Mise en forme et enrobage des ingrédients pharmaceutiques par procédés supercritiques

Ce travail de thèse a été dédié à l'élaboration de formulations de médicaments par procédé Supercritique Anti-Solvant (SAS). L'étude a été divisée en deux sections : la production de co-précipités de médicament / polymère en utilisant le procédé SAS et l’enrobage de particules de taille micrométrique en utilisant un lit fluidisé couplé au procédé SAS. L'éthyl cellulose a été choisi comme polymère biocompatible pour la préparation des deux systèmes. La micronisation de l'éthyl cellulose par procédé SAS a été réalisée avec succès; des particules submicroniques ayant une taille moyenne de 300 nm ont été obtenues. Les formulations composites micronisées, la quercétine et la rifampicine avec de l'éthyl cellulose ont été élaborées par co-précipitation à pression et température modérées (10 MPa et 35 °C). L'étude de faisabilité d'une nouvelle méthode d’enrobage par lit fluidisé en milieu supercritique couplé à l'utilisation du procédé SAS a été réalisée. Ce procédé vert alternatif permet d’enrober des particules micrométriques avec peu d'agglomération et une bonne qualité du film d’enrobage. Des expériences d’enrobage de billes de verre ont été effectuées dans des conditions opératoires variées pour deux configurations d'injection différentes, pulvérisation par le haut ou par le bas de l’autoclave. De meilleurs résultats ont été obtenus dans les expériences de pulvérisation par le haut, notamment en termes de qualité de revêtement. Ce travail de thèse apporte des éléments nouveaux et pertinents pour un meilleur contrôle des procédés d’enrobage en milieu supercritique.The elaboration of drug formulations using supercritical anti-solvent process was the subject of this thesis. The study was divided in two sections: production of drug/polymer co-precipitates using SAS process and coating of micron-sized particles using a fluidized bed coupled with SAS process. Ethyl cellulose was chosen as biocompatible polymer for preparing the two systems. The micronization of ethyl cellulose using GRAS ethyl acetate solvent through a supercritical anti-solvent process was successfully performed; submicron particles with mean size of 300 nm were obtained. Micronized drug composites of quercetin or rifampicin with ethyl cellulose at moderate pressure and temperature (10 MPa and 35 °C) were produced by co-precipitation using supercritical anti-solvent process. Depending on the operating conditions, different particle size, particle size distribution and morphology of the product, but also crystallinity and drug loading were observed.The feasibility study of a novel coating method using fluidization in supercritical medium coupled with SAS process has been demonstrated to be a good alternative green process to elaborate micron-sized coated particles with few agglomeration and good coating quality. Coating experiments of glass beads were carried out at different conditions for two different injection configurations, top and bottom spray. Better results were achieved in the top spray experiments in term of coating quality. This Ph. D. work brings new and relevant elements for a better control of the coating processes in supercritical medium

Supercritical anti-solvent precipitation of ethyl cellulose

International audienceSupercritical anti-solvent (SAS) process is considered to be a clean technology suitable for particle design. It is generally used in order to micronize compounds of interest under mild operating conditions of temperature and with very low residual solvent traces in the end-product. By varying the process parameters, the properties of the produced powders can be adjusted with defined size (generally micron or nanometer sized particles), morphology and a narrow particle size distribution. There is currently a growing interest for the elaboration of controlled delivery systems. For this purpose, the SAS process can also be applied in order to co-precipitate molecules of interest with biocompatible and/or biodegradable polymers.An experimental study dealing with supercritical anti-solvent (SAS) precipitation has been carried out in order to micronize a biocompatible polymer, ethyl cellulose, widely used as a drug carrier in controlled delivery systems for oral administration. Supercritical carbon dioxide was used as anti-solvent for the polymer and ethyl acetate (EtAc), generally recognized as safe (GRAS) by the FDA (Food and Drug Administration) as solvent. The influence of the variation of the main operating parameters upon the characteristics of the micronized polymer was evaluated. In particular, the temperature (308, 318 and 333 K), the polymer concentration (1, 3 and 4 wt%), the EtAc/CO2 molar ratio (5 and 8 mol%) and the capillary tube diameter (127 and 254 μm) while pressure was kept constant and equal to 10 MPa. Using a low organic solution concentration of 1 wt% and at a temperature of 308 K, ethyl cellulose was successfully micronized in submicron particles with a mean size of 300 nm. However, increasing the temperature or the polymer concentration in the organic solution favored the particle coalescence and even led to fiber formation

Supercritical antisolvent co-precipitation of rifampicin and ethyl cellulose

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Particle design applied to quercetin using supercritical anti-solvent techniques

International audienceQuercetin is a strong naturally occurring antioxidant that is exploited in pharmaceutical and cosmeticsapplications. Unfortunately, quercetin is highly susceptible to oxidation. Besides, its poor solubility inwater and low bioavailability upon oral administration limit the use in drug formulations for the treat-ment of human diseases. In an effort to overcome these drawbacks, the micronization and coprecipitationof quercetin particles with a low-cost biocompatible polymer (ethyl cellulose, EC) was studied by usingsupercritical anti-solvent process (SAS) with a non-toxic solvent ethyl acetate. The results showed thatSAS micronization of quercetin led to a reduction in the quercetin particle size and crystallinity withouta change in the needle-like habit. SAS coprecipitation of quercetin with EC at moderate pressure andtemperature (10 MPa and 35◦C) led to obtaining quasi-spherical particles. The coated polymer avoidthe growth of quercetin crystals, thus amorphous particles in the submicron range (mean size rangingbetween 150 and 350 nm) were formed. Promising coprecipitation results were reached with quite highprocess yields (above 85%) and encapsulation efficiencies up to 99% that provided a high stability to thecoated quercetin with EC against oxidation

Polystyrene based sub-micron scintillating particles produced by supercritical anti-solvent precipitation

International audiencescintillation microspheres (PSm) are a novel material employed in the measurement of radioactivity (α and β emitters). This work is focused on the formation of plastic scintillation particles through the precipitation and encapsulation of two fluorescent solutes (2,5-diphenyloxazol (PPO) and 1,4-Bis(5-phenyloxazol-2-yl) benzene (POPOP)) and an aromatic solvent 2,6-diisopropyl-naphthalene (DIN), which acts as an enhancer for α and β emitters discrimination, into a polymeric matrix of Polystyrene (PS) by Supercritical Anti-Solvent process (SAS) using ethyl acetate (EtAc) for dissolving the PS and supercritical CO2 as antisolvent. Different process parameters were varied; solute concentration in the organic solution (W, wt%), injection velocity of the organic solution (u, ms−1), molar ratio of the organic solvent regarding to CO2 (XEA) and injection capillary tube diameter (μm). In the different experimental conditions tested, SAS coprecipitation was successfully achieved resulting in yields higher than 90% and very low quantities of residual solvent (600–1200 ppm). The different Polystyrene based particles obtained were nearly spherical sub-micron particles (ranged between 150 and 400 nm) and also agglomerates of a few micrometers were observed in most of the studied conditions. Radiometric capacities of particles were evaluated through measuring different beta and alpha emitting radionuclide. The coprecipitates showed scintillation behavior when fluorescent solutes were added, therefore confirming their encapsulation