Chromatographic Separation of Bupivacaine Enantiomers by HPLC: Parameters Estimation of Equilibrium and Mass Transfer Un
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Chromatographic Separation of Bupivacaine Enantiomers by HPLC: Parameters Estimation of Equilibrium and Mass Transfer Under Linear Conditions IVANILDO JOSE´ DA SILVA JUNIOR, VIN´ICIUS DE VEREDAS, MARCOS JOSE´ SOUZA CARPES AND CESAR COSTAPINTO SANTANA∗ Laboratory of Bioseparations, Department of Biotechnological Process, School of Chemical Engineering, State University of Campinas, Campinas, SP, Brazil, PO Box: 6066, 13083-970 [email protected]
Received July 24, 2004; Revised May 25, 2005; Accepted August 2, 2005
Abstract. Bupivacaine is an amide type local anesthetic widely used in surgery and obstetrics because of its sustained peripheral and central nerve blockade. R-(+)-bupivacaine is more toxic to the central nervous and the cardiovascular systems than S-(−)-bupivacaine. To obtain S-(−)-bupivacaine with high degree of purity using a continuous simulated moving bed (SMB) unity, equilibrium and mass transfer parameters under dilute conditions were obtained by pulse experiments using 0,0 -bis[4-terc-butyl-benzoyl]-N,N -diallyl-L-tartar diamide immobilized R in silica (Kromasil CHI-TBB). The linear equilibrium constants were found to be 2.12 and 2.91 for R-(+)and S-(−)-bupivacaine, respectively. Axial dispersion coefficients were found to be practically the same for both enantiomers. A fast kinetic of mass transfer was observed. The internal resistance to the mass transfer controls all the mass transfer process in this chiral column and the pore diffusion coefficients were of the order 10−7 cm2 /s. The equilibrium and mass transfer parameters will be employed in future simulation and design of operating conditions of SMB unity. Keywords: 1.
Chiral separations, preparative liquid chromatography, mass transfer, equilibrium, bupivacaine
Introduction
The necessity to generate individual enantiomers for testing has become a growing priority in pharmaceutical research and development. This necessity is directly related to the increased knowledge of the effect differing enantiomers have in biological systems (Miller et al., 1999). It is well known that some optical isomers may exhibit completely different, and even opposing, pharmacological effects. As a consequence, new chiral separation methods are being proposed nowadays to produce single enantiomeric forms of chiral drugs (Azevedo et al., 1999). The use of chromatographic technique to obtain significant quantities of enantiomerically pure drug intermediates is well estab∗ To
whom all correspondence should be addressed.
lished and a simulated moving bed (SMB) chromatography in recent years has become a routine technique for the separation of enantiomers (Wang and Ching, 2004; Santos et al., 2004; Yu and Ching, 2003; Xie et al., 2003; Pais et al., 2000). The behavior of a chromatographic system is governed by three basic phenomena (Schulte et al., 1997): (i) the adsorption thermodynamics, described by equilibrium isotherms which give the composition in the stationary phase versus the composition in the mobile phase when equilibrium is reached, at given tem
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