Droplet‐confined spherical crystallization in water and the polymorph control through template‐induced nucleation

Abstract This work presents a spherical crystallization method in water based on droplet‐confined crystallization and successfully achieves polymorph control by template‐induced nucleation. Two typical drugs, low‐melting pendimethalin and high‐melting celecoxib, are selected as the model substances. Pendimethalin droplets are generated in water upon heating, and then cooling induces the formation of spherical particles (Form I). Polyvinyl alcohol is employed to regulate the droplet interface, enabling the transformation of pendimethalin from stable Form I to metastable Form II. Furthermore, we exploit the melting point depression principle induced by the formation of an eutectic mixture, and successfully develop a eutectic‐assisted spherical crystallization method in water for the high‐melting celecoxib. Polyethylene glycol promotes the formation of stable CXB Form III, while polyvinylpyrrolidone facilitates the nucleation of metastable Form I. Mechanism analysis, via density functional theory and molecular dynamics, reveals that the interactions of solute‐solvent and solute‐additive govern thermodynamic phase behavior and polymorph selectivity.