(429e) Determination of Supersaturation Fields By CFD in Supercritical Co-Crystallization Process

In the pharmaceutical sector, a new strategy at nanoscale for modulating the physical and chemical properties of drugs at macroscale is the formation of cocrystals, i.e. multicomponent assemblies of drug (API) and coformer held together by noncovalent interactions. Meanwhile, the need for improved manufacturing technologies is getting more and more crucial, notably because of the emergence of the generics that are less expensive than the original drugs and of the growing social concerns for environment protection and global change that motivate the emergence of alternative products and manufacturing routes. Crystallization assisted by CO₂, and especially the so-called SAS (Supercritical Antisolvent) process has emerged years ago as a promising alternative route for a better control of the particle size. Experimentally, the task is fastidious, and consequently promotes the development of simulation to better identify important parameters and to go off the case-by-case approach. A complete description of the Supercritical Antisolvent Process requires the modeling of several complex physical phenomena such as heat and mass transfer, hydrodynamic, phase equilibria of ternary or quaternary, and nucleation /growth of the species to be precipitated. Our team is currently developing a CFD code that takes in consideration all phenomena cited above, in case of the spray version of the antisolvent process, i.e. when the liquor solution is injected into a vessel pressurized with CO₂ at given temperature, pressure and flow rate. Simulations are performed in 3D configuration with the home-made Computational Fluid Dynamic code “Thetis”, by solving the classical Navier-Stokes model coupled with the Fick’s law to take into account the diffusion of the species. Let us mention however that due to the importance of the micromixing, turbulence was considered using a Large Eddy simulation model. By implementing further the equilibrium data for the solute to recrystallize, the spatial and time-dependent supersaturation field is analysed. As a first step, we propose simulations for the systems naproxen/acetoneand nicotinamide/acetone in classical SAS conditions, i.e. when the liquor solution (solute+solvent) is injected in the pressurized CO₂ reactor. Next, the supersaturation fields obtained in the previous configurations are compared with the ones in the case of SAS co-crystallization at the same pressure/temperature conditions, i.e. when the API (naproxen), the co-former (nicotinamide) and the solvent (acetone) are injected simultaneously in the pressurized reactor. The analysis of supersaturation cartographies of the species to crystallize show that the supersaturation levels are particularly modified in the case of co-crystallization.