Impact of low molecular weight excipient octaacetylmaltose on the liquid crystalline ordering and molecular dynamics in the supercooled liquid and glassy state of itraconazole.

Different experimental and theoretical techniques were applied to investigate basic physical properties of very stable and homogeneous solid dispersions formed by itraconazole and octaacetylmaltose. Differential scanning calorimetry as well as semi-empirical calculations have indicated that liquid crystalline ordering in itraconazole was completely suppressed in the binary mixtures. Molecular dynamics studies with the use of broadband dielectric spectroscopy have shown that the width of the structural relaxation process becomes smaller and fragility drops in solid dispersions with respect to the pure itraconazole. Moreover, the dynamics of secondary relaxation processes was affected by acetylated maltose. As demonstrated, ß- and γ-secondary modes shift to higher and lower frequencies, respectively. On the other hand, aging experiments revealed that isostructural relaxation times in the glassy state become systematically longer with the addition of modified carbohydrate. This is a very important finding in the context of the current discussion on the factors affecting physical stability of easily crystallizing APIs. It seems that beside intermolecular interactions and local reorientation, the global mobility might control the crystallization of amorphous solid dispersions. Finally, we have demonstrated that itraconazole in binary mixtures dissolves faster and to greater extent with respect to the crystalline and amorphous form of this API.

Impact of inter- and intramolecular interactions on the physical stability of indomethacin dispersed in acetylated saccharides.

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.

Enhancement of the physical stability of amorphous indomethacin by mixing it with octaacetylmaltose. inter and intra molecular studies.

PURPOSE: To demonstrate a very effective and easy way of stabilization of amorphous indomethacin (IMC) by preparing binary mixtures with octaacetylmaltose (acMAL). In order to understand the origin of increased stability of amorphous system inter- and intramolecular interactions between IMC and acMAL were studied. METHODS: The amorphous IMC, acMAL and binary mixtures (IMC-acMAL) with different weight ratios were analyzed by using Dielectric Spectroscopy (DS), Differential Scanning Calorimetry (DSC), Raman Spectroscopy, X-ray Diffraction (XRD), Infrared Spectroscopy (FTIR) and Quantitative Structure-Activity Relationship (QSAR). RESULTS: Our studies have revealed that indomethacin mixed with acetylated saccharide forms homogeneous mixture. Interestingly, even a small amount of modified maltose prevents from recrystallization of amorphous indomethacin. FTIR measurements and QSAR calculations have shown that octaacetylmaltose significantly affects the concentration of indomethacin dimers. Moreover, with increasing the amount of acMAL in the amorphous solid dispersion molecular interactions between matrix and API become more dominant than IMC-IMC ones. Structural investigations with the use of X-ray diffraction technique have demonstrated that binary mixture of indomethacin with acMAL does not recrystallize upon storage at room temperature for more than 1.5 year. Finally, it was shown that acMAL can be used to improve solubility of IMC. CONCLUSIONS: Acetylated derivative of maltose might be very effective agent to improve physical stability of amorphous indomethacin as well as to enhance its solubility. Intermolecular interactions between modified carbohydrate and IMC are likely to be responsible for increased stability effect in the glassy state.

Molecular dynamics of the supercooled pharmaceutical agent posaconazole studied via differential scanning calorimetry and dielectric and mechanical spectroscopies.

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 Nc determined 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.

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).

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.

Dielectric studies on molecular dynamics of two important disaccharides: sucrose and trehalose.

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 ß- 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 ß-relaxation process slows down as pressure increases. We interpreted this fact in view of increasing rigidity of the structures of disaccharides.

Enhancement of amorphous celecoxib stability by mixing it with octaacetylmaltose: the molecular dynamics study.

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.

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.

Magnetic resonance imaging of the skin.

A thorough examination of the skin is essential to screen various diseases accurately, evaluate the effectiveness of topically applied drugs and assess the results of dermatological surgeries such as skin grafts. The assessment of skin properties is also crucial in the cosmetics industry, where it is important to evaluate the effects skin care products have on these properties. The simplest and most widely used method of skin evaluation, the 'naked eye' assessment, enables researchers to assess only the skin surface and involves a large amount of inter-observer variability. Thanks to a great progress that has been made in physics, electronics and computer engineering in recent years, sophisticated imaging methods are increasingly available in day-to-day studies. The aim of this review was to present one of these techniques, namely the magnetic resonance imaging (MRI), and to discuss its possible use in skin examination and analysis. We present basic principles of MRI, as well as several interesting applications in the field of dermatology, and discuss the advantages and limitations of this method.