S-Naproxen is a pain killer that was shown to be 35 times more efficient than the R enantiomer. It can be purified by preparative supercritical fluid chromatography (SFC) using the chiral phase Whelk-O1 eluted with mixtures of a light alcohol and carbon dioxide. The different methods used in HPLC for the determination of equilibrium isotherms are discussed and their results compared. The influences of the column temperature, the outlet pressure, the flow rate, the nature and the concentration of the modifier are explained. In contrast with the situation in HPLC, the parameters of equilibrium isotherms in SFC depend strongly on the local pressure, hence vary significantly along the column. Once all these parameters have been acquired, it becomes possible to optimize the experimental conditions for maximum production rate of one enantiomer or for the optimum value of any other objective function. The elution band profiles recorded under optimum conditions are compared with those predicted by the calculations. Finally, these results explain why the production rate is higher in preparative SFC than in preparative HPLC and how much higher it is.