New methods to determine polymer / drug solubility diagrams

La dispersion moléculaire d’un principe actif (PA) dans un polymère est généralement utilisée pour accroitre à la fois la solubilité et la stabilité physique de sa forme amorphe. Cependant, ce type de formulation demande une parfaite connaissance de la solubilité du PA dans le polymère. Cependant, les méthodes actuelles pour déterminer les courbes de solubilité sont longues et fastidieuses à mettre en oeuvre. Dans cette thèse, nous présentons une méthode originale pour déterminer efficacement la solubilité des PA dans les polymères. L’originalité de cette méthode réside dans le fait que les états d’équilibre saturés sont ici atteints par démixtion d’une solution solide amorphe sursaturée en PA et non par la méthode classique de dissolution du PA cristallin au sein du polymère amorphe. Les états d’équilibre saturés sont donc beaucoup plus rapides à atteindre en raison de la mobilité moléculaire accrue résultant de la forte plastification du polymère imposée par les conditions de sursaturation. Nous avons aussi testé la possibilité de prédire les courbes de solubilité par des méthodes numériques ab-initio (par dynamique moléculaire et méthodes quantiques). Les méthodes expérimentales et numériques ont été validées en étudiant des systèmes polymère/PA dont les courbes de solubilité ont déjà été déterminées par des méthodes classiques. Les systèmes étudiés sont : PVPK12/indométacine, PVPK30/griséofulvine et β-cyclodextrine méthylée/griséofulvine. Les techniques d’investigations utilisées sont esentiellement l’analyse enthalpique différentielle à balayage (DSC) et la diffraction des rayons X sur poudre (DRX).The molecular dispersion of a drug into a polymer is generally used to increase both its solubility and the physical stability of its amorphous form. However, this formulation route requires a perfect knowledge of the solubility of the drug in the polymer. This property is in particular important for selecting appropriate polymers for formulations since it defines the maximal drug loading which prevents recrystallization. However, up to now, the determination of the solubility curve of drug/polymer systems is a long and tedious task. In this thesis we present an original method to determine faster the solubility of drugs into polymers. The originality of the method lies in the fact that the equilibrium saturated state is here reached by demixing of a supersaturated amorphous solid solution and not by the usual dissolution of a crystalline drug into an amorphous polymer. 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. We also test the ability of ab-initio numerical techniques (using molecular dynamics and quantum methods) to predict solubility curves. Both experimental and numerical techniques are validated using drug/polymer systems whose solubility curves have already been determined by conventional methods. The investigated systems are: PVPK12/indomethacin, PVPK30/griseofulvin and methylated β-cyclodextrine/griseofulvin. The investigation techniques are mainly Differential Scanning Calorimetry (DSC) and Powder X-Ray Diffraction (PXRD)

Nouvelles méthodes de détermination des diagrammes de solubilité polymère / principe actif

La dispersion moléculaire d un principe actif (PA) dans un polymère est généralement utilisée pour accroitre à la fois la solubilité et la stabilité physique de sa forme amorphe. Cependant, ce type de formulation demande une parfaite connaissance de la solubilité du PA dans le polymère. Cependant, les méthodes actuelles pour déterminer les courbes de solubilité sont longues et fastidieuses à mettre en oeuvre. Dans cette thèse, nous présentons une méthode originale pour déterminer efficacement la solubilité des PA dans les polymères. L originalité de cette méthode réside dans le fait que les états d équilibre saturés sont ici atteints par démixtion d une solution solide amorphe sursaturée en PA et non par la méthode classique de dissolution du PA cristallin au sein du polymère amorphe. Les états d équilibre saturés sont donc beaucoup plus rapides à atteindre en raison de la mobilité moléculaire accrue résultant de la forte plastification du polymère imposée par les conditions de sursaturation. Nous avons aussi testé la possibilité de prédire les courbes de solubilité par des méthodes numériques ab-initio (par dynamique moléculaire et méthodes quantiques). Les méthodes expérimentales et numériques ont été validées en étudiant des systèmes polymère/PA dont les courbes de solubilité ont déjà été déterminées par des méthodes classiques. Les systèmes étudiés sont : PVPK12/indométacine, PVPK30/griséofulvine et b-cyclodextrine méthylée/griséofulvine. Les techniques d investigations utilisées sont esentiellement l analyse enthalpique différentielle à balayage (DSC) et la diffraction des rayons X sur poudre (DRX).The molecular dispersion of a drug into a polymer is generally used to increase both its solubility and the physical stability of its amorphous form. However, this formulation route requires a perfect knowledge of the solubility of the drug in the polymer. This property is in particular important for selecting appropriate polymers for formulations since it defines the maximal drug loading which prevents recrystallization. However, up to now, the determination of the solubility curve of drug/polymer systems is a long and tedious task. In this thesis we present an original method to determine faster the solubility of drugs into polymers. The originality of the method lies in the fact that the equilibrium saturated state is here reached by demixing of a supersaturated amorphous solid solution and not by the usual dissolution of a crystalline drug into an amorphous polymer. 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. We also test the ability of ab-initio numerical techniques (using molecular dynamics and quantum methods) to predict solubility curves. Both experimental and numerical techniques are validated using drug/polymer systems whose solubility curves have already been determined by conventional methods. The investigated systems are: PVPK12/indomethacin, PVPK30/griseofulvin and methylated b-cyclodextrine/griseofulvin. The investigation techniques are mainly Differential Scanning Calorimetry (DSC) and Powder X-Ray Diffraction (PXRD).LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Femtosecond filamentation of optical vortices for the generation of optical air waveguides

