Does the molecular mobility and flexibility of the saccharide ring affect the glass-forming ability of naproxen in binary mixtures?

In this paper, we studied the impact of saccharides having a similar backbone but differing in the degree of freedom, local molecular mobility, flexibility of the ring and intermolecular interactions on the glass-forming ability (GFA) of naproxen (NAP) in binary mixtures. For this purpose, a series of methyl and acetyl derivatives of glucose (GLS) and anhydroglucose (anhGLS), as well as neat anhGLS have been used to produce homogeneous solid dispersions (SDs) of varying molar concentration of examined active pharmaceutical ingredient (API). Systematic measurements with the use of Differential Scanning Calorimetry (DSC) and Broadband Dielectric Spectroscopy (BDS) enabled us to determine the phase transitions, homogeneity and molecular mobility of the investigated binary mixtures as well as the impact of excipient on the crystallization tendency of NAP. It turned out that acetylated glucose (acGLS), one of the most mobile and flexible saccharides of all examined herein materials, is the best excipient enhancing the GFA of studied API. Although, it should be noted that upon storage at room temperature, we observed the recrystallization of NAP from binary mixtures. Interestingly, API always crystallized to the initial polymorphic form, as shown by X-ray diffraction (XRD) investigations. Finally, since additional measurements with the use of Fourier Transform Infrared (FTIR) Spectroscopy clearly indicated that there are no significant differences in the intermolecular interactions in the systems composed of NAP and all examined saccharides, one can postulate that the mobility and ring flexibility of the matrix have, , the most important impact on the crystallization tendency of NAP upon cooling. Consequently, it seems that in some cases, more mobile/flexible matrices can be a much better choice to enhance the glass-forming ability of studied pharmaceutical.

Impact of temperature on the physicochemical, structural and biological features of copper-silica nanocomposites.

Classical wet chemical synthesis was used to fabricate a hybrid composite that contained copper nanoparticles (average size ∼1 nm), which were embedded into a silicon oxide carrier. The structural and chemical alternations in the copper-functionalized silica were investigated in systems that were sintered at 573 K, 873 K, 1173 K, and 1473 K. A general trend, which was associated with the transformation of metallic copper with a cubic structure into copper(II) oxide with a monoclinic structure in the heat-treated systems, was found. XPS and FTIR spectroscopies also revealed the presence of copper(I) oxide, which formed a shell around the CuO. SEM and TEM showed gradual densification of the hybrid system at ever higher sintering temperatures, which corresponded with the gradual copper agglomeration. A temperature of 873 K was determined to be the temperature at which amorphous silica was transformed into cristoballite and tridymite, as well as the formation of a bulk-like copper structure. In relation to the physicochemical and structural data, high antimicrobial features that had a relatively low toxicity effect on the normal human fibroblasts (NHDF) below 250 mg/L was found for the initial copper-silica composite and the samples that were sintered at 573 K. In turn, a significant decrease in the biological impact was observed in the samples that were sintered at temperatures above 573 K. As a result, the paper discusses the model of structural modifications in copper-silica nanocomposite concerning their biological impact that was developed.

Dramatic slowing down of the conformational equilibrium in the silyl derivative of glucose in the vicinity of the glass transition temperature.

The vitrification process is usually preceded by a significant change (around 6-8 decades) in the viscosity, structural relaxation times, or diffusion that occurs in a relatively small range of temperatures in fragile liquids. Along with this phenomenon, conformations of the molecules vary as well. In fact, this process is studied in bulk polymers and high molecular weight materials deposited in the form of thin films. On the other hand, spatial rearrangement of small glass formers in the supercooled liquid state has not been intensively investigated, so far. Herein, data obtained from measurements carried out using various experimental techniques on supercooled 1,2,3,4,6-penta-O-(trimethylsilyl)-d-glucopyranose (S-GLU) have revealed that rotations of silyl moieties along with the deformation in the saccharide ring are significantly slowed down in the vicinity of the glass transition temperature (Tg). These intramolecular reorganizations affect the structural relaxation time, atomic pair distribution function, integrated intensity, as well as a number of bands and signals observed, respectively, in the Raman and NMR spectra. Data reported herein offer a better understanding of the conformational variation and time scale of this process in the complex and flexible molecules around the Tg.

