The structural properties resulting from the reciprocal influence between water and three well-known homologous disaccharides, namely trehalose, maltose and sucrose, in aqueous solutions have been investigated in the 4 -66 wt % concentration range by means of molecular dynamics computer simulations. Hydration numbers clearly show that trehalose binds to a larger number of water molecules than do maltose or sucrose, thus affecting the water structure to a deeper extent. Two-dimensional radial distribution functions of trehalose solutions definitely reveal that water is preferentially localized at the hydration sites found in the trehalose dihydrate crystal, this tendency being enhanced when increasing trehalose concentration. In a rather wide concentration range (4-49 wt %), the fluctuations of the radius of gyration and of the glycosidic dihedral angles of trehalose indicate a higher flexibility with respect to maltose and sucrose. At sugar concentrations between 33 wt % and 66 wt %, the mean sugar cluster size and the number of sugar-sugar hydrogen bonds (HBs) formed within sugar clusters reveal that trehalose is able to form larger clusters than sucrose but smaller than maltose. These features suggest that trehalose-water mixtures would be more homogeneous than the two others, thus reducing both desiccation stresses and ice formation.

Amorphous solids are conventionally formed by supercooling liquids or by concentrating noncrystallizing solutes (spray-drying and freeze-drying). However, a lot of pharmaceutical processes may also directly convert compounds from crystal to noncrystal which may have desired or undesired consequences for their stability. The purpose of this short review paper is (i) to illustrate the possibility to amorphize one compound by several different routes (supercooling, dehydration of hydrate, milling, annealing of metastable crystalline forms), (ii) to examine factors that favor crystal to glass rather than crystal to crystal transformations, (iii) to discuss the role of possible amorphous intermediates in solid-solid conversions induced by milling, (iv) to address the issue of chemical stability in the course of solid state amorphization, (v) to discuss the nature of the amorphous state obtained by the nonconventional routes, (vi) to show the effect of milling conditions on glasses properties, and (vii) to attempt to rationalize the observed transformations using the concepts of effective temperature introduced in nonequilibrium physics.

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By performing molecular dynamics simulations of binary Lennard-Jones systems with three different potentials, we show that increase of anharmonicity and capacity for intermolecular coupling of the potential is the cause of (i) the increase of kinetic fragility and nonexponentiality in the liquid state, (ii) the Tg-scaled temperature dependence of the nonergodicity parameter determined by the vibrations at low temperatures in the glassy state. Naturally these parameters correlate with each other, as observed experimentally by T. Scopigno et al., Science 302, 849 (2003). PACS numbers: 61.20.Ja, 64.60.Ht, 64.70.Pf The structural relaxation time, τ , of all glass-forming liquids increases on cooling. It becomes so long at some temperature T g that equilibrium cannot be maintained and the liquid is transformed to a glass. T g is defined as the temperature at which τ reaches some arbitrarily chosen long time, say 10 2 s. Although this behavior is shared by glass-formers of diverse chemical and physical structures, the scaled temperature dependence of τ in the liquid state can differ greatly from one liquid to another in the degree of departure from the Arrhenius scaled temperature dependence [1,2]. The departure can be characterized by the rapidity of the change of log(τ ) with T g /T at T g /T =1, which is given by the steepness index or the fragility m defined by [3]The values of m of glass-formers of all kinds vary over a large range, from the least value of about 17 for strong glass-formers (like silica) having nearly Arrhenius scaled temperature dependence of τ , to values as high as about 200 found for some glass-formers called fragile. Naturally, such large variations observed in m beg the question of its microscopic origin. Several attempts have been made in the past to correlate m with other dynamic or thermodynamic properties, with the hope that the correlations will lead to the factor or factors that determine m. . Glass-former with larger m or (1 − β) has a larger < u 2 > at the same value of T /T g and rise more rapidly as a function of T /T g , below T g as well as near and across T g in the liquid states [4]. (3) The correlation between m and the slope of the change of the configurational entropy, S c , with T /T g at T g [5]. (4) The correlation of m with the statistics of potential energy minima of the energy landscape [6,7]. (5) The correlation of m with the temperature dependence of the shear modulus of the liquid [8]. Perhaps the most intriguing of all correlations is (6) between m and the vibrational properties of the glass at temperatures well below T g found recently by T. Scopigno et al. [9]. The nonergodicity parameter, f (Q, T ), at Q=2 nm −1 at very low temperatures is determined by vibrations. From inelastic X-ray scattering data, its temperature dependence is well described by [1 + α (T /T g )] −1 . T. Scopigno showed that m and α are proportional for many glass-formers. Apparently, this last correlation (6) seems to be related to (2) for < u 2 (T /T g ) > from neutron scattering at tem...

Raman spectroscopy (in the low-frequency range and the amide I band region) and modulated differential scanning calorimetry investigations have been used to analyze temperature-induced structural changes in lysozyme dissolved in 1H2O and 2H2O in the thermal denaturation process. Low-frequency Raman data reveal a change in tertiary structure without concomitant unfolding of the secondary structure. Calorimetric data show that this structural change is responsible for the configurational entropy change associated with the strong-to-fragile liquid transition and correspond to about 1/3 of the native-denaturated transition enthalpy. This is the first stage of the thermal denaturation which is a precursor of the secondary structure change and is determined to be strongly dependent on the stability of the hydrogen-bond network in water. Low-frequency Raman spectroscopy provides information on the flexibility of the tertiary structure (in the native state and the transient folding state) in relation to the fragility of the mixture. The unfolding of the secondary structure appears as a consequence of the change in the tertiary structure and independent of the solvent. Protein conformational stability is directly dependent on the stability of the native tertiary structure. The structural transformation of tertiary structure can be detected through the enhanced 1H/2H exchange inhibited in native proteins. Taking into account similar features reported in the literature observed for different proteins it can be considered that the two-stage transformation observed in lysozyme dissolved in water is a general mechanism for the thermal denaturation of proteins.

In this paper we present a new protocol to determine faster the solubility of drugs into polymer matrixes. The originality of the method lies in the fact that the equilibrium saturated states are reached by demixing of supersaturated amorphous solid solutions and not by dissolution of crystalline drug into the amorphous polymer matrix as for usual methods. The equilibrium saturated states are thus much faster to reach due to the extra molecular mobility resulting from the strong plasticizing effect associated with the supersaturation conditions. The method is validated using the indomethacin/polyvinylpyrrolidone mixture whose solubility diagram was previously determined by usual techniques. The supersaturated states have been directly obtained in the solid state by comilling, and the investigations have been performed by differential scanning calorimetry and powder X-ray diffraction.

These results establish, for the first time, that Ibuprofen can exist under two different crystalline phases which constitute a monotropic system, the new form being metastable.

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