From Structurally Related Solvates to Divergent Anhydrous Polymorphs: Desolvation Pathways of Sotorasib

Sotorasib is a covalent KRAS G12C inhibitor with multiple hydrogen-bonding sites and conformationally flexible groups, making it prone to solvate formation. In this work, eight sotorasib solvates were obtained and systematically characterized, and their crystal structures were determined by SCXRD. Among them, SMeOHα, SDCE, and SMIX are previously unreported solvates. Except for SMIX, the other seven solvates crystallize in the same orthorhombic space group with similar unit-cell parameters and a conserved host−host hydrogen-bonding motif, while differences in guest stoichiometry, local interactions, and lattice occupancy generate distinct packing environments. Upon guest removal, these related solvates exhibit divergent post-desolvation evolution, with lattice destabilization followed by thermal-history-dependent structural reorganization toward different anhydrous polymorphs. Under dynamic heating, DSC reveals Form II-related thermal evolution for SACN and SMeOHα, while HSM further identifies melt-mediated recrystallization for SMeOHα. Molecular dynamics simulations and solvent-vapor-induced transformation experiments further indicate lattice adaptability during guest removal and exchange. These results highlight the roles of lattice environment and thermal history in regulating post-desolvation evolution and polymorph formation.