Crystallization-Based Resolution Process for the 2,3-Dibenzoyl-d/l-tartrate Salts of d-/l-Serine Benzyl Ester

Abstract

It is shown that the 2,3-dibenzoyl-D-/L-tartrate salts of D-/L-serine benzyl ester (salt pair 1, L-D,D-D; salt pair 2, D-L,L-L) behave like simple eutectic systems in their binary (melting) and ternary (solubility) systems. Due to this essential thermodynamic property, these salts are separable via crystallization. Metastable zone width data for primary nucleation of both salts were measured to support a rational process design. Resolution processes for both salt pairs were designed and executed successfully delivering diastereomeric salts in high purity. The presence of excesses of resolving agents, previously not considered, was systematically studied and found to possess the potential to further improve the performance of the selective crystallization processes.

Ternary and quaternary phase diagrams: key tools for chiral resolution through solution cocrystallization

“…The overall aspect of these diagrams strongly depends on the nature of the system under study. [22][23][24][25] This is also the case for our resolution technique based on enantiospecific cocrystallization in solution. Although, typically, cocrystallization processes in solution are developed using ternary phase diagrams, [26][27][28][29][30][31] these no longer suffice, as both enantiomers of the racemic mixture need to be taken into account, yielding a total of 4 variables (amount of solvent, coformer, and both enantiomers of target compound).…”

Solubility and Some Crystallization Properties of Conglomerate Forming Chiral Drug Guaifenesin in Water

“…The polythermal experiments were carried out by analogy with a published method . Known amounts of rac ‐ 1 or ( R )‐ 1 and 0.7 g of water were filled in small vials equipped with a magnetic stirrer.…”

“…%. Experiments were performed in analogy with a published work in the Crystal16 TM reactor system by detecting so‐called “cloud points” (the temperature where first crystals were detected) in cooling cycles.…”

“…The polythermal experiments were carried out by analogy with a published method. 35,36 Known amounts of rac-1 or (R)-1 and 0.7 g of water were filled in small vials equipped with a magnetic stirrer. The vials sealed were placed in a Crystal16 TM multiple-reactor system (Avantium Pharmatech BV, Amsterdam, The Netherlands).…”