Page 33 - Chiral Separation Techniques

8 1 Techniques in preparative chiral separations

technique, often crystallization [11, 94], in order to increase the global productivity
[10].
The type of CSPs used have to fulfil the same requirements (resistance, loadabil-
ity) as do classical chiral HPLC separations at preparative level [99], although dif-
ferent particle size silica supports are sometimes needed [10]. Again, to date the
polysaccharide-derived CSPs have been the most studied in SMB systems, and a
large number of racemic compounds have been successfully resolved in this way
[95–98, 100–108]. Nevertheless, some applications can also be found with CSPs
derived from polyacrylamides [11], Pirkle-type chiral selectors [10] and cyclodex-
trin derivatives [109]. A system to evaporate the collected fractions and to recover
and recycle solvent is sometimes coupled to the SMB. In this context the application
of the technique to gas can be advantageous in some cases because this part of the
process can be omitted [109].
Enantiomeric drugs or intermediates in their synthesis are the compounds most
often purified with this technology and reported in the literature, although many res-
olutions performed in the industry have not been published for reasons of confiden-
tiality. Some of the most recent examples in the field are summarized in Fig. 1-1.

1.3.1.4 Closed-loop Recycling with Periodic Intra-profile Injection (CLRPIPI)

An intermediate approach between HPLC and SMB chromatography, called
“closed-loop recycling with periodic intra-profile injection” (CLRPIPI) has been
described recently [110]. This is a new binary preparative separation technique
whose concept implies the combination of recycling with peak shaving and SMB.
Thus, once the pure fractions of the peaks are collected, the partially resolved frac-
tion is recycled into the column. A new injection of fresh sample is then produced
just between the two partially resolved peaks. The new mixture passes through the
column, at the end of which pure fractions are collected while the partially resolved
fraction is recycled again, and the process is repeated. This is similar to SMB as it is
a binary technique, but it is not continuous. The capital cost of this system is sub-
stantially lower than that of SMB devices but a high productivity is maintained. It
can be a good alternative when the amount of enantiomers to purify is not high
enough to justify the investment of a SMB instrument. Some examples of the use of
this technique in the purification of enantiomers, either by derivatization and sepa-
ration, on a nonchiral column [111], or by direct resolution on a CSP (Chiralpak AS)
[112] can be found in the literature.

1.3.1.5 Countercurrent Chromatography (CCC/CPC)

Countercurrent chromatography (CCC) refers to a chromatographic technique which
allows the separation of solutes in a two-phase solvent system subjected to a gravi-
tational field. Two immiscible liquid phases, constituted by one or more solvents or
solutions, are submitted to successive equilibria, where the solutes to be separated