Search

The second harmonic generation (SHG) is a nonlinear optical process occurring only in noncentrosymmetric space groups. The measurement of the SHG signal generated by powdered samples [1] is an extremely sensitive tool for the detection of noncentrosymmetric phases at the ppm level [2] and was already used successfully to detect the noncentrosymmetry of crystal arrangements such as conglomerates [3]. Recently, we developed a set-up for temperature resolved SHG (TRSHG) in order to monitor solid-solid transitions. In this communication, new possibilities of this technique for the characterization of organic compounds in the solid state are presented. In particular, the desolvation of lactose and the solid-solid phase transition of organic compounds (involving metastable equilibrium) are discussed.

Second harmonic generation (SHG) is a nonlinear optical effect occurring in crystals with non-centrosymmetric space groups [1]. The second harmonic generation efficiency of a given material depends mainly on (i) the intrinsic crystallographic features of the phase, (ii) the orientation of the crystal(s) (crystallographic axes) with reference to the fundamental beam orientation and polarization, (iii) the crystal size distribution. SHG was formerly proposed as a rapid, reliable and very sensitive test of non-centrosymmetry for powdered crystalline compounds [2] with applications to structure assignments and pre-screening of conglomerates [3]. It was also proposed as an efficient technique for the quantification of a crystalline phase inside an amorphous matrix [4] and, recently, we demonstrated that SHG can be used to assess the structural purity of an organic compound down to the ppm level [5]. Herein we investigate the SHG efficiency of several binary organic powder mixtures (recrystallized from a solvent) exhibiting eutectic phase behavior.

BN83495 is an API in development, used in the treatment of hormone dependent cancers. This molecule exhibits an interesting polymorphic landscape consisting of three polymorphic forms (I, II, and III), three 〈1:1〉 DMSO solvate polymorphs, and one 1,4-dioxane hemi-solvate. Among the three DMSO solvates, one can only be obtained in the presence of an inorganic impurity: the letovicite. Between the two polymorphic forms I and III, an enantiotropic transition has been highlighted. This solid–solid transition (Form I → Form III) seems to be controlled by the mosaicity of the particles, where both polymorphic form domains cohabit and this could remain unchanged for months. The reverse transition has not been detected in the solid state; slurrying in a solvent appears necessary to return to Form I. Each of the three polymorphs can be obtained by soaking in cold water the appropriate solvated compound. The crystal structure of each phase was determined from single crystal X-ray diffraction, except for Form II (the monotropic form under normal pressure). The analyses of the starting and final crystal structures involved in a desolvation process led to the proposal of mechanisms with and without transmission of structural information from the mother phase (i.e. the initial solvate) to the daughter phase. The presence of direct hydrogen bonds between BN83495 molecules in DMSO-I and 1,4-dioxane hemi-solvate seems to ensure the structural filiations during the desolvation mechanisms leading respectively to Form III and Form II.

Two-wave mixing in photorefractive InP:Fe crystals is revisited in terms of an externally applied dc field combined with the moving-grating technique. We show that the disagreement between theory and experiment that was previously observed in the literature can be reconciled by an examination of the influence of both the absorption along the propagation axis and the nonlinearities that occur at relatively large fringe modulations. A finite-difference method is used to demonstrate the dependence of these nonlinearities on the average incident intensity.

A comparative study of the temperature dependence of the two-wave mixing gain is performed at three wavelengths (i.e., 1.06, 1.32, and 1.54 µm) for the fringe spacing values Λ=1.6 µm and 5 µm. With the latter the gain sign changes at low temperature for λ=1.06 and λ=1.54 µm, but not for λ=1.32 µm. The gain measurements are performed both with and without an external electric field. The theoretical model must fit all the experiments. In our case the energy level of the second defect is found to be near the valence band. We demonstrate that the agreement between the theory and the experiments performed at room temperature is improved by incorporating the indirect transitions (involving the excited state of iron) into the two-defect model. The result of this approach is presented as the extended two-defect model.

