We studied hydration equilibria and phase transformations in a cytotoxic drug (BBR3576). The original sample is a hydrated compound that undergoes a structural phase transition when it looses about half of its structural water. Such a structural transition is completely reversible: the partially dehydrated form is stable up to 130°C (or up to 140°C for severalminutes) and reverts to the original form upon rehydration. Completely different phase relationships are observed if an original sample is fully dehydrated: when all water has been released, a metastable anhydrous phase forms, which undergoes an irreversible exothermic conversion to a stable phase. Upon rehydration at room temperature of such an anhydrous phase, a new hydrated form is obtained, which is definitely different from the original one.

GV150526A is a new drug recently developed by GlaxoWellcome. It belongs to a novel group of 2-carboxyindole derivatives and is therapeutically effective in the treatment or prevention of CNS disorders resulting from neurotoxic damage. We present a physicochemical characterization of the three solid forms (hydrates) of GV150526A carried out mainly by thermal methods. It is shown that: (1) the different forms can be qualitatively and quantitatively distinguished by their thermal properties; (2) dehydration is followed or accompanied by a structural relaxation of the substrate that takes place at different rates and with different enthalpies in the three forms; (3) two of the solid forms can be converted into a phase that is thermodynamically stable at room temperature by partial dehydration/rehydration in a solid/vapor process.

We study by molecular dynamics simulations the hydration of β-cyclodextrin. Our simulations show that within these barrel-shaped molecules hydrophobicity dominates, while at the top and bottom sides of the barrel interactions with water are mostly hydrophilic in nature. These results agree with crystallographic data at 120 K and, in particular, with the spontaneous hydration process of a cyclodextrin crystal in wet atmosphere. The predicted structure of the hydration shells is discussed and compared with previous molecular mechanics calculations which report an overall hydrophobic behavior. Moreover, the temperature dependence of the hydration process is discussed.

The hydration process of beta-CD in aqueous solution was analyzed by MM calculations. Monitoring the single waters molecules, it was found that beta-CD shows a global, not only limited to the internal cavity, hydrophobic behavior. The consequent hydration shells were evidenced and discussed: they appear connected to molecular packing rather than due to stronger directionated interactions type hydrogen bonds.

Abstract From a purely enthalpic standpoint, the ß-CD hydration, as studied by semiempirical calculations, appears improbable, in contrast to experiment. For the spontaneous hydration process, a compensation mechanism, connected with substrate stabilization and/or entropy increase, is suggested on the basis of simple thermodynamic considerations. The analysis is done on the basis of a single parameter Ew (> 0), which represents the energy needed to transfer a mole of water from the liquid to the ß-CD absorbed phase. The model, although simple, allows predictions largely consistent with the experimental results, while suggesting possible interpretations.

The hydration process of β-CD in aqueous solution was analyzed by MM calculations. Monitoring the single water molecules, it was found that β-CD shows a global, not only limited to the internal cavity, hydrophobic behavior. The consequent hydration shells were evidenced and discussed: they appear connected to molecular packing rather than due to stronger directionated interactions type hydrogen bonds

Abstract AM1 and PM3 calculations were carried out on ß-cyclodextrine (ß-CD) undecahydrate in the experimental conformation at 120 K. The calculated ß-CD/water interaction energies are very small and indicative for each water molecule of an unfavorable condition in respect to that of pure water. The conformationally optimized system was also studied: ß-CD appears highly symmetrical with negligible dipole moment, mainly because of the circular arrangement of the single vectors. Primary hydroxyls can easily rotate, while the secondary ones are stabilized by heteroannular hydrogen bonds and homoannular electrostatic interactions due to the consequent increase of the atomic charges. The ß-CD/water interaction energies in the optimized hydrated system are not significantly different from the experimental ones. This almost hydrophobic character is also shown by MM equilibrated solutions: all water molecules are rejected beyond 2.4 Å; between 2.4 and 2.9 Å highly structured water is present. From a purely enthalpic standpoint the molecule hydration appears highly improbable, thus the formation of ß-CD 11 H20 must involve a compensation mechanism.

Abstract On the basis of literature values of various spectroscopic quantities, the "experimental" five derivatives (1st to 5th) of the repulsive functions at the equilibrium distance were evaluated for the 20 alkali halide molecules, retaining the truncated Rittner model for the attractive forces. A self-con-sistency test showed that the used experimental values are reliable. Different analytical forms of the repulsive potential were then critically evaluated by comparison with the experimental derivatives. The repulsive functions were characterized by two, three, four or five empirical parameters. It has been shown that only functions with at least three parameters are sufficiently accurate to reproduce spectroscopic quantities such as ße and γe : the classical two parameter functions appeared too crude in this context.

