Page 283 - Chiral Separation Techniques

262 10 The Use of SMB for the Manufacture of Enantiopure Drug Substances: From …

control can all be used to control outlet flow rates. Our experience led us to the
design of a system using a recycling pump, which is fixed with respect to the
columns as shown in Fig. 10.3a (reliability, minimum number of valves). To use
pumps instead of valves to deliver the flowrates, and to counterbalance the effect of
the recycling pump by the use of an asynchronic shift of the inlet/outlet lines.

10.3.2 Operating Conditions

The steps when designing a SMB which would allow one to process a given amount
of feed per unit time have been described in detail [46, 57]. The procedure described
was based on modeling of nonlinear chromatography. The procedure is rigorous,
versatile and mainly requires the determination of competitive adsorption isotherms.
If the adequate tools and methods are used, the procedure is not tedious and requires
less work than is sometimes claimed. The procedure is briefly described below.

10.3.2.1 Step A: Acquisition of Relevant Physico-Chemical Parameters

In order to determine rigorously the process parameters, a few relevant parameters
are to be experimentally determined on a laboratory scale column.

Equilibrium adsorption isotherms: It would be impossible to design a distilla-
tion unit without knowledge of the boiling points and liquid-vapor equilibrium. Sim-
ilarly, the calculation of chromatographic processes requires the knowledge of the
partition of the solutes between the liquid and the solid phases at a given temperature
at equilibrium (adsorption isotherm). In the case of a multicomponent mixture, there
is usually a competition between the various compounds for the accession to the
adsorption sites. Consequently, the concentration of a given species on the station-
–
ary phase C ; does not only depend on C but on all liquid phase concentrations. Each
i i
adsorption isotherm is a relation of the following type:
C = f C C …) (3)
,
(
,
i
2
i
1
1
The adsorption isotherm becomes linear at low concentrations :
C = K C i (4)
⋅
i
i
The knowledge of these adsorption isotherms allows quantification of the respec-
tive affinity for the stationary phase with respect to the different solutes. Many dif-
ferent isotherm equations have been described in the literature, and experimental
methods allowing their determination are reviewed by [58]. As a first approximation,
modified competitive Langmuir isotherms can often he used:
1 Note that the initial slope of the adsorption isotherm can be easily obtained from the knowledge of the retention time
1− ε


1+
associated to a small injection performed on a column, as this retention time is given by: t = t · where
⋅K
R o  ε 
t = ε ·V/Q is the “zero-retention time” based on the external bed porosity ε (commonly, ε is about 0.36–0.4).
0