Effects of Solvation and Noncovalent Interaction on Stabilizing the Molecular Structure of Etoricoxib

This study investigated the conformational equilibrium and molecular association of etoricoxib (ETR) in saturated solutions, focusing on the molecular factors that govern its organization in solution.

A combination of experimental and computational methods was employed. One-dimensional and two-dimensional NMR spectroscopy, including mixing-time-dependent NOESY and DOSY measurements, were utilized to examine the conformational populations of ETR and its molecular association as a function of solvent. Quantum chemical calculations, including continuum-solvation calculations, determination of 1:1 ETR-solvent complexes, energy-decomposition analysis, and analysis using the quantum theory of atoms in molecules (QTAIM), provided supplementary qualitative models to investigate specific solute-solvent and solute-solute interaction patterns.

Two main ETR conformational families were identified, with relative abundances strongly dependent on the solvent. The ETR-1/4 family predominated in DMSO-d₆ and C₆D₆, whereas the ETR-2/3 family was predominant in CDCl₃. DOSY NMR revealed significant solvent-dependent differences in the apparent hydrodynamic behavior of ETR, with the qualitative trend in molecular association observed as C₆D₆ < DMSO-d₆ < CDCl₃. Quantum-chemical calculations indicated distinct interaction patterns for the selected ETR-solvent complexes and for the crystal-derived dimer models, providing qualitative insight into the molecular interactions responsible for the observed solvent-dependent behavior.

The results demonstrate significant changes in the conformational distribution and molecular association of ETR in saturated solutions as a function of solvent. The conformations observed in solution correspond to those found in the known polymorphic and solvated forms of ETR, enabling comparison between molecular arrangements in the solution phase and the solid state.