Productivity and solvent waste in supercritical fluid chromatography for preparative chiral separations: a guide for a convenient strategy

Abstract

The advent of supercritical fluid chromatography (SFC) in the 90s has changed preparative liquid chromatography. SFC is an improved way for separating chiral compounds during drug discovery processes yielding upwards of one hundred grams of pure enantiomers or during clinical trials requiring higher quantities.The need to purify approximately 45 mg of racemic mixture raises concerns regarding processing parameters, including injection volumes and frequency, column size, chromatographic method, and feed composition. In this study, Chiralpak® AD-H amylose tris(3,5-dimethylphenylcarbamate) polysaccharide-based stationary phase columns of various dimensions were investigated for the purification of propranolol using EtOH (+0.3% triethylamine)/CO2 15/85 v/v as the mobile phase. Production rate (mg/h), productivity (kilograms of racemate separated per kilogram of chiral stationary phase per day; kkd), solvent usage (L/g) and environmental factor (E Factor) were calculated for four column sizes for sequence and stacked modes of injection. The parameters were optimized to determine a method yielding high productivity or reduced environmental impact.In the stacked mode of injection, which allows for rapid processing compared with the sequential mode, the shortest column presents the best productivity of 0.176 kkd. A semi-preparative column (30 mm i.d.) yielded the best production rate of 467 mg purified per hour but had the worst environmental impact with an E Factor of approximately 56,414 (due to the solvent volume used during column equilibration). At Column Dilution (ACD) and mixed stream injection mode were also compared to separate 495 mg of propranolol. With ACD injection, 915 mL of ethanol and approximately 48 min were required, whereas with mixed stream injection, 1200 mL of ethanol and 63 min were required.