Pascale Subra-Paternault

A complete 3D simulation of a crystallization process induced by supercritical CO2 to predict particle size

Abstract Crystallization induced by compressed CO2 is a process that operates under several MPa of pressure. By rendering on-line measurements very difficult to perform, simulation appears as a suitable tool to better identify the important parameters of the process. A mathematical model is developed in the case of a spray-crystallization process in which a solution of minocycline-ethanol is injected into carbon dioxide as antisolvent. The model accounts for the main physical phenomena involved, i.e. hydrodynamics, mass transfer, phase equilibrium, crystallization kinetics. Simulations are performed in 3D with a special insight in turbulence modeling. Numerical results are compared with experimental data from literature. Although experimental and simulated PSD fit satisfactorily, results emphasize the major role of the crystal–fluid interfacial tension on the accuracy. Numerical investigations are further performed to highlight the effects of injection velocity and solution concentration on the spatial distribution of the important variables in crystallization.

Preparation and study of naproxen in silica and lipid/polymer hybrid composites

Three different powdered hybrid inorganic–organic composites for pharmaceutical use have been successfully obtained using CO2 as an antisolvent in a batch mode process. Naproxen was chosen as the hydrophobic Class II model drug, for which its dissolution rate in water must be enhanced. As excipients, two kind of commercial lipids (G44/14 and G50/13) and a mixture of Eudragit RS100 and Eudragit RL100 polymers were used. Silica microparticles have also been incorporated into the formulation to restrict the naproxen crystals growth and to obtain a powdered material with appropriate micromeritic properties. The morpho-chemical characteristics of these microcomposites and their different release profiles are reported. Importantly, the components have not suffered structural or chemical modifications during the processing and no specific chemical bonds were detected between them. High drug loading has been achieved in the three cases. Water dissolution of the drug formulations is controlled mainly by the wetting properties and nature of the excipients and by the size of the crystals. Among the materials prepared, samples made with Gelucires (hydrophilic species) result in the fastest release of naproxen. We thus conclude that lipid-based ternary formulations display a synergetically accelerated release compared to binary mixtures.