Evaluation of non-traditional modifiers for analytical and preparative enantioseparations using supercritical fluid chromatography

Preparative SFC is rapidly becoming the preferred separation technology for enantioseparations in pharmaceutical discovery. Traditional SFC modifiers for chiral resolutions include methanol, ethanol, isopropanol and occasionally acetonitrile. Under preparative conditions poor racemate solubility in these solvents can lead to poor peak shape and low purification throughput. This paper discusses the applicability of mixtures of non-traditional modifiers such as dichloromethane and tetrahydrofuran with methanol and immobilized chiral stationary phases (CSPs) for the routine analytical and preparative enantioseparations of pharmaceutical racemates. It was shown that the addition of dichloromethane or tetrahydrofuran did not result in lower average selectivity for the analytical separation of a series of racemates, but for individual racemates there were instances of drastic increases and decreases in selectivity relative to methanol modifier and coated CSPs when non-traditional modifiers and immobilized CSPs were used. While the use of methanol/dichloromethane modifier mixtures with immobilized CSPs was not shown to be as universal compared to traditional modifiers and coated CSPs, the use of methanol/dichloromethane modifier mixtures with immobilized CSPs was shown to improve purification throughput drastically for racemates with poor methanol solubility.

► Dichloromethane and tetrahydrofuran were evaluated as SFC modifiers.
► Comparisons were made to traditional SFC modifiers such as methanol.
► Non-traditional modifiers can result in drastic changes in selectivity.
► Use of dichloromethane/methanol modifier is useful for poorly soluble racemates.