On the method development of immobilized polysaccharide chiral stationary phases in supercritical fluid chromatography using an extended range of modifiers.

Polysaccharide-derived selectors are often used in the separation of enantiomers by supercritical fluid chromatography (SFC). Their recognition patterns are normally investigated with alcohols and acetonitrile as modifiers. The present paper describes the results of a research program designed by Pfizer and Chiral Technologies Inc. to explore the potential of other solvents (i.e. ethyl acetate, tetrahydrofuran, dichloromethane) in SFC by using a series of polysaccharide-derived supports with broad solvent versatility (CHIRALPAK IA, IB, IC, ID, IE and IF). The contribution of such extended solvent range to the overall success rate, as well as to overcome racemization, solubility and stability issues was confirmed by using standard non-proprietary samples and research molecules. Elution patterns with such lower polarity solvents, compared to alcohols, and the role of the different additives were also investigated.

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.

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

This article discusses the chromatographic resolution of a racemic pharmaceutical intermediate. Preparative batch high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), steady-state recycling (SSR), and simulated moving bed (SMB) were used to resolve a total of 12.2 kg of a racemic pharmaceutical intermediate. In this study, a first batch of 0.8 kg of racemate was separated on the preparative batch HPLC and SFC, and subsequently another 5.9 kg of racemate was separated on the SSR. Lastly, a third batch of 5.5 kg was separated on the SMB. The separation conditions and results of these techniques are discussed. The productivities and solvent costs of SFC versus HPLC are compared. The productivities and solvent costs of SMB, SSR, and HPLC are also compared. The analytical method development and process optimization of these processes are also discussed in this article.

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

The SSR and SFC techniques were used for the enantiomeric resolution of three pharmaceutical intermediates at various sample scales. The separation conditions, the sample purities and yields, the productivities and the solvent consumptions were discussed in three case studies in this paper. In case (I), the SSR process was used for a low selectivity resolution of 2.0 kg of pharmaceutical intermediate. By using this separation process, a productivity of 750 g racemate/kg stationary phase/day was achieved, while solvent usage was minimized ( approximately 200 l/kg racemate). Case (II) pertained to the effectiveness of the SSR process. Productivity using SSR techniques increased by a factor of 4.5, while solvent usage decreased by a factor of 4.1 when compared to the productivity and solvent usage of batch HPLC. Case (III) compared SFC purification to HPLC purification. The SFC process was more effective in terms of an increase in productivity and a reduction in solvent usage. Based on these results, it appears that SSR and SFC are very useful choices at the early stage of the drug development for a high throughput and a rapid turn around of samples.

Resolution of a racemic pharmaceutical intermediate. A comparison of preparative HPLC, steady state recycling, and simulated moving bed.

Preparative HPLC and simulated moving bed (SMB) chromatography were used to resolve significant quantities of a racemic pharmaceutical intermediate. In addition, smaller scale studies using closed-loop recycling and steady state recycling (SSR) were performed so that a meaningful comparison of all these techniques could be made using the same real world separation. A highly optimized, six-column SMB process was clearly the superior technique and was used for the process-scale (247 kg of racemate) resolution. At the more moderate lab-scale (33 kg of racemate and 19 kg of racemate), a frequently used but less optimized eight-column SMB process was used. It was found that SSR was comparable to the lab-scale SMB process in productivity and solvent consumption. Thus, it appears that SSR can be a useful choice at such moderate scales. Finally, at moderate scales when neither SSR nor SMB is available, it was found that acceptable results were obtained with both closed-loop recycling and with a two-step preparative process.