International audienceWe study the filamentation in air of multi-millijoule optical vortices and compare them with the classical filamentation regime. The femtosecond vortex beam generates multiple plasma filaments organized in a cylindrical geometry. This plasma configuration evolves into a meter-scale tubular neutral gas column that can be used as a waveguide for nanosecond laser pulses at 532 nm. It appears that optical vortices produce a more uniform heating along the propagation axis, when compared with Gaussian or super-Gaussian beams, and that the resulting low-density channel is poorly sensitive to the laser input power thanks to the combination of filamentation intensity clamping and phase vorticity

Control of large electric spark through laser filamentation in air

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Structure determination of phase II of the antifungal drug griseofulvin by powder X-ray diffraction

International audienceTwo new crystalline polymorphs of the widely used anti­fungal drug griseofulvin (phases II and III), which originate from the crystallization of the melt, have been detected recently. The crystal structure of phase II of griseofulvin {systematic name: (2S,6′R)-7-chloro-2′,4,6-trimeth­oxy-6′-methyl-3H,4′H-spiro­[1-benzo­furan-2,1′-cyclo­hex-2-ene]-3,4′-dione}, C17H17ClO6, has been solved by powder X-ray diffraction (PXRD). The PXRD pattern of this new phase was recorded at room temperature using synchrotron radiation. The starting structural model was generated by a Monte Carlo simulated annealing method. The final structure was obtained through Rietveld refinement with soft restraints for inter­atomic bond lengths and angles, except for the aromatic ring, where a rigid-body constraint was applied. The symmetry is ortho­rhom­bic (space group P212121) and the asymmetric unit contains two mol­ecules

Cumulative air density depletion during high repetition rate filamentation of femtosecond laser pulses: Application to electric discharge triggering

International audienceWe study the influence of the laser repetition rate on the generation of low-density channels of air left in the path of femtosecond laser filament. At high repetition rates, we observe the formation of a permanent millimeter-wide low-density channel that exceeds the depth and width of the transient depletion due to a single filament. We also show that this permanent cumulative effect decreases the breakdown voltage between two electrodes and can alter the path of the discharge. By comparing this effect in air and in pure nitrogen, we show that an accumulation of O−2 ions contributes to the reduction in the breakdown voltage

Study of consecutive long-lived meter-scale laser-guided sparks in air

We study the creation and evolution of meter-scale long-lived laser-guided electric discharges and the interaction between consecutive guided discharges. The lifetime of guided discharges from a Tesla high voltage generator is first increased up to several milliseconds by the injection of additional current. The subsequent discharge evolution is measured by recording the electric current and by Schlieren and fluorescence imaging. A thermodynamic model of the gas evolution is developed to explain the discharge evolution. Finally, we analyze the succession of laser-guided discharges generated at 10 Hz

Control of the acoustic waves generated by intense laser filamentation in water

International audienceExperiments and simulations are performed to study filamentation and generation of acoustic waves in water by loosely focused multi-millijoules laser pulses. When the laser pulse duration is increased from femtosecond to nanosecond duration, a transition is observed from a filamentary propagation with extended and low energy density deposition to a localized breakdown, related to high energy density deposition. The transition suggests that Kerr selffocusing plays a major role in the beam propagation dynamics. As a result, the shape, the amplitude and the spectrum of the resulting pressure wave present a strong dependence on the laser pulse duration

45 W average-power, high-energy deep-UV generation at 257 nm in LBO

International audienceWe report on high average-power, high-energy picosecond fourth-harmonic generation in LBO. The first stages of a Yb:YAG laser chain operating at 1 kHz repetition rate generate few-picosecond 220 mJ chirped pulses at 1030 nm fundamental wavelength. They are frequency-converted in a cascade of three LBO crystals to generate the second-, third-, and fourth harmonics at 515 nm, 343 nm and 257 nm respectively. Crystals thicknesses and angular phase matching detuning were calculated as a function of pulse duration through broadband nonlinear optical numerical simulations. Last crystal is both conduction-cooled on edge and surface-cooled at center through forced-air flow to mitigate heating due to nonlinear absorption in the deep-UV and reduce temperature gradients. Chirped-pulse duration was experimentally adjusted to achieve stable 20% overall conversion efficiency. Near-field beam profiles were continuously recorded at 10 Hz, for all four wavelengths involved, together with corresponding energies, showing no significant beam degradation over 50 hours. Temperatures of the two last crystals were monitored and will help optimize surface cooling for future power ramping-up

Improving supersonic flights with femtosecond laser filamentation

International audienceWhen a flying object becomes supersonic, a concomitant increase of drag leads to a considerable rise of fuel consumption. We show experimentally that an embarked Terawatt femtosecond laser can significantly decrease this drag. A 50% transient reduction of drag is measured on a test model placed in a supersonic wind tunnel at Mach 3. This effect is initiated by the thin hot air column created in front of the supersonic object by filamentation of the laser pulse. We also show that this technique offers possibilities for steering