(241f) Design and Operation of Crystallization-Based Enantioselective Processes: Enantioselective Crystallization of Chiral Compounds On An Enzymatic Reactive Environment

Crystallization is a widely used separation and purification technique for a vast number of specialty chemicals and pharmaceutical compounds. However, its application on enantioselective separations can become troublesome. Enantiomeric compounds have the same physiochemical properties (other than optical rotation); as a result, an excess of the desired enantiomer is necessary to obtain enantiopure crystals. 

  To achieve the necessary enantiomeric excess, we are performing enantioselective enzymatic reactions on supersaturated solutions. To increase the productivity of the process, reaction and separation are performed in parallel in a single vessel. Preliminary work has shown the possibility of performing such a process utilizing chemoenzymatic reactions and kinetic resolutions. Present work is focused on using reaction and crystallization kinetics to design processes in which the operational time is minimized. As a case study, we are investigating the enantioselective deacylation of N-acetyl-DL-methionine by L-aminoacylase. The solubility of the DL-methionine has been measured as a function of substrate concentration, enantiomeric excess, and temperature. The information is being used to set the boundaries of the operation in which an enantiopure crystal can be recovered.  The concentration in the reactive crystallizer is analyzed online by combining optical rotation, refractive index, and focused beam refractive measurements (FBRM).  These signals can be used to monitor solution and crystals properties. Hence, we can control the chemical and enantiomeric purity of the crystals and their respective size distribution.