Syn-Anti Conformational Equilibrium of Indomethacin: A Combined NOESY and Quantum Chemical Study

To elucidate the conformational equilibrium of Indomethacin in solution and to establish its relationship with solvent environment and solid-state polymorphism.

A combined experimental-computational approach was employed. One- and two-dimensional NOESY NMR spectroscopy were used to quantify cross-relaxation rates and derive conformation-sensitive internuclear distances in DMSO-d6 and CDCl3. Conformer populations were determined using the initial rate approximation and isolated spin-pair approximation. Quantum-chemical calculations based on Density Functional Theory (B3LYP-D3(BJ)/def2-TZVP, SMD solvation model) were performed to evaluate conformer energetics and solvent effects.

Two conformer families, syn- and anti-, were identified as key structural motifs governing indomethacin behavior. InDMSO-d6, the syn-conformer dominates (80.8%), whereas in CDCl3 the equilibrium shifts toward nearly equal populations (51.5% syn, 48.5% anti), revealing a strong solvent-dependent effect. Experimentally derived NOESY distances showed excellent agreement with computed geometries. DFT calculations confirmed the energetic preference of syn-type conformers while demonstrating significant solvent-induced changes in relative stability. Importantly, a direct correlation between solution-phase conformational equilibrium and known polymorphic forms was established.

This study demonstrates that solvent-controlled conformational equilibria play a probable role in determining the solid-state forms of indomethacin. The integrated NOESY-DFT methodology provides a robust and quantitative framework for conformational analysis and offers a predictive tool for rational design and optimization of pharmaceutical solid forms.