Supercritical fluid chromatography and steady-state recycling: phase appropriate technologies for the resolutions of pharmaceutical intermediates in the early drug development stage.

The use of phase appropriate technologies is critical for efficiently moving drug candidates forward in the early stages of drug discovery and development. Phase appropriate purification technology develops the analytical method and subsequently scales up the method and turns the sample around quickly (Kennedy et al., J Chromatogr A 2004; 1046:55). In this article, separation results and conditions from supercritical fluid chromatography (SFC), high-performance liquid chromatography (HPLC), and steady-state recycling (SSR) for the resolutions of three pharmaceutical intermediates in the early stage of the drug development are discussed. The first study used SFC and SSR to separate an impurity for a Good Manufacturing Practice (GMP) campaign. The analytical method development and scale-up conditions are discussed. Productivity, solvent usage, and sample solubility under SFC and SSR conditions are also compared. The second study compared SFC to batch HPLC in separating a diastereomer. Due to higher separation efficiency, SFC was able to resolute multiple peaks. The third study involved the addition of dichloromethane as a co-solvent in SFC purification--improving sample selectivity and solubility. From the separation results of these purifications, SFC and SSR are clearly phase appropriate technologies in the early drug development stage.

Yan TQ ，Orihuela C ，Preston JP ，Xia F ... -  《-》

Rapid and high throughput separation technologies--steady state recycling and supercritical fluid chromatography for chiral resolution of pharmaceutical intermediates.

Yan TQ ，Orihuela C 《JOURNAL OF CHROMATOGRAPHY A》

The application of preparative batch HPLC, supercritical fluid chromatography, steady-state recycling, and simulated moving bed for the resolution of a racemic pharmaceutical intermediate.

Yan TQ ，Orihuela C ，Swanson D 《CHIRALITY》

Purification method development for chiral separation in supercritical fluid chromatography with the solubilities in supercritical fluid chromatographic mobile phases.

Gahm KH ，Tan H ，Liu J ，Barnhart W ，Eschelbach J ，Notari S ，Thomas S ，Semin D ，Cheetham J ... -  《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》

Evaluation of flash supercritical fluid chromatography and alternate sample loading techniques for pharmaceutical medicinal chemistry purifications.

Flash chromatography is the preferred approach for small molecule purification in pharmaceutical discovery. This paper will discuss the potential for flash supercritical fluid chromatography (SFC) as an alternative technology for these purifications. It was shown that the high sample loadings seen with flash LC could also be achieved using flash SFC. The dry load injection technique greatly increases the amount of sample that can be applied to a flash SFC column while still achieving separation. Flash SFC has much lower solvent usage and higher purification productivities relative to flash LC. Product concentrations post purification were higher for flash SFC vs. flash LC, reducing the time required to isolate dry product. There still exist a number of technical details to be worked out with flash SFC, mainly around the equipment and column/cartridge technology.

Miller L ，Mahoney M 《-》