(252d) Chiral Separation Using a Novel Combination of Cooling Crystallization and a Hollow-Fiber Membrane Barrier

Enantioseparation is a key process in the production of several pharmaceutical materials. A combination of cooling crystallization and hollow-fiber membrane was used for enantioseparation to increase product yield and purity over that achievable with traditional preferential crystallization. Crystallization occurred in two vessels, the contents of which were cooled at a programmed rate after opposite chirally pure seed crystals were added to each. Solute exchange across the membrane was designed to reduce the concentration of the non-seeded species in each vessel, while simultaneously providing additional solute for crystallization in the opposite vessel.

Resolution of DL-glutamic acid was used as a model system in demonstrating the approach. The present work extends results previously reported¹ by increasing the yield through cooling a racemic feed solution 21°C below original saturation conditions. This was made feasible by using a hollow-fiber membrane in place of the flat-plate membrane used in the previous work. The additional area provided by the hollow-fiber membrane increased the rate of mass transport across the membrane, which allowed a more rapid cooling rate and greater reduction in temperature without the occurrence of primary nucleation. These system modifications increased both product yield and purity. Experimental results show that yield was a factor of 11.4 times that which could be achieved with simple crystallization, while only a 50% improvement was achieved with the flat-plate membrane. The resulting product purity was > 99.9%, which is significantly better than the >94% achieved in earlier work.

¹ A. Svang-Ariyaskul, W. J. Koros, and R. W. Rousseau, Chem. Eng. Sci., 64, 1980(2009).