Studying tautomerism in an important pharmaceutical glibenclamide confined in the thin nanometric layers.

The uniform thin films with variable thicknesses (d = 49, 120, 220 nm) of active pharmaceutical ingredient (API) glibenclamide (GCM) was spin-coated and investigated using broadband dielectric, grazing incident FTIR spectroscopies, atomic force microscopy, and ellipsometry. Data analysis revealed that nanoconfined systems consist of a mixture of amide and imidic acid forms of this pharmaceutical, wherein the ratios of both tautomeric forms in the thin films were different with respect to the molten supercooled bulk system. Moreover, changes in the populations of glibenclamide tautomers, i.e. higher amide to imides ratio in the spatially restricted API with respect to the bulk sample, had a strong impact on the character of the proton transfer reaction. In this context, the kinetic curves constructed on the base of infrared data for the bulk system follow the sigmoidal shape, characteristic for the autocatalytic reaction, while results obtained for the confined samples provide exponential character and indicate first-order transformation. This allows hypothesizing that the autocatalytic nature of the tautomerism in the bulk sample is most likely related to the formation of the amide tautomers which further catalyze the progress of imide-amide transformation. Our results are the first studies showing that the change in the thickness of the film may affect the properties and isomerization kinetics in a pharmaceutical systems. Finally, our data open a new perspective for developing new drug delivery systems.

Unexpected Crossover in the kinetics of mutarotation in the supercooled region: the role of H-bonds.

Intra- and intermolecular studies on the molten L-sorbose have been carried out at variable temperature conditions to determine the crosover temperature (T c ). In addition, isothermal time-dependent FTIR and Raman measurements were performed to probe the pace of mutarotation and activation energy of this reaction in the studied saccharide, which varied from 53-62 kJ/mol up to 177-192 kJ/mol below and above T c , respectively. To explain the change in activation barrier for the mutarotation a complementary analysis using difference FTIR spectra collected around T c = 365 K in the hydroxyl region has been done. It was found that the alteration of kinetic parameters and molecular dynamics around T c are strictly related to the variation in the strength of H-bonds which above T c are significantly weaken, increasing the freedom of rotation of functional groups and movement of individual molecules. That phenomenon most likely affects the proton transfer, underlying molecular mechanism of mutarotation, which may lead to the significant increase in activation barrier. The new insight into a molecular aspect of the mutarotation around T c has created an opportunity to better understanding the relationship between physics of condensed matter and the potential role of H-bonds dynamics on the progress of the chemical reaction in highly viscous systems.

A study on the progress of mutarotation above and below the Tg and the relationship between constant rates and structural relaxation times.

Comprehensive FTIR studies on the progress of mutarotation in d-fructose mixed with maltitol have been carried out over a wide range of temperatures, both above and below the glass transition temperature Tg. In addition to the analysis of single bands, we have developed a completely new approach considering the full spectral range to follow the overall progress of the reaction. We have found that at the calorimetric Tg, there is a clear change in the temperature dependence of constant rates. The activation barrier for mutarotation changes from around 59 kJ mol-1 (the supercooled state) to around 249 kJ mol-1 (the glassy state). This dramatic variation in the activation barrier is consistent with the change in the mechanism of this specific chemical conversion, as theoretically considered by Wlodarczyk et al. [Phys. Chem. Chem. Phys., 2014, 16, 4694-4698]. Alternatively, it can also be connected to the change in the viscosity of the sample. Additionally, we investigated the relationship between constant rates (k) of mutarotation, structural relaxation times (τα), and dc conductivity (σdc) above and below the glass transition temperature. It was found that there was a linear correlation between all these quantities; they scale with various exponents changing at Tg. Our results also indicate that a single activation barrier might not be sufficient to describe the mutarotation process.