Investigating the Solvent Effect on Crystal Nucleation of Etoricoxib

Induction time measurement experiments for etoricoxib (ETR) were carried out in four solvents. The results suggest the crystal nucleation of ETR becomes increasingly more difficult in the order: toluene, acetone, acetonitrile, and ethanol, and this order is well correlated with the interfacial energies determined by the classical nucleation theory. The solute–solvent interaction was investigated by solution infrared spectroscopy, molecular dynamic simulations, and density functional theory computed 1:1 solute–solvent binding energies. The strength of binding energy at the sulfonyl on the ETR molecule is not only related to the infrared spectral shift of the sulfonyl band but also related to the nucleation rate. The needle-like crystal morphology along the b-axis of ETR form I in four solvents indicates that the molecular arrangement along the ac plane is extremely limited in cluster growth during nucleation. The sulfonyl, as a hydrogen bond acceptor, participates in the formation of several hydrogen bonds in the two-dimensional structure of the ac plane. Thus, the combination of solvent on the sulfonyl retards the nucleation of ETR. The stronger the solvent interacts with the sulfonyl on the ETR molecule, the more energy is required for desolvation, and the slower the ETR nucleation becomes.