Prediction of the phase diagram of liquid–liquid phase separation during crystallization via a molecular mechanism study

Oiling-out is a unique liquid–liquid phase separation phenomenon in solution crystallization. The unknown microscopic mechanism of oiling-out makes it difficult to control and significantly reduces the separation efficiency. In this work, an adsorption–desorption mechanism of temperature-driven molecular clustering is proposed based on the configuration search and the transformation process monitoring of dimers. This mechanism indicates that the stable and sufficient solute dimers in the solvent is the key condition for inducing oiling-out, accompanied by the transformation among various dimer configurations. Based on this mechanism, a prediction method of oiling-out phase diagram has been established through configurational stability analysis and determination of the total energy-temperature curve. This prediction method has been successfully applied to five systems: pyraclostrobin, vanillin, ethyl vanillin, citric acid, and benzoic acid. Importantly, the purity of pyraclostrobin is increased from 42.76% to 99.32% with the assistance of the oiling-out phase diagram. These findings not only provide advanced insights into understanding and controlling oiling-out during crystallization, but also highlight the role that oiling-out plays in the molecular assembly process of crystal nucleation.