Solvent-Antisolvent Competitive Interactions Mediate Imidacloprid Polymorphs in Antisolvent Crystallization

Imidacloprid (IMI) polymorphs were first found to be sensitive to the content of antisolvent in an antisolvent crystallization process using formic acid (FA) as a solvent and water (W) as an antisolvent. Characterized by XRD, DSC, POM, and Raman, the obtained crystals change from Form II into Form I as the FA/W ratio becomes lower than 1:1. Combined with Hirshfeld surface analysis, it illustrates that IMI molecules have the tail-to-tail and tail-to-head packing modes at a FA/W ratio of 1:1, whereas they adopt the tail-to-tail parallel packing at a FA/W ratio of 2:1. Molecular dynamic simulations disclose that the molecular conformations in the IMI aggregates turn to be approximately the distinct conformations in the corresponding unit cells of crystal Form I and II. The competing parameters were put forward around the active sites of IMI on the basis of the coordination numbers calculated through RDF profiles to understand deeply the competition mechanism of the solute-solvent interactions versus the solute-antisolvent interactions. It is found that as the content of water increases, the solute-antisolvent interactions gradually turn to be dominant around the specific sites, which promotes the conformation change of IMI and then facilitates the nucleation for Form I. These results provide a useful route to study the nucleation pathway of polymorphic products.