Design of spherical agglomeration via salt-induced liquid–liquid phase separation

•A novel spherical agglomeration technology (SI-SA) is proposed in this work.•SI-SA technology avoids the usage of toxic bridging liquid.•Phase separation and good wettability of organic solvents are necessary.•Phase separation is achieved in miscible binary system by adding salts in SI-SA.•Spherical crystals of three drugs in 16 systems are prepared using SI-SA. In this study, a novel strategy for spherical agglomeration via salt-induced liquid–liquid phase separation (SI–SA) was developed. SI–SA technology achieves phase separation in the miscible binary anti-solvent crystallization system by adding certain amounts of salts, avoiding the use of toxic bridging liquids. Water–organic solvent–salt systems that induced phase separation were selected using phase separation experiments. The wetting performance of the organic solvent was estimated by droplet experiments, and organic solvents with stronger wettability for crystals than water would be selected for further verification. Spherical agglomeration experiments were designed based on the ternary phase diagrams of these selected systems. Water–organic solvent–salt systems of benzoic acid were selected, starting with six organic solvents and four salts. A total number of 16 water–organic solvents–salt systems were effectively predicted using the SI-SA strategy. The in-situ process analysis tool indicated that the formation of spherical particles of benzoic acid underwent a process of crystallization, phase separation, wetting, two-step agglomeration, and consolidation. The stirring rate and mass ratio of salt to final crystals were found to be important for controlling the morphology and particle size of the spherical crystals. The spherical particles of aspirin and salicylic acid were successfully predicted in different systems via SI–SA technology, demonstrating the universality and potential usage of SI–SA technology in industry.