Thermodynamic assessment of two-step nucleation occurrence in supercritical fluid

For the crystallization of an API in supercritical CO₂, a two – step nucleation mechanism involves the apparition of metastable liquid droplets in the vapour phase composed of the API dissolved in the CO₂, before crystallization. To find out the pressure and temperature conditions such a two – step mechanism could be observed, we studied the stability / metastability / instability for {(S)-Naproxen + CO₂} and {(RS)-Ibuprofen + CO₂} vapour binary mixtures. Thermodynamic computations proposed in the paper, have shown that a mixture of API and CO₂ at elevated pressures can be unstable and/or metastable with respect to a liquid-vapour equilibrium and at the same time with respect to a solid-vapour equilibrium. Depending on the degree of supersaturation, such a mixture can potentially first decompose via spinodal decomposition into coexisting liquid and vapour phases, which turn due to nucleation and growth theory to a solid-fluid equilibrium.