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.