Thermal expansion of L-ascorbic acid

The specific volume of vitamin C has been investigated by X-ray powder diffraction as a function of temperature from 110¿K up to complete degradation around 440¿K. Its thermal expansion is relatively small in comparison with other organic compounds with an expansivity av of 1.2(3) × 10-4¿K-1. The structure consists of strongly bound molecules in the ac plane through a dense network of hydrogen bonds. The thermal expansion is anisotropic. Along the b axis, the expansion has most leeway and is about 10 times larger than in the other directions.Postprint (author's final draft

An integrated view of theiInfluence of temperature, pressure, and humidity on the stability of trimorphic cysteamine hydrochloride

Understanding the phase behavior of pharmaceuticals is important for dosage form development and regulatory requirements, in particular after the incident with ritonavir. In the present paper, a comprehensive study of the solid-state phase behavior of cysteamine hydrochloride used in the treatment of nephropathic cystinosis and recently granted orphan designation by the European Commission is presented employing (high-pressure) calorimetry, water vapor sorption, and X-ray diffraction as a function of temperature. A new crystal form (I2/a, form III) has been discovered, and its structure has been solved by X-ray powder diffraction, while two other crystalline forms are already known. The relative thermodynamic stabilities of the commercial form I and of the newly discovered form III have been established; they possess an overall enantiotropic phase relationship, with form I stable at room temperature and form III stable above 37 degrees C. Its melting temperature was found at 67.3 +/- 0.5 degrees C. Cysteamine hydrochloride is hygroscopic and immediately forms a concentrated saturated solution in water with a surprisingly high concentration of 47.5 mol % above a relative humidity of 35%. No hydrate has been observed. A temperature composition phase diagram is presented that has been obtained with the unary pressure temperature phase diagram, measurements, and calculations. For development, form I would be the best form to use in any solid dosage form, which should be thoroughly protected against humidity.Postprint (author's final draft

Polymorphism and solvation of indomethacin

Indomethacin crystallizes from solutions in tetrahydrofuran as a solvate exhibiting the mole ratio 1 indomethacin:2 tetrahydrofuran. Upon heating, desolvation into indomethacin phase I occurs through partial amorphization and transitory formation of a phase, which is different from the crystallographically known polymorphs. The X-ray powder diffraction pattern of the solvate was tentatively indexed on a triclinic lattice (a = 31.454(5) , b = 17.883(3) , c = 10.551(2) , alpha = 70.55(2)A degrees, beta A = 105.31(2)A degrees, gamma A = 136.70(1)A degrees). Assuming Z = 6 (1 indomethacin + 2 tetrahydrofuran) formula units per unit cell, the solvate's specific volume is similar to the value calculated using additivity

The relation between twinning and disorder in the gamma form of pyrazinamide

International audiencePyrazinamide (PZA), an active pharmaceutical ingredient (API) is a first-line drug for the treatment of tuberculosis. Its molecular structure is shown in the figure below. Pyrazinamide possesses at least four known polymorphs, named alpha (P21/n), beta (P21/c), gamma (Pc) and delta (P1 ̅). Among these polymorphs, the gamma form exhibits a distinctively different packing from the other three polymorphs as one intermolecular hydrogen bond (N-H...N) links the amide group with the pyrazine ring forming linear chains of single H-bonded molecules. Moreover, crystals of the gamma form are very often twinned.Single crystals of gamma can be obtained by sublimation. In the literature, disorder has been reported in crystals of the gamma form [1,2], which takes the form of two molecular orientations in which the pyrazine ring and the amide moiety of the disordered molecules have been exchanged. Although the crystal structure of the gamma form explicitly including disorder had been found to be energetically quite close to the ideally ordered crystal structure [2], it has not been clear until now whether the disorder is static or dynamic and how twinning may be related to the disorder.Disorder and twinning of the gamma form of PZA have been investigated experimentally. Single crystal X-ray diffraction as a function of temperature has led to results that demonstrate that the disorder site occupancy is independent of the temperature, thus suggesting that the disorder is static. For twinned crystals, the morphology of each domain of the twinned crystals are different from that of single crystals. The twin interface is found to be (100). This is shown in the figure on the right in which the 100 faces are facing each other, while the orientation of the molecules at the twin boundary are shown below. The orientation of ‘disordered’ molecules and the orientation of the molecules on the twin boundary are the same, implying that both phenomena are closely related

