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With the aim of exploring the potential of ultra-fast chiral chromatography for high-throughput analysis, the new sub-2 micron Whelk-O 1 chiral stationary phase (CSP) has been employed in supercritical fluid conditions to screen 129 racemates, mainly of pharmaceutical interest. By using a 5-cm long column (0.46cm internal diameter), a single co-solvent (MeOH) and a 7-min gradient elution, 85% of acidic and neutral analytes considered in this work have been successfully resolved, with resolution (Rs) larger than 2 in more than 65% of cases. Moreover, almost a half of basic samples that, for their own characteristics, are known to be difficult to separate on Whelk-O 1 CSP, have shown Rs greater than 0.3. The screening of the entire library could be accomplished in less than 24h (single run) with 63% of positive score. For well-resolved enantiomers (Rs roughly included between 1 and 3), we show that method transfer from gradient to isocratic conditions is straightforward. In many cases, isocratic ultra-fast separations (with analysis time smaller than 60s) have been achieved by simply employing, as isocratic mobile phase, the eluent composition at which the second enantiomer was eluted in gradient mode. By considering the extension and variety of the library in terms of chemico-physical and structural properties of compounds and numerousness, we believe that this work demonstrates the real potential of the technique for high-throughput enantioselective screening.

The extraordinary advancement in developing highly efficient packing materials for liquid chromatography (LC) has only partly touched chiral separations due, in part, to practical problems in synthesis and functionalization of sub-2-µm particles with chiral selectors, and, in part, to the lack of clear understanding of mass-transfer mechanisms in chiral chromatography. However, there is increasing demand for ultrafast chiral separations, mainly from fine chemical and pharmaceutical companies. This review revisits the most important achievements in enantioselective ultra-high-performance LC (eUHPLC) by focusing, in particular, on brush-type chiral stationary phases, as they are the most promising materials for transition from traditional high-performance LC (HPLC) to ultra-high-speed and ultra-high-pressure regimes. We also attempt to predict possible future trends and solutions that will contribute to making eUHPLC a routine technique in analytical laboratories.