1420
Ind. Eng. Chem. Res. 2006, 45, 1420-1425
SEPARATIONS From Analytical Chromatography to Simulated Moving Bed Chromatography: Resolution of Omeprazole Enantiomers Feng Wei,* Bo Shen, and Mingjie Chen Ningbo Institute of Technology, Zhejiang UniVersity, Ningbo 315100, People’s Republic of China
Enantioseparation of omeprazole was conducted with a chiral simulated moving bed chromatography (SMBC) process. The coated triphenylcarbamate cellulose chiral stationary phase (CSP) was preparared and used as the CSPs in the SMBC, while ethanol was selected as the eluent after several solvents were screened using analytical chromatography. S-Omeprazole with a purity of 96.4% was obtained from the SMBC. A simulated moving bed (SMB) model was used to simulate the SMBC process. The size required for SMBC is small; therefore, the dead volume caused by connection tubes is somewhat large, relative to the column volume. If the dead volume was supposed to be zero, the simulation would be very bad. Two approaches were used to take into account any effects that were due to the dead volume. The simulations match the experimental data well and can effectively validate the given operation conditions. 1. Introduction Simulated moving bed chromatography (SMBC) has been an important technology for the resolution of chiral drugs.1-5 Because it is a continuous process that enables stable and automatic operation, SMBC has significant advantages over batch chromatography, in terms of solvent consumption and productivity. Also, SMBC is possible to achieve high product purities, even though the resolution on a single column is very poor. For an effictive SMBC process, it is important to, first, select a suitable chiral stationary phase (CSP) and a mobile phase, in which there could be a compromise among the separation factor, the capacity factor, and the solubility of solute.2 The other important factor is the determination of optimum operation conditions, such as feed, eluent, and interior flow rates and switching time. Totally empirical approaches are too timeconsuming, expensive, and, in most cases, even impossible; therefore, mathematical models are often used for this task. Different strategies for the simulation have been suggested recently.6-10 Based on the adsorption isotherms and other parameters, the simulation can predict if the desired purity and yield of product can be reached under a given set of operating conditions. However, when the volume of tubes connecting columns is too large, relative to the column volume, some time will be required for the solute to move through these tubes. Thus, the simulation that assumes zero dead volume may lead to unreasonable results,11,12 because the actual moving time could be significantly longer than the modeling moving time, especially when the size of the chromatographic columns is very small. Omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, depicted in Figure 1), is a substituted benzimidazole that inhibits gastric acid secretion by covalently binding to the proton pump (H+/K+ ATPase) at * To whom correspondence should be addressed. Tel: +86-57488229075. E-mail:
[email protected].
the surface of gastric parietal cells and inhibiting the final step in secretion of the H+ ions into the gastric lumen. The omeprazole molecule, which contains a chiral sulfoxide group, consists of S and R isomers at a ratio of 1:1. The preparation of S-omeprazole as the desired active ingredient has been studied extensively. For example, Erlandsson et al.13 have reported poor resolution, using coated triphenylcarbamate cellulose (TPCC) as the CSP and hexane/2-propanol/dimethylamine (80/20/0.1, v/v/v) as the mobile phase through batch chromatography. However, preparation using SMBC has not been reported. In this work, the enantioseparation of omeprazole was investigated with SMBC, using the coated TPCC as the CSP and pure ethanol as the mobile phase, after several solvents were screened by analytical chromatography. The operating conditions of SMBC were optimized to produce high-purity S-omeprazole. A modified model that considered the dead volume8,14 was used to simulate the experimental data, and good results were obtained. 2. Simulated Moving Bed (SMB) Strategies of Modeling The SMBC model used in this study is similar to that proposed by Haag;15 however, the dead volume due to connection tubes was seriously considered. These connection tubes were supposed to be columns packed with inert packings, as shown by the dashed rectangle in Figure 2. Their diameter and voidage are equal to those of chromatography columns, and, hence, the total dead volume of imaginary columns is equal to the entire real dead volume. During each switch interval, the model for component i in column k, based on the linear driving force model, is
∂Ci,k 1 - ∂qi,k ∂Ci,k ∂2Ci,k + ) -uk + DL,i 2 ∂t ∂t ∂Z ∂Z
(1)
∂qi,k ) kf,i(q*i,k - qi,k) ∂t
(2)
where q* is the solid concentration in equilibrium with the liquid
10.1021/ie050529a CCC: $33.50 © 2006 American Chemical Society Published on Web 01/20/2006
Ind. Eng. Chem. Res., Vol. 45, No. 4, 2006 1421
initial conditions for the chromatographic and imaginary column k at the beginning of the nth switch interval; that is,
Figure 1. Structure of omeprazole.
Ci,k(tn ) 0,Z) ) Ci,k+1(tn-1 ) ∆t,Z)
(8)
qi,k(tn ) 0,Z) ) qi,k+1(tn-1 ) ∆t,Z)
(9)
C′i,k(tn ) 0,Z) ) C′i,k+1(tn-1 ) ∆t,Z)
(10)
where tn represents some time during the nth switch interval ∆t. For the first switch interval, we have the following equations of the initial conditions:
Ci,k(t1 ) 0,Z) ) qi,k(t1 ) 0,Z) ) C′i,k(t1 ) 0,Z) ) 0
Figure 2. Scheme of the simulated moving bed chromatography (SMBC) system.
concentration (C), and k is the index of columns, numbered from the first one in zone I. The imaginary columns are packed with inert particles without adsorption abilities; therefore, the model for imaginary column k is
∂C′i,k ∂C′i,k ∂2C′i,k ) -uk + DL,i 2 ∂t ∂Z ∂Z
(3)
Boundary and initial conditions for each column should be given to solve the equations. The relationships between the inlet concentration of column k and the outlet concentration of imaginary columns k - 1 during a switch interval are taken as boundary conditions. Thus, by the mass balance, we have
CFeedFFeed + C′i,k-1(t,L′)Fk-1 Fk (for the inlet concentration of the first column in zone III) (4)
Ci,k(t,0) )
C′i,N(t,L′)FN Fk (for the inlet concentration of the first column in zone I) (5)
Ci,k(t,0) )
Ci,k(t,0) ) C′i,k-1(t,L′) (for the inlet concentration of the other columns) (6) C′i,k(t,0) ) Ci,k(t,L) (for the inlet concentration of all the imaginary columns) (7) After each switch interval ∆t, the inlet and outlet ports are moved by one column in the direction of the fluid flow (as indicated by the dotted arrow in Figure 2); thus, the concentration profile in the chromatographic and imaginary column (k + 1) at the end of the (n - 1)th switch interval are just the
(11)
The model is spatially discreted to obtain ordinary differential equations (ODEs) in the framework of the method of lines.16,17 The convective terms are approximated using five-point biased upwind finite-difference schemes, and the dispersion items are approximated with five-point centered schemes. The ODEs then were solved by the ODE solvers in Matlab. The relative error between the average concentration of each component in the extract and raffinate stream for the successive cycles was used to determine if the steady state is reached. The steady state is supposed to be reached if the relative error is