The relation between twinning and disorder in the gamma form of pyrazinamide

International audiencePyrazinamide (PZA), an active pharmaceutical ingredient (API) is a first-line drug for the treatment of tuberculosis. Its molecular structure is shown in the figure below. Pyrazinamide possesses at least four known polymorphs, named alpha (P21/n), beta (P21/c), gamma (Pc) and delta (P1 ̅). Among these polymorphs, the gamma form exhibits a distinctively different packing from the other three polymorphs as one intermolecular hydrogen bond (N-H...N) links the amide group with the pyrazine ring forming linear chains of single H-bonded molecules. Moreover, crystals of the gamma form are very often twinned.Single crystals of gamma can be obtained by sublimation. In the literature, disorder has been reported in crystals of the gamma form [1,2], which takes the form of two molecular orientations in which the pyrazine ring and the amide moiety of the disordered molecules have been exchanged. Although the crystal structure of the gamma form explicitly including disorder had been found to be energetically quite close to the ideally ordered crystal structure [2], it has not been clear until now whether the disorder is static or dynamic and how twinning may be related to the disorder.Disorder and twinning of the gamma form of PZA have been investigated experimentally. Single crystal X-ray diffraction as a function of temperature has led to results that demonstrate that the disorder site occupancy is independent of the temperature, thus suggesting that the disorder is static. For twinned crystals, the morphology of each domain of the twinned crystals are different from that of single crystals. The twin interface is found to be (100). This is shown in the figure on the right in which the 100 faces are facing each other, while the orientation of the molecules at the twin boundary are shown below. The orientation of ‘disordered’ molecules and the orientation of the molecules on the twin boundary are the same, implying that both phenomena are closely related

Vers un élargissement sélectif de l'Union européenne. Dix pays - deux cercles

Of the ten applicants for European Union membership from central/eastern Europe, only five have been accepted: the Czech Republic, Estonia, Hungary, Poland, and Slovenia. We use data analysis methods on quantitative criteria reflecting the qualitative decisions to "objectivate" the Commission's choices. Beginning with a multivariate analysis, we conclude that the choice was appropriate in objective terms. Our second series of analyses, however, shows that the main decision-making criterion was not the countries present capacity to achieve viable integration into the EU, but rather their potential ability to do so. This ex ante criterion can become self-fulfilling for both the accepted and the rejected countries: the accepted countries may find it easier to obtain financing, while the rejected countries - Bulgaria, Latvia, Lithuania, Romania, and Slovakia - may face a re­striction in their access to finance and a widening gap with the accepted countries.Parmi les dix pays de l'Est candidats à l'adhésion à l'Union européenne, seuls cinq ont été retenus : Hongrie, Pologne, République tchèque, Slovénie et Estonie. L'analyse des données, à partir de critères quantitatifs approchant les décisions qualitatives exprimées, permet d'« objectiver » le choix de la Commission. Une première série d'ACM (analyse factorielle des composantes multiples) conclut à la pertinence objective du choix de la Commission. Une seconde série d'analyses montre, en revanche, que la sélection s'est opérée essentiellement non sur la capacité actuelle d'intégration viable des différentes économies mais sur leur potentiel. Cet a priori peut devenir auto-réalisateur pour les pays retenus (dynamique de financement favorable), comme pour les pays exclus - Bulgarie, Roumanie, Slovaquie, Lettonie et Lituanie (limitation des sources de financement et accroissement de l'écart avec les premiers).Ricoeur-Nicolaï Nathalie, Lakhoua Fadhel, Auzouy Béatrice, Meunier Nicolas, Miotti Luis. Vers un élargissement sélectif de l'Union européenne. Dix pays - deux cercles. In: Revue économique, volume 50, n°6, 1999. pp. 1101-1122

Relation between Twinning and Disorder in the γ Form of Pyrazinamide

International audienc

Vers un élargissement sélectif de l'Union européenne. Dix pays - deux cercles

[fre] Parmi les dix pays de l'Est candidats à l'adhésion à l'Union européenne, seuls cinq ont été retenus : Hongrie, Pologne, République tchèque, Slovénie et Estonie. L'analyse des données, à partir de critères quantitatifs approchant les décisions qualitatives exprimées, permet d'« objectiver » le choix de la Commission. Une première série d'ACM (analyse factorielle des composantes multiples) conclut à la pertinence objective du choix de la Commission. Une seconde série d'analyses montre, en revanche, que la sélection s'est opérée essentiellement non sur la capacité actuelle d'intégration viable des différentes économies mais sur leur potentiel. Cet a priori peut devenir auto-réalisateur pour les pays retenus (dynamique de financement favorable), comme pour les pays exclus - Bulgarie, Roumanie, Slovaquie, Lettonie et Lituanie (limitation des sources de financement et accroissement de l'écart avec les premiers). [eng] Of the ten applicants for European Union membership from central/eastern Europe, only five have been accepted: the Czech Republic, Estonia, Hungary, Poland, and Slovenia. We use data analysis methods on quantitative criteria reflecting the qualitative decisions to "objectivate" the Commission's choices. Beginning with a multivariate analysis, we conclude that the choice was appropriate in objective terms. Our second series of analyses, however, shows that the main decision-making criterion was not the countries present capacity to achieve viable integration into the EU, but rather their potential ability to do so. This ex ante criterion can become self-fulfilling for both the accepted and the rejected countries: the accepted countries may find it easier to obtain financing, while the rejected countries - Bulgaria, Latvia, Lithuania, Romania, and Slovakia - may face a re­striction in their access to finance and a widening gap with the accepted countries.

Poly((3,5-dimethylpyrazol-1-yl)methyl)benzene ligands: synthesis, crystal structure and catecholase activities

International audienc