amorphous binary system. By dielectric measurements and theoretical calculations within the framework of density functional theory (DFT), we studied the role of acMAL in enhancing the stability of amorphous CEL in mixtures and postulated which interactions between CEL and acMAL molecules can be responsible for preventing devitrification.

Glibenclamide (GCM) is an oral hypoglycemic agent of the sulfonylurea group used in the treatment of non-insulin-dependent diabetes. Crystalline GCM is characterized by low bioavailability, which is attributed to its poor dissolution properties. It prompted us to prepare this drug in its amorphous form as a means to enhance its dissolution characteristics. Two different methods were used to convert crystalline GCM into the glassy form: quench-cooling of the melt and cryogenic milling. To monitor solid-state properties of the amorphous samples, X-ray powder diffraction (XRD), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), ultraperformance liquid chromatography (UPLC) and spectroscopy, and broadband dielectric spectroscopy (BDS) were applied. The results of UPLC separations along with associated infrared and NMR measurements unambiguously showed that the thermal degradation of the quenched GCM, as suggested in literature reports, does not occur. A similar analysis performed on the cryomilled material also did not indicate any chemical decomposition. On the other hand, both methods confirmed that the conversion to the amorphous form is connected with the amide−imidic acid tautomerism of the examined drug. Moreover it was shown that this transformation occurs regardless of the manner of amorphization. Finally, dielectric spectroscopy was employed to study the molecular dynamics of vitrified GCM. The analysis of the ε′′(f) in terms of the KWW function from the dielectric measurements revealed the existence of an “excess wing” attributed to the true Johari−Goldstein process based on Ngai’s coupling model. The dielectric properties of GCM obtained in the amorphous form both by rapid cooling of the melt and the cryogenic grinding of crystalline sample were also compared.

Despite the potential importance of c-myc protein to cell proliferation and apoptosis, nothing is known about the contribution of this prolo-oncogene to the development of the ovarian follicles in humans. Therefore the localization of c-myc in the human ovary was the main aim oj this study.Localization oj c-myc mRNA in 15 human ovaries was assessed by in situ hybridization. Atresia oj the antral follicles was determined by in situ 3'-end labeling of fragmented DNA.Proto-oncogene c-myc was found in all the stages of follicular development except the primordial stage. The corpus luteum was also positive for c-myc mRNA. There was no positive staining for c-myc in either the corpus albicans or the postmenopausal ovary.These data indicate that the expression of c-myc may play a role in the molecular mechanisms of cell proliferation and apoptosis in the human ovary.

Nonsteroidal anti-inflammatory agents (NSAIDs) such as aspirin (ASA) damage the gastric mucosa both in normal subjects and in arthritic patients. The aim of this study was to investigate the protective action of a new H2-receptor antagonist, ebrotidine, in the prevention of ASA-induced acute mucosal injury in the stomach of healthy volunteers. In a double-blind randomized crossover study 10 male volunteers received treatment with either placebo plus ASA (500 mg) or ebrotidine (800 mg) plus ASA twice daily for 3 days with 10 days' washout period between treatments. The mean number of gastric erosions seen at endoscopy after treatment with ebrotidine plus ASA (2.0 ± 0.3) was significantly lower than that after placebo plus ASA (3.7 ± 0.2). This reduction in lesion core by ebrotidine was accompanied by a significant increase in gastric blood flow (by 15% in corpus and 26% in antrum), by a rise in transmucosal potential difference (by 12%), and by a decrease of mucosal microbleeding. Ebrotidine afforded substantial protection from ASA-induced injury to the gastric mucosa, and this was accompanied by increase of the mucosal blood flow. We conclude that ebrotidine provides mucosal protection for patients taking NSAIDs

This study was designed to assess the gastroprotective and secretory effects of ebrotidine, a novel H2-receptor antagonist, in humans. Two groups (A and B) of male subjects with normal gastric mucosa were used. Group A (six subjects) was treated for 3 days with either ebrotidine or placebo in a randomized, crossover study, and on the 4th day 100 ml of 50% ethanol was sprayed on the mucosa via an endoscope. Pretreatment with ebrotidine significantly reduced the endoscopic score of mucosal damage and deep hemorrhagic lesions caused by ethanol as compared with those in placebo-treated subjects. In group B (six subjects) the 24-h pH-metry was assessed with an intraluminal pH electrode placed in the gastric corpus and connected to portable recording apparatus. A single oral dose of ebrotidine (800 mg) caused a significant reduction in circadian acidity and resulted in a marked and significant inhibition of acid secretion for about 6h on administration. We conclude that ebrotidine is highly effective as a gastroprotective agent, and as an H2-receptor antagonist shows a potent inhibitory effect on gastric acid secretion in humans.

Type A complete spinach chloroplasts (photosynthetic control ratio ≅ 5) were frozen in liquid nitrogen, in the presence or absence of 50 percent glycerol (v/v). By considering five parameters related to the non cyclic electron transfer in the light (oxidant : K-ferricyanide) it was shown that the uncoupling due to freezing and thawing was partially prevented by glycerol. However glycerol was responsible for a slight uncoupling in fresh chloroplasts. The clearest uncoupling effect of freezing, and chiefly of glycerol, concerned the inhibition of the electron flow which follows the stimulation caused by a limiting quantity of ADP (state 4).

Introduction: The relationship between the appropriateness of the transthoracic echocardiography (TTE) and its clinical impact is still a matter of debate. Objective: The aim of this study was to assess the degree of adherence to the appropriate use criteria for echocardiography, in a tertiary public hospital in the United Kingdom, as well as the clinical impact of the exam on patient management. Methods: 859 TTE’s performed consecutively during January 2014 were reviewed to assess its appropriateness, and were classified as appropriate, uncertain or inappropriate using the 2011 guidelines. Subsequently, patient’s files were examined to determine the clinical impact of the TTE which was assigned to one of the following three categories: (1) active change in care, (2) continuation of current care, or (3) no change in care. Patients which files were not available were excluded (259). All classifications were evaluated by two independent cardiologists, with no direct relation to the study. Results: Our sample had a mean age of 63 ± 17 years with a gender balance. The majority of the exams were requested at the outpatient (81.4%) clinic, by cardiologists (50.3%) and general practitioners (13.4%). Regarding the main findings, in 7.6% of the studies there were moderate to severe systolic dysfunction; 4.0% showed severe valvular heart disease and 5.1% had significant pulmonary hypertension. Relatively to the appropriateness of the TTE requests, 76.5% were considered appropriate, 7.1% inappropriate and 12.6% uncertain. With respect to the clinical impact of the TTE’s, 42.7% of the exams led to an active change in care, 15.6% to a continuation of the care and 11.5% revealed no change in care. Age (β0.90, P=0.05) and outpatient setting (β4.4, P<0.01) were the most important predictors of an active change of care exam. On the contrary, the appropriateness of the TTE’s requests (β1.1, P=0.56) and the specialist ordering the exams (β0.81, P=0.26) were not independently associated. Conclusion: Our data showed that almost 8 out of 10 TTE were considered appropriate, and 4 out of 10 exams had an active clinical impact.

Partially purified chloroplast ATP synthase was reconstituted into asolectin liposomes. A valinomycine induced potassium diffusion potential from outside to inside the vesicles promoted a measurable ATP synthesis. If valinomycine was replaced by nigericine, practically no ATP was formed