Rational Screening Approach for Classical Chiral Resolution under Thermodynamic Equilibrium: A Case Study of Diphenyl-Substituted N-Methyl-Piperazine

Abstract

Separation of racemic mixtures by the formation and crystallization of diastereomeric salts (classical resolution) is an important process in the pharmaceutical industry. We have developed and implemented a high-throughput screening workflow to effectively guide the development and optimization of a thermodynamically favored resolution process. A case study is presented for optical resolution of a diphenyl-substituted N-methyl-piperazine derivative, a racemic compound with a eutectic point of 60% ee. Through a rational screening approach, the effect of equilibrium solubility on resolution efficiency was systematically evaluated with regards to resolving agent, solvent composition, resolving agent stoichiometry, and racemate concentration. An isothermal solubility phase diagram was obtained, and solid-state characterization was performed on the diastereomeric salts to understand their phase behaviors under the optimal resolution conditions. The highest resolution efficiency was achieved when the diastereom...