Chiral resolution by diastereomeric salt crystallization

Chiral crystallization with the use of resolving agents to form diastereomeric salts is a widely used technique for resolving chiral compounds. However, the approach to resolve chiral compounds by this method is still conducted mainly on a trial-and-error basis. An integrated approach is proposed to study this method experimentally. In the first step, the formation of diastereomeric salts is studied. Issues on resolving agent and solvent selections have to be considered. In the next step, the solid liquid phase equilibrium of the diastereomeric salts system is studied. By constructing the appropriate phase diagram, it can be decided whether it is feasible to recover the desired diastereomeric salts in an equilibrium based crystallization process. The desired diastereomeric salts can also be recovered under kinetic conditions. Because of that, the possibility of a kinetic based crystallization process is investigated in the third step. Supersaturated diastereomeric salts solution is seeded with pure form of the desired diastereomeric salt and the crystallization is stopped well before reaching equilibrium. The approach is illustrated by using a chiral non-steroidal anti-inflammatory drug, Ibuprofen (IBU), as a model system. (S)-IBU is more potent than (R)-IBU and there is a great deal of interest to separate them. N-methyl-D-glucamine (NMDG) is chosen as the resolving agent. Diastereomeric salt is successfully formed in an acetone solution. 7.3% and 22.57% of pure NMDG-(S)-IBU can be recovered in an equilibrium based and kinetic based crystallization process respectively