Separation of Drug Enantiomers by Distillative Crystallization:Phenylglycinol

Chiral drugs comprise more than one-half of drugs worldwide. Enantiomers can differ considerably in their pharmacological properties and toxicological effects. Generally, only one enantiomer can show the desired pharmacological properties while the counter enantiomer may be toxic. The demands for separation of chiral compounds are continuously increases in the pharmaceutical, agricultural and food industries. However, it is usually very difficult to separate the chiral compounds by conventional separation methods due to the similar structures between them. Low-pressure crystallization at three-phase equilibrium (distillative freezing, DF) technology has been first introduced in our group to separate the mixture of the volatile compounds with close boiling temperatures at a reduced pressure. Basically, the DF process is operated at triple point condition, in which the liquid mixture is simultaneously vaporized and solidified due to the three-phase equilibrium. Therefore, it combines distillation and crystallization to result in pure crystal products. DF will be applied in the separation of enantiomers in this two-year proposal. Phenylglycinol is selected for the new separation system because of a potential application of R-phenylglycinol in the synthesis of a key precursor of HIV-1 protease inhibitors. In the first year, the basic principles of DF in the separation of enantiomers will be examined in detail. A batch experimental set-up will be designed to perform the DF experiments. A model will be developed to describe the DF process and direct the DF experiments. The effects of the cooling rate and the stirring rate on the crystal purity and recovery rate will be examined. In the second year, a continuous three-stage DF apparatus will be developed. As the design of industrial-scale equipment is a challenging problem since an efficient process is required to provide the liquid mixture with a large exposure surface area available for simultaneous vaporization and crystallization. The effects of the operating temperature and pressure, and the residence time in each stage on the crystal purity and productivity will be examined in detail.

Project ID:PB10007-7264
External Project ID:NSC100-2221-E182-049