Using a molecular diversity model to choose test probes from a chemical library, guest authors Ray McClain and Matt Przybyciel
characterized 12 supercritical fluid chromatography (SFC) achiral stationary phases with 60 compounds from four chemical classes
— amines, amides, alcohols and carboxylic acids — to establish guidelines for the rational selection of the optimum stationary
phase for separations. Efficiency, selectivity and peak shape were used as the evaluation criteria.
The use of supercritical fluid chromatography (SFC) as a separation technique continues to grow (1–6). SFC offers a number
of advantages to chromatographers for both analytical and preparative separations. These advantages include the "green" aspect
of using carbon dioxide as a mobile phase, the ease of isolation of purified components from preparative separations, and
decreased analysis times because of the high diffusivity and low resistance to mass transfer encountered in SFC. For many
years, SFC has proven extremely useful for chiral preparative separations (7–12). Achiral SFC separations utilize stationary
phases from "normal-phase" high performance liquid chromatography (HPLC), such as unmodified silica, diol, amino and cyano
(13). During the past 10 years, a number of commercially available stationary phases have been developed specifically for
SFC applications (14). However, not all of these columns are well-suited for all structural classes of compounds, presenting
a bottleneck when arrays of chromatographic data must be acquired and interpreted to find a suitable match. Recently, chemometric
approaches have been developed to predict retention and selectivity for a variety of stationary phases used for SFC (1,15–19).
These approaches can be a useful tool for column selection with a particular set of analytes. Despite this, many chemometric
approaches don't provide any guidance regarding peak shapes of the separated components. In addition, the chemometric models
generally require physical or chemical information for the compounds of interest, such as excess molar refraction, dipolarity
and polarizability, hydrogen bond donor (acidity), hydrogen bond acceptor ability (basicity) and McGowan's volume (19); for
many analytes of interest, information such as this is not readily available.
Separations of Chemical Libraries
Many pharmaceutical laboratories are involved in the characterization and purification of large chemical libraries that are
employed in high-throughput screening for new drug development. These libraries are particularly challenging in the chemical
diversity that they represent (20,21). Library molecules may contain a variety of different functional groups and may differ
substantially in properties such as pK
a
, hydrophobicity, molecular weights and molecular surface area, to name just a few. SFC–mass spectrometry (MS) has been shown
to be a useful tool for the purification of chemical libraries (3,20,22–25); however, the selection of the appropriate stationary
phase for the separation of chemicals in the library carrying out these separations can be difficult, especially with the
variety of SFC stationary phases that have recently been commercialized (14). Furthermore, most chromatographers performing
purifications prefer to avoid using mobile phase additives, such as amines, because it complicates compound recovery and can
lead to product degradation. This poses a unique challenge for chromatographers performing purifications on a vast array of
molecules. Chromatographers separating chemical libraries would like chemical compound selectivity, as well as good peak shapes,
to optimize their purifications without the use of mobile phase additives. Ideally, one would like to have a set of screening
stationary phases that the chromatographer could employ to separate a wide variety of molecules containing various functional
groups. To this end, we would like to identify a limited set of stationary phases that can separate a wide variety of molecules
and maintain good peak shape without mobile phase additives. 
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