Understanding the Role of Solvent Polarity in the Molecular SelfAssembly Process of Etoricoxib Solvates

In this paper, a comprehensive study of the solid and solution chemistry of etoricoxib (ETR) was conducted through the combined experimental identification and theoretical calculation. Six new solvates were discovered by studying 24 solvent properties and corresponding crystallization processes. The solvent H-bond donor ability was found to act as a key factor in the formation of ETR forms I and V, while the solvent polarity was found, for the first time, to determine the formation of ETR solvates. The crystal structures of all the new solvates were resolved by single crystal X-ray diffractions and analyzed in terms of intermolecular interactions, crystal-packing motifs, and host molecular geometry conformation. It was determined that the methylpyridine ring and methylsulfonyl polar functional groups play an important role in the self-assembly of ETR solvates. Theoretical calculations, including solvent-centric molecule pairwise interaction energies, energy topological analysis, and molecular electrostatic potential distribution, indicated that the host-guest strong electrostatic interaction plays an important role in the formation of ETR solvates. Solvents with higher polarity are easier to be incorporated into the lattice by connecting the surrounding ETR molecules via strong electrostatic interactions. Besides, the FTIR spectrum of ETR in different solutions further manifested that the solvents with higher polarity have a stronger binding ability with ETR molecules. Lastly, the self-assembly pathways of ETR in various solvent systems were proposed according to the intermolecular electrostatic interaction and solution-structure link, which deepens the understanding of ETR solvate formation and gives guidance for the new solid form development at the molecular level.