La cristallisation par effet anti-solvant, comme technique de production de micro/nanoparticules, présente certains inconvénients. En effet, pour des molécules nouvellement synthétisées ou découvertes, comme le LASSBio-294, les solubilités dans l'eau et dans les solvants organiques sont faibles ce qui limite l'application de cette opération. L'utilisation de solvants alternatifs ouvre de nouvelles perspectives de recristallisation de ce type de molécules. Dans ce travail, nous nous sommes intéressés à la cristallisation du LASSBio-294 en utilisant un liquide ionique comme solvant. Ce sont des sels organiques fondus à température ambiante, qui ont la particularité d’avoir une tension de vapeur nulle. Ils constituent une nouvelle classe de solvants non volatiles et ininflammables qui présentent des propriétés originales. Dans un premier temps, des liquides ioniques (LIs) dérivés du cation imidazolium ont été utilisés comme solvant alternatif. La solubilité a été mesurée dans 5 LIs,dans l’eau et dans des mélanges eau/LI. Dans l’eau pure la solubilité est très faible (5 ppm). En revanche, dans certains LIs, elle est supérieure à 200 mg/g solution. Les résultats de solubilité dans des mélanges eau/LI ont permis de choisir le rapport eau/LI pour l’obtention d’un bon rendement en solide. En complément, une étude de la stabilité du solide en suspension a été menée dans différents systèmes aqueux. Cette étude a montré sa possible hydrolyse. Dans un deuxième temps, la recristallisation a été réalisée avec le 1-éthyl-3-méthylimidazolium méthyl phosphonate [emim][CH3O(H)PO2] comme solvant et l’eau comme anti-solvant. Deux approches sont présentées en vue de favoriser le mélange : l'utilisation de dispositifs de mélange et l'introduction des ultrasons pendant le processus de cristallisation. L’influence de paramètres tels que le rapport anti-solvant/solvant, la concentration initiale et la présence d'additifs a été étudiée. Les solides formés puis séchés en étuve ont été caractérisés par granulométrie laser, microscopie électronique à balayage, diffractométrie de rayons X, calorimétrie différentielle à balayage et test de dissolution. Malgré une diminution de la taille des particules élémentaires, l'état d'agglomération des cristaux obtenus n'a pas permis une augmentation de la vitesse de dissolution. En modifiant le mode de séchage (séchage par atomisation), cette agglomération est réduite et la dissolution améliorée. De plus, la présence d'un polymère entérique en solution lors du séchage par atomisation des cristaux synthétisés a eu un effet notable sur la structure des agglomérats formés. Ces derniers peuvent se désagréger, se disperser et se dissoudre rapidement. / The anti-solvent crystallization allows obtaining micro/nanoparticles, but it presents some disadvantages. In the case of new pharmaceutical molecules, as the LASSBio-294, the solubility in water or organic solvents is very low limiting the application of this operation. The use of Ionic Liquids (ILs) as alternative solvents opens new perspectives in pharmaceutical processing through anti-solvent crystallization process. Unlike conventional solvents, ILs are entirely composed of ions. ILs are organic salts, usually liquid at room temperature, and which are composed of a relatively large asymmetric organic cation and of an inorganic or organic anion. ILs derived from imidazolium cation are used as alternative solvents for this drug, water being used as anti-solvent. First, the solubility is measured in 5 ILs, in water and in water/IL mixtures. In pure water, the solubility is very low (5 ppm). However, for some ILs, it is greater than 200 mg/g solution. The results of solubility in water/IL mixtures permit to choose a water/IL ratio leading to a good solid theoretical yield. Then recrystallization is performed with 1-ethyl-3-methylimidazolium methyl phosphonate [emim][CH3O(H)PO2] as the preferred solvent. Antisolvent crystallization represents a class of process characterized by the mixing between a solution and an antisolvent to produce solid particles. The influence of solvent/anti-solvent ratio, initial concentration, and additives is studied. The solids formed and dried in an oven are characterized by laser granulometry, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and dissolution test. Despite the decrease of elementary particles size, the agglomeration state of particles does not permit to improve the dissolution rate. The agglomeration is reduced and the dissolution improved by modifying the drying process (spray drying). Moreover, the presence of an enteric polymer during the spray drying process has a significant impact on the structure of the formed agglomerates. These are disaggregated, dispersed and dissolved very quickly.

