Physicochemical study of the solid forms of a new drug.

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.

Physico-chemical characterization of a novel tricyclic beta-lactam antibiotic.

GV118819X, a novel tricyclic beta-lactam antibiotic of GlaxoWellcome, is a racemic mixture of two diastereoisomers, A and B. Of the two diastereoisomers, only A is available as a pure compound. By analyzing mixtures of GV118819X and A, a partial phase diagram is constructed, which indicates the presence of a eutectic when the A fraction is approximately 39%. Moreover, the melting enthalpies of the eutectic mixture and of diastereoisomer B can be estimated. With the exception of the pure A form, all mixtures undergo important modifications in morphology and microstructure as a consequence of thermal treatments, which induce melting/amorphization of the eutectic, and crystallization of the A form. Analyses of the sieved fractions of GV118819X demonstrate that it consists of acicular crystals of different composition, with the larger crystals having a larger A fraction than the smaller ones. Grinding causes melting/amorphization of the eutectic and, following hours-long treatments, the formation of a substantial fraction of submicron particles with unusually low melting temperatures.

Solid-state characterization of a novel chemotherapeutic drug.

We present the results of a thermal, spectroscopic, diffractometric, and microscopic study of a novel DNA intercalator synthesized by Novuspharma S.p.A. (code name BRR 2778, purity by high-performance liquid chromatography: 99.4%). We found that the form that is stable at room temperature contains 1.5 water molecules per unit of formula (or about 4.7% in mass): this water is reversibly lost in two stages below 80 degrees and 90 degrees C in dry and wet nitrogen atmosphere, respectively. The hydrated compound is a pseudo-polymorph and dehydration is accompanied by a structural change that modifies the diffraction pattern without changing the shape of the microcrystals. Annealing above 150 degrees C causes decomposition of the anhydrous form and (above 190 degrees C) amorphization of the solid residue occurs.

Hydration, stability, and phase transformations of a new antitumor drug.

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 degrees C (or up to 140 degrees C for several minutes) 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.

Thermoanalytical and spectroscopic characterisation of solid-state retinoic acid.

Thermoanalytical (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TG/FTIR)) and spectroscopic (X-ray diffraction (XRD), ultraviolet-visible (UV-Vis), mass spectrometry (MS) and Fourier transform infrared diffuse reflectance (DRIFT) measurements have been used to characterise solid-state retinoic acid (RA) from a chemico-physical point of view. Between 130 and 160 degrees C, a phase transition takes place that does not correspond to the transition between the known monoclinic and triclinic phases (DSC and XRD evidence). By annealing in air (in the 130-160 degrees C temperature range and for different times), an exothermic oxidative degradation occurs that, depending on the thermal treatment, competes with the mentioned phase transition (TGA evidence). Spectroscopic techniques (UV-Vis, MS and DRIFT) allow one to conclude that the new solid phase is still constituted by retinoic acid with a different orientation of the side chain. Finally, RA does not undergo stable melting: the fragmentation patterns, both in air and in nitrogen, have been examined by TG/FTIR.

Nature of conductivity in SrSiO3-based fast ion conductors.

In this paper we report the preparation and characterization of Sr1-xNaxSiO3-0.5x samples, recently proposed as oxide ion conductors. We show that Na-doping unlikely takes place in the silicate phase, and that a secondary glassy phase is at the origin of the transport properties, thereby suggesting that the conductivity is due only to a limited extent to oxide ion migration in the crystalline system.

Determination of the nateglinide polymorphic purity through DSC.

It is well known that the control of the crystallization of drugs to ensure that only the approved and desired polymorph is present in the formulation is a crucial point of a preformulation study. In this regard, the aim of the present work is to devise a method for the quantification of the polymorphic purity of nateglinide in mixtures formed by polymorphs H and B. In order to achieve this goal, binary systems of known composition have been prepared and the melting peaks of both polymorphs have been recorded by differential scanning calorimetry. Experiments have determined that the method of preparation of the mixtures has to be carefully evaluated. Indeed it has been shown that grinding the samples induces transition from B to H form. Furthermore, it could be observed that the enrichment of the binary mixture with H form is caused by heating. Therefore, after having prepared the mixture without grinding stage, we propose a method to evaluate the content of H polymorph in mixture with the B one from the melting peak of B.

New solid modifications of nateglinide.

New modifications of the antidiabetic drug nateglinide were found and characterized by means of thermal analysis, vibrational spectroscopy and X-ray powder diffractometry. In particular it has been verified that the product obtained during the final steps of the nateglinide synthesis is the hemihydrate form which melts at about 86 degrees C provided that the adopted experimental conditions hinder the removal of the crystallization water. Otherwise, if the crystallization water is removed, the hemihydrate transforms to a new anhydrous polymorph that melts at 102.8 degrees C. The anhydrous polymorph, if stored at room temperature and humidity, gradually changes to H polymorph while, if stored in water vapour saturated atmosphere, it gets back water and reverts to the hemihydrate form. On the contrary, both an isothermal treatment at 80 degrees C and melt cooling bring to the B polymorph.

Thermodynamic relationships between nateglinide polymorphs.

The physico-chemical characterization of the polymorphs of nateglinide (named B, H and S), an antidiabetic agent, has been performed by means of thermal, diffractometric, spectroscopic and electron microscopic measurements. It has been established that S polymorph can crystallize from the melt obtained from both B and H samples or also following an isothermal treatment of both forms at temperatures lower than the relevant melting points. By X-ray diffraction it could be shown that the three polymorphs have different crystal structure. On the other hand the indication has been drawn from IR spectra that the molecular structure of B is sensibly different from those of H and S forms that have a very similar molecular structure. Finally, the microstructure features of the three polymorphs have been examined by scanning electron microscopy. Our analyses have allowed to evaluate the relative stability of the three polymorphs through the construction of the energy vs. temperature diagram. In particular, S polymorph, the highest-melting form, has resulted to be the only stable form, while the B and H forms are metastable.