Resolution of Double Salts via Crystallization‐Induced Diastereomeric Transformation (CIDT)

Abstract The efficient enantioseparation of racemic compounds remains a critical challenge in pharmaceutical manufacturing. This investigation examines the crystallization‐induced diastereomeric transformation (CIDT) of ( S )‐ketoprofen‐( S )‐phenylethylamine salts as a strategy for obtaining high‐purity diastereomeric salts. Solubility phase diagrams were constructed for diastereomeric salts. A double salt system was identified, and a solvent system of 2‐propanol and heptane (50:50 wt.%) was optimal for crystallization. Among the seven base catalysts screened, DBU (1,8‐diazabicyclo[5.4.0]undec‐7‐ene) was found to be the most effective. Optimization studies demonstrated that 5–10 mol% DBU provides the highest purity (98.8 %) with 26.2 % yield. These results provide insights into the dual role of DBU as a catalyst (forming mixed salts) and cosolvent, influencing yield. The findings highlight CIDT as a robust method for the enantioseparation of diastereomeric salts in pharmaceutical applications.