That said, many of the molecules we make are on the greasy side. GDB-17, Jean-Louis Reymond’s recent computational enumeration of small molecules with 17 or fewer heavy atoms, reveals that most potential molecules tend to be much more polar than similarly sized compounds that have actually been made. One likely reason for this is that purifying highly water-soluble molecules is difficult; it’s hard to wash away inorganic reagents, and they often stick to the normal silica gel that chemists use to purify conventional molecules. Reverse-phase HPLC is useful, but can be tedious and low throughput.
In a recent issue of Drug Discovery Today, Andrew Hobbs and Robert Young of GlaxoSmithKline provide practical tips on using reverse-phase flash chromatography as an alternative to HPLC. They report working at scales from milligrams to tens of grams and are able to separate some very polar molecules. There’s a lot of good stuff in this paper on choosing columns, solvents, and loading techniques. A lot of these details get pretty nuanced, so it’s nice to have them in one place. If you’re trying to isolate hydrophilic molecules, definitely check it out.