A molecular thermodynamic model for chiral drug purification using chiral ligand exchange chromatography

NR-20081 Chiral ligand exchange chromatography (CLEC) separates enantiomers of alkaloids, amino and carboxylic acids, barbiturates, β-blockers and other adrenergic drugs. It relies on subtle energetic differences between ternary homo- and hetero-chiral complexes formed between a ligand capable of chelating a divalent transition-metal ion and an enantiomer. CLEC separation efficiency is strongly dependent on column operating conditions, including pH, temperature, mobile-phase composition, and feed composition. Each enantiomer participates in a large number of solution and stationary-phase complexes within the column. As a result, the mechanism of separation is complex and poorly understood, making it difficult to identify optimal column operating conditions using conventional empirical strategies. A new model for CLEC-based separations is presented that provides a molecular understanding of the separation process. It combines the non-ideal equilibrium dispersion model of chromatography with multiple chemical equilibria theory to accurately predict enantiomer transport and partitioning, elution band profiles, and separation efficiency over a wide range of permissible column operating conditions. Mass transport parameters are determined by moment analysis and used to show that solute mass transfer and binding is limited by pore diffusion during separation of α-amino acid racemates on a Nucleosil Chiral-1 column (bearing a L-hydroxyproline as the chiral selector) or of dopa enantiomers on a Chirex 3126 column (bearing a derivative of D-penicillamine as the chiral selector). As a result, the local equilibrium approximation can be applied at all standard column operating conditions. Stoichiometries and formation constants for all equilibrium complexes formed in the column are taken from standard thermodynamic databases or independent potentiometric titration experiments. Model performance is assessed through comparison with chromatograms for hydrophobic amino-acid racemates loaded on a Nucleosil Chiral-1 CLEC column. The model is then applied to a medically relevant separation: the resolution of dopa enantiomers on a Chirex 3126 CLEC column. In both cases, the model is shown to provide an accurate and detailed picture of the separation process useful for elucidating the mechanism of separation and the associated influence of key column operating variables on speciation profiles. Finally, the model is successfully applied to a restricted optimization of column operating conditions for the separation of D,L-valine, indicating that it may provide a rapid and comprehensive path to process optimization.Applied Science, Faculty ofChemical and Biological Engineering, Department ofGraduat