Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Chemical and Biochemical Engineering

Supervisor

Dr. Ajay K. Ray

2nd Supervisor

Dr. Sohrab Rohani

Joint Supervisor

Abstract

Chirality is a major concern in the modern pharmaceutical, food and agricultural industries. The importance of enantiopure drugs has risen dramatically in recent years due to FDA regulations requiring that all chiral bioactive molecules must be isolated and tested for the efficacy and safety, and have to be as pure as possible containing a single pure enantiomer. There are essentially three strategies that can be applied to obtain single pure isomers: (a) extraction from plants and animal materials (b) enantio-selective asymmetric synthesis so that only one isomer is formed in the first place, or (c) making a racemate and finding a method for separating the enantiomers. Only few enantiomers exist in nature and most of them are racemates. A highly efficient chiral asymmetric synthesis route would be the ideal situation, but it usually takes about 10-15 years to develop a synthesis recipe. Hence, the best strategy would be to synthesize the drug in racemate form and separate the isomers to produce single pure enantiomer.

Among the variety of enantioseparation methods, chromatography and crystallization are the most dominant methods for the recovery of pure enantiomers. However, both methods have limitations. Crystallization cannot obtain enantiopure enantiomers from the racemic compound directly. In SMB, solvent consumption increases exponentially if desired purity requirement is close to 100%. In this work, the coupling of SMB for enrichment followed by direct crystallization is applied for the chiral resolution to circumvent limitations of each method. In order to take advantage of both the processes, SMB chromatography is used for partial enrichment thereby reducing solvent consumption followed by direct crystallization to obtain 100% pure enantiomers. Here, the chiral resolution of mandelic acid as racemic compound was considered to investigate the performance of the hybrid SMB-crystallization process theoretically as well as experimentally. The solubility and metastable zone limit of (R,S)-MA and (R)-MA in water and the crystallization kinetics parameters of (R,S)-mandelic acid and (R)-mandelic acid by optimization of the crystallization model based on the necessary experimental data collected in unseeded cooling batch crystallizers were determined. For the SMB part, the choice of mobile phase and determination of binary competitive equilibrium isotherms parameters of (R,S)-Mandelic acid and the experimental and modeling studies of SMB process have also been accomplished.

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