Methanesulfonic acid in chiral supercritical fluid chromatography: the quest for perfect peaks and the trials of resolution

The increase in complexity of chiral molecules produced in the pharmaceutical industry often results in difficulties when separating stereoisomers in both analytical and preparative scale. Screening chiral selectors, modifiers, and additives is time consuming; however, it is the current go-to solution to solve challenging cases. In this study, methanesulfonic acid (MSA) was evaluated as an additive for the supercritical fluid chromatographic separation of stereoisomers from a series of analogue compounds, using four types of chiral selectors; the results were compared to those obtained from more common additives such as formic acid, trifluoroacetic acid, and diethylamine. All eight compounds were baseline resolved on at least two of the four columns tested when using MSA, and overall MSA gave the highest number of resolved peaks and the most symmetrical peaks, when compared to the use of the other additives tested. As proof of principle, one of the compounds was successfully used for testing the scale up from analytical to preparative separation. Based on the results, MSA showed promise as an additive for the separation of polar species in chiral SFC, without the need for water in the modifier. Though not a universal solution to resolving stereoisomers, MSA could help in cases where resolution is lost due to peak tailing or high retention.