Theoretical Examination on the Chiral Separation Mechanism of Ibuprofen on Cellulose Tris(4-methylbenzoate)

The mechanism of separating the small chiral drug molecules on large soft polymers is essential in pharmaceutical science. As a case study, the differentiation mechanism of ibuprofen, (<i>R</i>,<i>S</i>)-2-(4-isobutylphenyl)propanoic acid, with cellulose tris(4-methylbenzoate) (CMB) as the chiral stationary phase (CSP) was investigated by combining the molecular docking simulation and multi-level layered terminal-to-center elongation (ML-T2C-ELG) method. Our results demonstrated that, based on the optimized geometry using the ML-T2C-ELG method, the complexation energy of <i>S</i>-ibuprofen with CMB obtained at B3LYP-D3(BJ)/6-311G(d) level is more negative than that of <i>R</i>-ibuprofen, which is caused by the greater hydrogen bonding and π-π stacking interactions between CMB and <i>S</i>-ibuprofen. The results are in line with the experimental observations of high-performance liquid chromatography (HPLC) that the retention time of <i>S</i>-ibuprofen on CMB is longer than that of <i>R</i>-ibuprofen. Moreover, the ML-T2C-ELG method was found to be valuable for optimizing the geometries of such flexible and large systems, which allows for a more accurate description of interactions between soft polymers and small molecules when coupled with the docking simulation. It is anticipated that this study can provide beneficial insights for future optical resolution mechanisms of other chiral drugs.