Determine the amount that can be separated.
The "loading study" step is aimed at determining the maximum loading capacity of the CSP. The study consists of injecting
on an analytical column (4.6-mm diameter X 250-mm long) packed with preparative CSP (typically 16 or 20 μm) an increasing
volume of a concentrated solution of the racemic mixture until the separation is lost (see Figure 2). From these data valuable
information about the behavior of the compound as a function of the concentration is collected. This information is entered
into a computer model which in turn calculates the parameters required to operate an SMB unit. At this point an estimation
of the production rate is obtained and the size of the SMB unit required to produce the desired amount of the single enantiomer
can be calculated.
Figure 2: Example of a loading study. By increasing the volume injected, the peaks change shape according to their equilibrium
isotherm. This information is used to model the SMB process and calculate the throughput. (FIGURE: AMPAC FINE CHEMICALS)
Demonstrate proof of concept.
Simulations are not always perfect, and it is usually a good practice to demonstrate the separation on a small-scale unit.
On such a unit, equipped with columns of 4.6 or 10 mm in diameter, 20–200 g of material can be processed (see Figure 3). This
amount is enough to achieve steady state and obtain a representative sample of the product. The columns can be packed in house
or purchased from the packing manufacturer.
Figure 3: Bench-top simulated moving bed unit, 8 columns of 4.6 mm or 1 cm in diameter. This unit is used for proof of concept.
(PHOTO: AMPAC FINE CHEMICALS)
This step can take 2–4 weeks, which is long enough to evaluate the productivity as well as the robustness and the stability
of the separation. At this stage, chemists can start developing the isolation process post-SMB separation (e.g, crystallization,
solvent exchange, drying).
Scale-up for clinical quantities.
The scale-up from the demonstration run is straightforward. Chromatography processes are scaled up on the basis of the linear
velocity at the particle level (i.e., the flow rate is multiplied by the ratio of the column diameters squared.) For example,
if 50 g of racemic feed can be processed per day on a 10-mm diameter column, then a 50-mm SMB unit can process 1250 g per
day (25X). This is a very easy process to scale-up. As a matter of fact, performances often improve with the diameter of the
columns because of the favorable ratio of column to piping volume.
Following the demonstration step, it is frequent that 5–25 kg are separated using the 8 X 50-mm unit to supply material for
Phase I. This material can be made according to current good manufacturing practices and purified in a matter of weeks. This
work is still conducted on lab-scale equipment, and the overall cost is very reasonable.
Conduct production at pilot scale.
Typically, a campaign involving the separation of 200–500 kg of racemic feed follows the scale-up phase. Normally, this is
to supply material for Phase II or Phase III clinical trials. At this stage, the separation process is well characterized.
The effort is more concentrated in the handling of solvent (recycling, composition adjustment etc.) and the product recovery
(solvent exchange, crystallization, drying, etc.). All these steps are conducted in equipment that is similar to commercial-scale
units. This provides a complete and accurate picture of the final process at commercial scale.