Dutch Resolution: Nucleation Inhibition in an Ephedrine-Cyclic Phosphoric Acid System
Joanne S. C. Loh, Willem J. P. van Enckevort, Elias Vlieg, Claire Gervais, Reinier F. P. Grimbergen, and Bernard Kaptein
Cryst. Growth & Design 6 (2006) 861-865

Abstract:
While the significant improvements in diastereomeric salt resolution using Dutch resolution have been experimentally established, little is known about the mechanism involved when more than one member of a family of resolving agents are added to a racemate. Investigation into the (-)-ephedrine-cyclic phosphoric acid resolution system has revealed a nucleation inhibition effect introduced by a member of the family that hinders the crystallization of the more soluble diastereomeric salt. In this way, the less soluble diastereomer is obtained with largely improved enantiomeric excess and yield. Comparison between experimental results and known phase diagrams indicates that for this system nucleation inhibition only occurs between compounds that are able to form (partial) solid solutions. It is suggested that adsorbed inhibitor molecules block the growth of the (super)critical 3D nuclei at the earliest stages of their development and thus delay the nucleation of the undesired salt.