Continuous chiral CPC in practice: Process intensification for voriconazole enantioseparation

A recent study from RotaChrom Technologies shows that continuous chiral separation by centrifugal partition chromatography (CPC) can be achieved for rac-voriconazole while maintaining chiral performance throughout intensification. Starting from an initial batch method, the process was advanced to cyclic continuous stacked injection and finally to continuous multiple-dual mode (MDM) CPC (Continuous CPC) on RotaChrom’s Continuous CPC platform, delivering 99.8% purity, 99.9% ee, 81% isolated yield, and an approximately 25-fold productivity increase over classical resolution (Figure 1.).

Cyclodextrin-mediated chiral recognition in liquid-liquid systems

The separation relies on cyclodextrin-mediated chiral recognition in a fully liquid biphasic system. Cyclodextrins (CDs) act as soluble chiral selectors in the aqueous phase, enabling enantiodiscrimination through selector-dependent partitioning between the two liquid phases. Because the CD selector remains confined to one liquid phase, while the solute can be collected from the other phase, the separation enables straightforward product recovery, a simplified downstream processing, resulting in the lowest possible production cost (cost of good sold, COGS).

From batch to continuous MDM operation

From a process-engineering perspective, the key result is that chiral CPC was intensified stepwise from batch to cyclic continuous and then to continuous operation without loss of the chiral performance required for preparative enantioseparation. The decisive step was the transition to Continuous CPC, a dual-rotor concept based on repeated ascending and descending (ASC/DSC) switching and dual-outlet fraction collection, enabling genuinely continuous chiral separation rather than repeated batch injections.

Productivity and industrial relevance

In the final MDM process, lower-cost high-DS (degree of substitution) RM-β-CD replaced SBE-β-CD while maintaining the partitioning and selectivity required for continuous operation. The resulting productivity reached 6.0 g·L⁻¹·h⁻¹, corresponding to an approximately 7.5-fold increase over cyclic continuous operation and an approximately 25-fold increase over classical resolution. These results position continuous chiral CPC as a technically feasible and industrially relevant route for intensified enantioseparation.

Reference:
Kiss, A.; Rutterschmid, D.; Muráth, S. Scalable Enantioseparation of rac-Voriconazole by Centrifugal Partition Chromatography: Process Intensification Leading to Continuous Operation. Separation and Purification Technology 2026, 137728. DOI: 10.1016/j.seppur.2026.137728.