Thermodynamics of Oiling-Out in Antisolvent Crystallization. II. Diffusion toward Spinodal Decomposition

The extensive use of antisolvent crystallization for poorly soluble chemicals is hindered by oiling-out. This study delves into solute diffusion kinetics upon antisolvent addition. We conducted time-dependent simulations on a hypothetical micrometric diffusion couple, utilizing chemical potential gradients as driving forces within the Maxwell-Stefan model. Our computations compared two types of interflux coupling: drags and thermodynamics. The thermodynamic force dominates solute diffusion behavior. Antisolvent influx elevates solute chemical potential. This energy wave drives the solute to focus toward the good solvent and leads to the competition between crystallization and oiling-out. Through microfluidics and simulations, characteristic times of oiling-out and two sites of antisolvent-induced spinodal decomposition were identified. Diffusion trajectories on the phase diagram unveiled local thermodynamic conditions and impacts of mixing parameters. Initial antisolvent gradient dominates the strength of the focusing effect. Initial solute concentration acts as an offset in diffusion trajectories. Faster agitation in antisolvent and smaller droplets of solution both effectively enhance solute focusing. These findings are general, allowing mixing processes to be designed into metastable phase regions, with local compositions staying above the designed concentrations for prolonged durations. Elevated supersaturations and extended diffusion times offer favorable conditions for nucleation of metastable phases.