Page 85 - Chiral Separation Techniques

3.5 Acceleration of the Discovery Process 61

their ultimate length is limited by the overall pressure drop that can be tolerated by
the system. SMB technology helps to solve both these difficulties [50].
A better solution for preparative columns is the development of separation media
with substantially increased selectivities. This approach allows the use of shorter
columns with smaller number of theoretical plates. Ultimately, it may even lead to a
batch process in which one enantiomer is adsorbed selectively by the sorbent while
the other remains in the solution and can be removed by filtration (single plate sep-
aration). Higher selectivities also allow overloading of the column. Therefore, much
larger quantities of racemic mixtures can be separated in a single run, thus increas-
ing the throughput of the separation unit. Operation under these “overload” condi-
tions would not be possible on low selectivity columns without total loss of resolu-
tion.
Another important issue that must be considered in the development of CSPs for
preparative separations is the solubility of enantiomers in the mobile phase. For
example, the mixtures of hexane and polar solvents such as tetrahydrofuran, ethyl
acetate, and 2-propanol typically used for normal-phase HPLC may not dissolve
enough compound to overload the column. Since the selectivity of chiral recognition
is strongly mobile phase-dependent, the development and optimization of the selec-
tor must be carried out in such a solvent that is well suited for the analytes. In con-
trast to analytical separations, separations on process scale do not require selectivity
for a broad variety of racemates, since the unit often separates only a unique mixture
of enantiomers. Therefore, a very high key-and-lock type selectivity, well known in
the recognition of biosystems, would be most advantageous for the separation of a
specific pair of enantiomers in large-scale production.
Despite continuing progress in the design of new selectors, the process is slow as
it mostly involves a traditional one-selector/one-column-at-a-time methodology.

3.5 Acceleration of the Discovery Process

3.5.1 Reciprocal Approach

The first approach to the accelerated development of chiral selectors reported by
Pirkle’s group in the late 1970s relied on the “principle of reciprocity” [51]. This is
based on the concept that if a molecule of a chiral selector has different affinities for
the enantiomers of another substance, then a single enantiomer of the latter will have
different affinities for the enantiomers of the identical selector. In practice, a separa-
tion medium is prepared first by attaching a single enantiomer of the target com-
pound to a solid support that is subsequently packed into a HPLC column. Race-
mates of potential selectors are screened through this column to identify those that
are best separated. The most promising candidate is then prepared in enantiopure
form and attached to a support to afford a CSP for the separation of the target race-
mate. This simple technique was used by several groups for the screening of various