Advanced drug discovery techniques have produced more lipophilic compounds. Formation of an amorphous solid dispersion of such poorly water-soluble drugs improves their solubility and dissolution. This results in greater in vivo bioavailability. Thus, it is one of the recent trends in the development of oral dosage forms. In solid dispersions, the carrier is crucial for ensuring the functionality and stability of these systems. Larch arabinogalactan FiberAid grade (AGF) is generally recognized as safe (GRAS) designated, amorphous polymer. The objective of this dissertation project was to perform a comprehensive evaluation of AGF as a carrier for amorphous solid dispersions. First, a detailed characterization of the AGF polymer was performed. A special focus on its use as a solid dispersion carrier was emphasized. The glass transition temperature and the degradation temperature of the AGF polymer were ~82 oC and ~185 oC, respectively. The AGF polymer had good hygroscopicity. Ibuprofen-AGF solid dispersions were evaluated for dissolution enhancement. Ibuprofen-Hydroxypropyl methylcellulose grade K3 (HPMCK3) solid dispersions were investigated simultaneously as a control polymer dispersion. The ibuprofen-AGF solid dispersions were amorphous at nearly 20% ibuprofen load. The dissolution of the ibuprofen from AGF solid dispersions was significantly greater than that of the neat ibuprofen. The formation of the amorphous state of ibuprofen and solution-state ibuprofen-AGF interactions were the mechanisms of the ibuprofen dissolution enhancement. At a 10% ibuprofen load, the dissolution of the AGF solid dispersion was found greater than that of the dissolution of the HPMCK3 solid dispersion. Secondly, the itraconazole-AGF solid dispersions and the ketoprofen-AGF solid dispersions were characterized and compared them with the ibuprofen-AGF solid dispersions. The comparisons were established for the miscibility and dissolution enhancement. The order of increase in dissolution was ketoprofen-AGF solid dispersions > itraconazole-AGF solid dispersions> ibuprofen-AGF solid dispersions. The same order was observed for the solid-state miscibility of these drug-AGF solid dispersions. Additionally, the solid dispersions of 9 drugs with the AGF polymer were investigated to elucidate the detailed mechanism of drug crystallization inhibition by the AGF polymer. The inherent tendency of the AGF polymer to inhibit the drug crystallization, drug-AGF solid-state hydrogen bonding and the anti-plasticizing effect of AGF were the mechanisms underlying the crystallization inhibition by the AGF polymer. Last, a storage stability of ibuprofen-AGF amorphous solid dispersions after storage under accelerated conditions (for 3 months) and ambient conditions (for 6 months) was investigated. The amorphous ibuprofen from AGF solid dispersions was physically and chemically stable under stability conditions. In summary, the AGF polymer was evaluated as a novel carrier for formation of an amorphous solid dispersions. The studies established that the AGF polymer was comparable to HPMCK3 polymer. The AGF polymer could be more advantageous than the HPMC polymer for the preparation of solid dispersion when faster dissolution is desired at lower drug load. / Pharmaceutical Sciences

Poorly water soluble drugs have been manipulated to make them more soluble, increasing the bioavailability of these drugs. Several cryogenic processes allow for production of drug nanoparticles, without mechanical stress that could cause degradation. The Ultra Rapid Freezing (URF) process is a technique which improves water solubility of drugs by reducing primary drug particle size by producing amorphous solid dispersions. Heat conduction is improved, using a cryogenic material with a high thermal conductivity relative to the solution being frozen to maintain the surface temperature and heat transfer rate while the solution is being frozen. With URF technology, the freezing rate is fixed, which drives the particle formation and determines its characteristics. Supersaturation of drug in aqueous solution can allow for better absorption of the drug via the oral and pulmonary routes. Drug formulations that supersaturate the dissolution media show the possibility for increased bioavailability from an amorphous drug form. If the concentration of drug in solution is significantly increased, higher chemical potential will lead to an increase in flux across an exposed membrane, leading to higher blood levels for an amorphous drug, compared to an identical crystalline formulation. During oral delivery, supersaturated drug concentrations would also saturate PGP efflux sites in the gut lumen, increasing the drug's bioavailability. Saturated PGP sites show zero order efflux kinetics, so increasing the drug concentration in supersaturated biological fluid will increase serum drug levels. High supersaturation levels maintained for prolonged periods would have a beneficial effect on a drug's absolute bioavailability. Pulmonary administration offers therapeutic advantages over more invasive routes of administration. Limited amount of metabolizing enzymes like CYP 3A4 in lung tissue along with avoidance of first pass metabolism are advantages to pulmonary delivery. The objective of the research presented in this dissertation is to show the versatility of nanoparticulate poorly water soluble drug formulations. Due to the reduced particle size and the URF manufacturing process, a wide range of applications can be used with these nanoparticles. Oral and pulmonary administration routes can be explored using nanoparticles, but in vitro cell culture testing can show clinical benefits from this type of processing technology. / text

En raison de leur complexité croissante, la solubilité des nouvelles entités chimiques en milieu aqueux est de plus en plus faible. Ainsi, le développement de beaucoup de principes actifs échoue à cause d’une hydrosolubilité insuffisante. De nombreuses technologies existent pour améliorer la solubilité et/ou solubilisation de tels composés. Cette thèse est ciblée sur la formulation de dispersions solides amorphes par extrusion à chaud. En particulier, un principe actif d’intérêt industriel sera formulé en utilisant une extrudeuse bi-vis disponible sur la plateforme Gala®. Cette technologie autorise l’utilisation d’un grand nombre de matrices, ce qui peut nécessiter un grand nombre d’essais expérimentaux. Une attention particulière est donc portée à l’utilisation de méthodes prédictives de la miscibilité entre les composants qui peuvent ainsi permettre une première sélection des matrices. Sur la base de ces résultats, une étude sur le procédé de hot melt extrusion a ensuite été réalisée. / The aqueous solubility of new chemical entities is increasingly weak, due to their complex structure, and many API fail in development due to insufficient solubility. Many technologies exist to enhance the solubility and / or dissolution of such compounds in aqueous media. Among all of these methods, this thesis is focused on the formulation of amorphous solid dispersions by hot melt extrusion. A lot of matrix can be used to formulate with this technology, so few methods to estimate miscibility between API and matrices will also be presented in this thesis. Finally, a study about the hot melt extrusion process will also be presented.