Many drug substances are chirally pure, as only one enantiomer of the drug substance is pharmacologically active. Enantioselective synthetic routes can achieve this through chemical means, but may fall victim to chiral erosion in steps downstream to the installation of stereocenters either due to differences in solubility properties or a propensity to epimerize. Further, not every drug substance is amenable to an enantioselective synthesis. In this talk, we will discuss the development of a crystallization-induced dynamic resolution (CIDR) of a racemic drug substance using a chiral acid as the resolving agent. High-throughput solubility (HTS) screens identified alcohols to have high selectivity for the desired enantiomer within a CIDR since they exhibit low solubility for the desired enantiomer and high solubility for the undesired enantiomer. Initial process invention focused on high-boiling alcohols given the kinetic barrier of epimerization was experimentally determined to be ~30 kcal/mol, indicating the rate to be highly-temperature dependent. A first round of DoE highlighted the formation of a single in-process impurity which was not quality impacting but became highly-yield impacting at temperatures >85C. Adding water to the system helped limit this impurity, but any added water resulted in increased solubility of the desired salt, limiting the maximum achievable yield of the system.
With these learnings in hand, EtOH was chosen as the main solvent in the process as it balanced the rates of impurity formation versus racemization. A combination of temperature-dependent HTS and racemization kinetic measurements were conducted, enabling the development of DynoChem models to predict the process performance across scales. The process was quickly scaled-up from 1-g to 10-g to 350-g in the lab, achieving >80% yield with high chiral and achiral purity. Further process optimization, enabled by the process models built on data generated in vials from <1mL, enhanced the overall yield of the process to ~85% across while maintaining consistent quality of the isolated drug substance at a >10 kg scale.
