Multicomponent phase diagram study for a "zero-discharge" chiral drug crystallization resolution method and its application for green chiral separation of (RS)-propranolol

It is a significant challenge to solve the problem of excessive waste of mother liquor for diastereomeric crystallization. Aimed at sustainability, a "zero-discharge" pairwise crystallization-circulating (membrane) extraction coupling (PC-CE or PC-CME) method was developed and applied for resolution of (RS)-propranolol. Over 15 cycles of mother liquor in situ reuse, two diastereomeric salt crystals, namely S 2 L 1 . MA and R 2 D 1 . MA (i.e., salt of (R)-/(S)-propranolol, dibenzoyl-(L)-/(D)-tartaric acid, and methanol with a stoichiometry of 2:1:1), were produced in succession with enantiomeric excess (ee) values ranging from 94.66 % to 98.74 % and 94.71 % to 98.78 %, respectively. S 2 L 1 . MA and R 2 D 1 . MA can be further easily treated into homochiral propranolol products. Meanwhile, the two mother liquors were regenerated to racemic state. Based on a multicomponent crystallization phase diagram, the mechanism of PC-CE or PC-CME was theoretically elucidated. A three-dimensional phase diagram of (RS)-propranolol was drawn through detailed solubility determinations. The crystal composition was analyzed using 1 H NMR, HPLC, FTIR, and UV-Vis. Eight kinds of crystals were discovered within the phase diagrams. A simplified racemic pseudo-ternary phase diagram was introduced to facilitate the theoretical analysis and the precise prediction. Furthermore, a comparative analysis of mother liquor entrainment demonstrated that PC-CME has a greater stability than PC-CE. The multicomponent phase diagram studies offer theoretical guidance for the broad application of the PC-CE or PC-CME method in various chiral resolution fields.