Page 37 - Chiral Separation Techniques

12 1 Techniques in preparative chiral separations

1.3.2 Subcritical and Supercritical Fluid Chromatography

Supercritical fluid chromatography (SFC) refers to the use of mobile phases at tem-
peratures and pressures above the critical point (supercritical) or just below (sub-
critical). SFC shows several features that can be advantageous for its application to
large-scale separations [132–135]. One of the most interesting properties of this
technique is the low viscosity of the solvents used that, combined with high diffu-
sion coefficients for solutes, leads to a higher efficiency and a shorter analysis time
than in HPLC.
As a matter of fact, the main advantage in comparison with HPLC is the reduc-
tion of solvent consumption, which is limited to the organic modifiers, and that will
be nonexistent when no modifier is used. Usually, one of the drawbacks of HPLC
applied at large scale is that the product must be recovered from dilute solution and
the solvent recycled in order to make the process less expensive. In that sense, SFC
can be advantageous because it requires fewer manipulations of the sample after the
chromatographic process. This facilitates recovery of the products after the separa-
tion. Although SFC is usually superior to HPLC with respect to enantioselectivity,
efficiency and time of analysis [136], its use is limited to compounds which are
soluble in nonpolar solvents (carbon dioxide, CO ). This represents a major draw-
2
back, as many of the chemical and pharmaceutical products of interest are relatively
polar.
Although some applications for preparative-scale separations have already been
reported [132] and the first commercial systems are being developed [137, 138],
examples in the field of the resolution of enantiomers are still rare. The first prepar-
ative chiral separation published was performed with a CSP derived from (S)-N-(3,5-
dinitrobenzoyl)tyrosine covalently bonded to γ-mercaptopropyl silica gel [21]. A
productivity of 510 mg/h with an enantiomeric excess higher than 95 % was
achieved for 6 (Fig. 1-3).
Examples with other Pirkle-type CSPs have also been described [139, 140]. In
relation to polysaccharides coated onto silica gel, they have shown long-term stabil-
ity in this operation mode [141, 142], and thus are also potentially good chiral selec-
tors for preparative SFC [21]. In that context, the separation of racemic gliben-
clamide analogues (7, Fig. 1-3) on cellulose- and amylose-derived CSPs was
described [143].

Fig. 1.3. Chemical structures of racemic compounds resolved by SFC.