A DSC characterization of the sulfur-tetracyanoethylene (TCE) system was performed, and the thermal traces obtained quantitatively analyzed. It was shown that (a) some type of solid state interaction takes place between sulfur and TCE, which forces part of the sulfur to be "frozen" into its rhombic form; (b) variable amounts of sulfur and TCE fail to melt at their expected melting temperatures; and (c) a much higher than expected enthalpy change is associated with sulfur polymerization. A phenomenological model is proposed according to which the sulfur and TCE that fail to melt at their melting temperatures undergo fusion in the wake of the liquid-phase sulfur polymerization process. It is shown that the model proposed is valid in the entire composition range studied.

Abstract The Rietveld profile refinement has been applied to X-ray powder diffraction data on Naß''-gallate, a solid electrolyte isostructural with Naß''-alumina and characterized by different types of lattice defect. Several structural models have been refined and discussed in order to understand if a statistical comparison of the structure discrepancy factors can be used as a reliable criterion to retain or reject structural changes from one model to the other. It is shown that, due to the correlation between structural parameters and to the poor sensitivity of the structure discrepancy factors to chemical composition, some care is necessary to direct correctly the refinement and to obtain a reliable structural model

The Rietveld profile refinement has been applied to X-ray powder diffraction data on Na-beta"-gallate, a solid electrolyte isostructural with Na-beta"-alumina and characterized by different types of lattice defect. Several structural models have been refined and discussed in order to understand if a statistical comparison of the structure discrepancy factors can be used as a reliable criterion to retain or reject structural changes from one model to the other. It is shown that, due to the correlation between structural parameters and to the poor sensitivity of the structure discrepancy factors to chemical composition, some care is necessary to direct correctly the refinement and to obtain a reliable structural model.

Abstract Monte Carlo simulations of muscarine water solution were carried out using ab-initio SCFLCAO- MO interaction potentials. The overall results indicate that in water solution the preferred conformation, on the basis of enthalpic considerations, should be the one having the dihedral angle H02-02-C4-H4, τ, equal to 180°. The molecule shows a first hydration shell with about 35 water molecules: of these only about 25 are constantly present, 18 are at a distance equal to lower than 2.5 A and only 5 have an interaction energy larger than -21 kJ/mole. The results do not support the hypothesis that the role of Ol in muscarinic activity is that of increasing hydrophylic bonds

MC simulations, in the NpT version, were carried out on molten Agl, on the basis of the literature interionic potentials proposed for the simulation of the superionic α-phase of solid Agl. A systematic analysis showed that none of the examined potentials can satisfactorily reproduce the experimental characteristics of the melt. Moreover, it has been pointed out that tests of pair potentials through simulations at constant volume can be misleading.

The interaction between cross-linked polyvinylpyrrolidone (PVP-XL) and trimethoprim (TMP) has been studied by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Photoacoustic Spectroscopy (FTIR/PAS). DSC measurements show that very different thermal traces are obtained on ground and not-ground mixtures suggesting that some type of interaction takes place in the first ones. SEM analysis however shows that TMP particles of much smaller dimension than expected can be easily found inside polymer cavities in not-ground mixtures, indicating that an interaction takes place in these mixtures too, leading to drug particles fragmentation and ingestion by polymer cavities. FTIR/PAS measurements give very similar spectra for both types of mixtures thus showing that basically the same interaction phenomena take place independent on whether mixtures were or were not co-ground. Spectra analysis leads to the conclusion that hydrogen bonds are responsible for component interaction and that polymer-adsorbed water plays an important role in the process. Taking into account the polymer water content, an interaction model is proposed by which a mixture composition of maximum interaction can be calculated which is in good agreement with that obtained, on a purely phenomenological basis, by DSC measurements. The surprisingly different thermal behaviours of ground and not-ground mixtures, and particularly the fact that TMP apparently fails to melt in the first ones, are explained on the basis of the very small cluster sizes obtained, in the ground mixtures, as a consequence of the combined effects of component interaction and co-grinding.

In order to account for the dependence of the calibration constant of a heat flux DSC cell on experimental variables and standard related properties, a study has been undertaken of the entire DSC trace. Part of this study has already been published.

Abstract Monte Carlo simulations on molten AgCl were carried out in order to test the applicability of the interionic potentials recently proposed for this salt in the solid phase. None of the literature potentials can be used as such: in all cases pairs of like ions reach too short distances of approach causing the collapse of the system. It was proved that, in order to obtain equilibration of the system, the pair potentials of like ions must be recalculated. On the basis of these modified potentials, MC simulations of molten AgCl were carried out at 728 (m.p.), 1000 and 1500 K. The polarization energy effect was also analyzed with the use of a soft ion model.

Abstract This paper describes a method for a simple evaluation of the polarization energy in molten salt systems, by which it is possible to go, without heavy computational cost, from the rigid to the soft ion model. The method is based on the observation that, within the movements of single ions in the Monte Carlo chain, the deviation of the polarization energy is a linear function of the deviation of the Coulomb energy. An extended numerical application has been carried out for molten Lil at 800, 1200 and 1453 (b. p.) K. The parameters that are mostly affected by the used model are put into evidence.