Study on the Resolution Effect of Chiral Separation of Finerenone Using Different d-Tartaric Acid Derivatives

Abstract

Chiral separation is critical in pharmaceutical quality control for its divergent pharmacological activities. Since Finerenone (S-Fin), the S-enantiomer exhibits its pharmacological efficacy, whereas the R-enantiomer (R-Fin) remains inactive, thereby necessitating the development of an efficient chiral separation strategy to isolate S-Fin. This study compared the chiral separation efficiency of three d-tartaric acid derivatives: dibenzoyl tartaric acid (D-DBTA), ditoluoyl tartaric acid (D-DTTA), and Di-o-toluoyl-d-tartaric acid (D-DOTA) and D-DOTA was the most effective chiral resolving agent. The enantiomeric excess (ee) achieved is approximately 10% higher using D-DOTA than that obtained using D-DBTA and D-DTTA. The solubilities of S-Fin and R-Fin with d-tartaric acid derivatives were measured in ethanol–water. The largest solubility difference was found between S/R-Fin-D-DOTA, reaching 96.68 mg/mL. The smallest difference, 1.25 mg/mL, was observed for the S/R-Fin-D-DTTA pair. S/R-Fin-D-DBTA showed a difference of 31.26 mg/mL. These results suggest that D-DOTA is the most effective resolving agent. Single-crystal analysis reveals that D-DBTA and D-DTTA form ethanol solvates upon salt formation, whereas D-DOTA results in the formation of a hydrated form. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) further indicated solvent loss at approximately 170 °C, highlighting the relatively strong hydrogen bonding interactions of the incorporated solvent. Notably, compared to D-DBTA and D-DTTA as chiral agents in the patents, the application of D-DOTA provides a novel approach to the successful separation of S-Fin. This study suggests the critical role of solvents in chiral resolution and presents an efficient and low-cost strategy for the chiral separation of structurally related compounds.