The Impact Of Chiral Supercritical Fluid Chromatography In Drug Discovery: From Analytical To Multigram Scale

By: Dauh-Rurng Wu, Leslie Leith, Balu Balasubramanian, Todd Palcic, and David Wang-Iverson

A significant responsibility for the analytical group within Drug Discovery Chemistry at Bristol Myers-Squibb (Princeton, NJ) is the chromatographic purification of chiral compounds, both intermediates and final products, for a wide variety of chemotypes. Initially, the main tool of choice was preparative HPLC. When numbers of requests and amounts of compound requiring chiral purification were relatively low, HPLC was quite adequate for the task. However, as chirality began to play an increasingly important role in medicinal chemistry, so too has the need for increased capacity in chiral chromatographic separations. The requests can range from tens of milligrams for a promising early lead, to tens of grams for key intermediates to be used in library syntheses, to hundreds of grams of an intermediate or final product for preclinical toxicity testing. As the demand increases, especially in the range of tens to hundreds of grams, HPLC-based separations become more and more of a bottleneck due to limitations in flow rate and the need to remove large amounts of solvent from the purified fractions.