Amorphous dispersions of the Biclotymol antiseptic are obtained in polyvinylpyrrolidone (PVP), for different drug loadings, by comilling at temperatures below the glass transition of both components. Characterization of the dispersions by scanning differential calorimetry and temperature-dependent broadband dielectric spectroscopy shows them to be homogeneous amorphous molecular mixtures. A single glass transition with pronounced enthalpy recovery peak is observed, indicative of the formation of a homogeneous glass state characterized by substantial aging. The polymer has a considerable antiplasticizing effect on the drug, increasing its glass transition temperature (Tg) to well above room temperature. The Tg of the mixture increases linearly with the macromolecular mass fraction. Three (macro)molecular relaxations are identified in the isothermal dielectric spectra of the mixtures. The slowest process corresponds to the cooperative (a relaxation) dynamics of the polymer chains and drug molecules simultaneously, and its relaxation time becomes longer the higher the polymer content. The fastest one is an intramolecular relaxation mode of Biclotymol and is virtually unaffected by the presence of the polymer. Finally, the intermediate relaxation, which is also observed in pure PVP, is assigned to the motion of the polymer side groups. Its activation barrier increases with increasing drug content, indicative of a direct interaction of the drug with the pyrrolidone moieties, likely via hydrogen bonding to the carbonyl oxygen. Contrary to pure PVP, the mixtures are not hygroscopic. Mechanical amorphization by cryomilling thus yields glassy molecular mixtures at arbitrary drug concentration, with enhanced physical stability against crystallization and enhanced chemical stability against hydrolysis reactions.

The objective of this research project is to develop a method that enables the identification of conglomerates rather than racemic compounds or solid solutions for their chiral resolution by crystallization. Then, evaluate the trends of conglomerate formation. The first part of the manuscript is specifically dedicated to the design and implementation of the in situ SHG set-up. The new SHG device allows to screen conglomerates in suspensions at various temperatures and in various solvents and to follow phase transition. The reliability of the experimental in situ SHG set-up was tested by using inorganic material (Quartz and KDP) which are efficient for SHG effects. The applicability of the method to chiral organic compounds was demonstrated by the study of the solid-solid transition between the conglomerate and the racemic compound phases of histidine monohydrochloride hydrate and imeglimin propionate. The second part concerns the characterization of the chiral compound chlocyphos, the search and identification of its conglomerate derivatives and their chiral separation by using preferential crystallization. Crystal structures of the chlocyphos salts are determined by SC-XRD and the strong tendency of alkyl-amine salts to crystallize as conglomerates with similar crystal packing is highlighted. Through careful analysis of their crystal and molecular structures, a trend with respect to alkyl amine moiety length starting from ethyl to cyclohexyl can be established. The elaboration of the binary phase diagram of conglomerate with partial solid solutions in ethylammonium chlocyphos is also investigated.; L’objectif premier de cette thèse était de développer une méthode expérimentale qui permet d’identifier les conglomérats des composés racémiques ou des solutions solides pour leur séparation par voie de cristallisation. Ainsi évaluer des tendances de formation des conglomérats. La première partie est spécifiquement consacré à la conception et à l’installation de la génération de seconde harmonique (in situ SHG). Le nouveau dispositif de la SHG permettra de repérer des conglomérats en solution en variant les températures de cristallisation et de suivre les transformations entre phases auxquelles au moins une phase se cristallise dans un groupe d’espace non-centrosymétrique. La fiabilité de cette méthode expérimentale de SHG est testée en utilisant les composés inorganiques (Quartz et KDP) qui sont efficients pour l’effet de la SHG. La transversalité de la méthode pour les composés organiques chiraux a été démontrée par l’étude de la transition de phase entre le conglomérat et le composé racémique du monochlorhydrate hydraté d’histidine d’une part et du propionate de l’imeglimine d’autre part. La deuxième partie traite la caractérisation du composé chiral chlocyphos, de la recherche et de l’identification de conglomérats dérivés du chlocyphos et leur séparation chirale par voie de la cristallisation préférentielle. Les structures cristallines des sels du chlocyphos ont été résolues par la diffraction des rayons X sur monocristal (SC-XRD) et la tendance qui s’est dégagée est la formation de conglomérats avec les alkyle-amines à partir de l’éthyle jusqu’au cyclohexyle avec une similarité des structures cristallines. L’élaboration du diagramme de phase binaire du conglomérat avec une solution solide partielle du chlocyphos de l’éthylamine a été abordée.

