SEPARATION OF OPTICAL ISOMERS FOR PHARMACEUTICAL APPLICATIONS

Abstract

In this thesis, a process which integrated simulated counter-current chromatography (SCC) and multi-stage crystallisation for the recovery of (-)-praziquantel from the racemic mixture is reported. (-)-praziquantel has the advantage of high efficacy and low toxicity compared to racemic praziquantel for population-based chemotherapy of a broad range of parasitic infections. With the present laboratory scale of production, about 11. 7 g of enantiomerically pure (-)-praziquantel can be obtained per day at a recovery of 80%. Several chiral stationary phases (CSPs) have been characterised for the chromatographic enantioseparation of praziquantel. Microcrystalline cellulose triacetate (MCTA) shows a higher separation factor compared to other polysaccharide derivative CSPs studied. With methanol as the mobile phase, the MCTA system provides additional advantage of easy solvent recovery. The high solubility of praziquantel in methanol also provides a high throughput. An empirical approach for the design of enantioseparation using an elution volume design principle is presented. The optimum condition for the present separation is determined from systematic experimental studies using this design approach. The SCC process is proved to be an efficient and cost effective separation method for obtaining high optical purity of enantiomers. It provides a better utilisation of the whole sorbent bed and a reduction in the cost of the expensive sorbent. It is deduced from the result of the SCC that complete resolution solely by - chromatographic method might result in low recovery. Therefore, the possibility of using crystallisation for complete resolution of the isomers 1s investigated. It is found that the solubility behaviour of the praziquantel enantiomeric system exhibits a ternary polymorphism. The pseudoracemate behaviour exhibited by the system is prominent when the optical purity of the initial solution is low. When the purity of the initial solution is high, pure crystals of the excess enantiomer are formed when the solution is crystallised. With the help of the solubility phase diagram, enantiomerically pure praziquantel crystals are obtained by performing a multi-stage crystallisation of the partially resolved compound from the SCC process. Using the pure enantiomers so processed, the competitive multicomponent isotherms of praziquantel enantiomers on cellulose triacetate are determined by the concentration pulse technique. The detailed study of the multi-component isotherm of an enantiomeric system has been done for the first time and provides an efficient method for similar studies in the future. A model comprising a non-selective linear term and a selective first order improved Langmuir term is found to provide an excellent fit to the data. It is postulated that this CSP consists of two types of binding sites: one responsible for the achiral, non-selective interactions and one responsible for the chiral, selective interactions. The adsorption isotherms determined are utilised in the theoretical analyses and optimisation of the SCC separation process. A dispersed plug flow model with periodical port motion is used to simulate the SCC process. This model has proved to provide adequate accuracy and simplicity in simulating both the transient and cyclic steady-state behaviours of the present complex system.