The objective of this research project is to develop a method that enables the identification of conglomerates rather than racemic compounds or solid solutions for their chiral resolution by crystallization. Then, evaluate the trends of conglomerate formation. The first part of the manuscript is specifically dedicated to the design and implementation of the in situ SHG set-up. The new SHG device allows to screen conglomerates in suspensions at various temperatures and in various solvents and to follow phase transition. The reliability of the experimental in situ SHG set-up was tested by using inorganic material (Quartz and KDP) which are efficient for SHG effects. The applicability of the method to chiral organic compounds was demonstrated by the study of the solid-solid transition between the conglomerate and the racemic compound phases of histidine monohydrochloride hydrate and imeglimin propionate. The second part concerns the characterization of the chiral compound chlocyphos, the search and identification of its conglomerate derivatives and their chiral separation by using preferential crystallization. Crystal structures of the chlocyphos salts are determined by SC-XRD and the strong tendency of alkyl-amine salts to crystallize as conglomerates with similar crystal packing is highlighted. Through careful analysis of their crystal and molecular structures, a trend with respect to alkyl amine moiety length starting from ethyl to cyclohexyl can be established. The elaboration of the binary phase diagram of conglomerate with partial solid solutions in ethylammonium chlocyphos is also investigated.; L’objectif premier de cette thèse était de développer une méthode expérimentale qui permet d’identifier les conglomérats des composés racémiques ou des solutions solides pour leur séparation par voie de cristallisation. Ainsi évaluer des tendances de formation des conglomérats. La première partie est spécifiquement consacré à la conception et à l’installation de la génération de seconde harmonique (in situ SHG). Le nouveau dispositif de la SHG permettra de repérer des conglomérats en solution en variant les températures de cristallisation et de suivre les transformations entre phases auxquelles au moins une phase se cristallise dans un groupe d’espace non-centrosymétrique. La fiabilité de cette méthode expérimentale de SHG est testée en utilisant les composés inorganiques (Quartz et KDP) qui sont efficients pour l’effet de la SHG. La transversalité de la méthode pour les composés organiques chiraux a été démontrée par l’étude de la transition de phase entre le conglomérat et le composé racémique du monochlorhydrate hydraté d’histidine d’une part et du propionate de l’imeglimine d’autre part. La deuxième partie traite la caractérisation du composé chiral chlocyphos, de la recherche et de l’identification de conglomérats dérivés du chlocyphos et leur séparation chirale par voie de la cristallisation préférentielle. Les structures cristallines des sels du chlocyphos ont été résolues par la diffraction des rayons X sur monocristal (SC-XRD) et la tendance qui s’est dégagée est la formation de conglomérats avec les alkyle-amines à partir de l’éthyle jusqu’au cyclohexyle avec une similarité des structures cristallines. L’élaboration du diagramme de phase binaire du conglomérat avec une solution solide partielle du chlocyphos de l’éthylamine a été abordée.

Amorphous pharmaceuticals (excipients and active ingredients) are considered as one of the most promising approach to overcome the poor water solubility issue related to many drug molecules. Preparing poorly soluble drugs in the amorphous state is thus becoming an essential strategy for incorporating drugs into highly effective dosage forms. Recent developments have highlighted the need of a better understanding of the impact of preparation pathway onto the resulting amorphous solids. The aim of this thesis is to contribute to a rational knowledge of the differences in the amorphous state generated by two distinct preparation pathways: quenching from the melt and high-energy milling. Physico-chemical properties of the amorphous materials were studied using a set of analytical methods (structural, thermal and spectroscopic) coupled to quantum DFT calculations. It was demonstrated for two compounds of pharmaceutical interest that depending on the preparation methods, properties such as physical stability and crystallization kinetics might differ, leading to distinct behaviors upon storage. Melt-quenched states have been found to possess a good stability over time, while milled ones exhibit a lower stability resulting in an easier tendency toward crystallization. Moreover, beyond the glass transition temperature, it was outstanding to note that all discrepancies in physico-chemical properties are suppressed. Our findings indicate also that the propensity of both inspected molecular compounds to be amorphized rises as milling temperature decreases. This thesis also provides new insights to elaborate adequate stabilization protocols for amorphous pharmaceuticals., Considérer les composés pharmaceutiques sous forme amorphe est l’une des approches les plus prometteuses pour maîtriser la très faible solubilité de nombreuses molécules médicamenteuses. La récente évolution des formes amorphes dans l’industrie nécessite une meilleure compréhension de l’impact des méthodes de préparation sur les états amorphes générés. L'objectif de cette thèse est de contribuer à une compréhension rationnelle des différences de l’état amorphe produit par deux voies distinctes : fusion-trempe et broyage haute-énergie. Les propriétés physico-chimiques des matériaux amorphes ont été étudiées au moyen de méthodes analytiques couplées à des calculs quantiques. Il a été démontré pour deux molécules pharmaceutiques qu’en fonction des méthodes de préparation, les propriétés telles que la stabilité physique et les cinétiques de cristallisation pouvaient différer, donnant lieu à des comportements bien distincts lors de leur stockage. Pour ces deux composés, les états obtenus par fusion-trempe possèdent une meilleure stabilité que leur équivalent broyé. De plus, au-delà de la température de transition vitreuse, plus aucune différence physico-chimique n’a été constatée. Il a également été noté pour ces deux composés que l’état amorphe pouvait être atteint plus facilement lorsque la température de broyage diminuait. Cette thèse apporte de nouvelles perspectives pour élaborer une stratégie adéquate de stabilisation des composés amorphes pharmaceutiques.

The objective of this thesis is the development of a method based on the optical second harmonic generation (SHG) phenomenon to analyze crystalline organic compounds. In particular, a platform allowing to perform measurements of second harmonic generation resolved in temperature (TR-SHG) on samples in powdered form has been developed. This thesis tackles a number of concepts, from the crystallization of organic compounds to their nonlinear optical properties and the various existing heterogeneous equilibria between the different states of matter and crystalline phases. The development and the relevance of the SHG techniques are widely investigated through the monitoring of a monotropic or order-disorder transitions. In addition, first insights of the uses of SHG method to solve issues such as the monitoring of crystallization of amorphous material or dehydration under controlled humidity and also the possibility to elaborate binary phase diagrams were also studied., Cette thèse porte sur le développement de méthodes optiques basées sur le phénomène de génération de deuxième harmonique (SHG) afin analyser les composés organiques cristallins. En particulier, une plate-forme permettant d'effectuer des mesures de la génération de deuxième harmonique résolue en température (TR-SHG) sur des échantillons sous forme de poudre a été développée. Cette thèse aborde un certain nombre de concepts, de la cristallisation des composés organiques à leurs propriétés optiques non linéaires et des équilibres hétérogènes existant entre les différents états de la matière et les phases cristallines. Le développement et la pertinence des techniques SHG sont largement étudiés par le suivi de transitions monotropiques ou désordonnées. De plus, les fondations de l'utilisation de la méthode SHG pour résoudre des problèmes tels que le suivi cristallisation de la matière amorphe ou la déshydratation sous l'humidité contrôlée, ainsi que la possibilité d'élaborer des diagrammes de phase binaires sont élaborés.