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Continuous Purifications in Multistep Continuous Flow Synthesis of Pharmaceutical Compounds

Róbert Örkényi

Budapest University of Technology and Economics, Department of Organic Chemistry and Technology, H-1521 Budapest, Hungary

RotaChrom Technologies LLC. H-2370 Dabas, Hungary

E-mail: robert.orkenyi@rotachrom.com

The continuous-flow synthesis of active pharmaceutical ingredients (APIs) and their intermediates is actively encouraged by regulatory agencies, not to mention its advantages compared to batch processing.[1–3] However, the continuous manufacturing of the final dosage form of drugs by coupling the synthesis with formulation[4] demands highly pure APIs. Consequently, continuous-flow purification is inevitable in most cases. Nonetheless, continuous synthesis is usually followed by ‘discontinuous’ purification because the number of available options for continuous purification is limited.

The existing methods can be classified as in-line work-up or final product purification techniques, according to the position in a multistep sequence, where they are preferably used.

Rotachrom multistep flow system

In this presentation, flow chemistry challenges and preparative continuous-flow purification techniques are reviewed and discussed in case of APIs, such as Milnacipran, Amitriptyline, Olanzapine, Artemisinin etc… By focusing on the final-product purifications, multiple dual-mode (MDM) centrifugal partition chromatography (CPC) is discussed in detail.[5]

CPC is a counter-current separation technique[6,7] widely used for the purification of natural products, small molecules and biologics, which does not require a solid stationary phase; two non-miscible phases are applied instead; one of them is used as the mobile phase and the other as the stationary phase which is maintained inside the rotating column by the centrifugal force.

Keywords:

continuous purification, continuous-flow manufacturing, multistep synthesis, centrifugal partition chromatography

Publications:

1, R. Örkényi et.al., Angew. Chemie Int. Ed. 201756, 8742–8745.
https://onlinelibrary.wiley.com/doi/10.1002/anie.201703852

2, P. Bana et. al., Bioorg. Med. Chem. 201725, 6180–6189.
https://www.sciencedirect.com/science/article/pii/S0968089616315085

References:

[1]       Z. Brennan, “http://www.in-pharmatechnologist.com/Processing/FDA-calls-on-manufacturers-to-begin-switch-from-batch-to-continuous-production,” can be found under http://www.in-pharmatechnologist.com/Processing/FDA-calls-on-manufacturers-to-begin-switch-from-batch-to-continuous-production, 2015.

[2]       K. Lövei, P. Bana, R. Örkényi, I. G. Túrós, J. Éles, Z. Novák, F. Faigl, Chim. Oggi – Chem. Today 2016, 34, 19–22.

[3]       P. Bana, R. Örkényi, K. Lövei, Á. Lakó, G. I. Túrós, J. Éles, F. Faigl, I. Greiner, Bioorg. Med. Chem. 2017, 25, 6180–6189.

[4]       A. Balogh, A. Domokos, B. Farkas, A. Farkas, Z. Rapi, D. Kiss, Z. Nyiri, Z. Eke, G. Szarka, R. Örkényi, et al., Chem. Eng. J. 2018, 350, 290–299.

[5]       R. Örkényi, J. Éles, F. Faigl, P. Vincze, A. Prechl, Z. Szakács, J. Kóti, I. Greiner, Angew. Chemie Int. Ed. 2017, 56, 8742–8745.

[6]       A. Berthod, in Compr. Anal. Chem. Vol. 38, Countercurrent Chromatogr. Support. Liq. Station. Phase, 2002, pp. 1–397.

[7]       J. B. Friesen, J. B. McAlpine, S.-N. N. Chen, G. F. Pauli, J. Nat. Prod. 2015, 78, 1765–1796.

Continuous Purifications in Multistep Continuous Flow Synthesis of Pharmaceutical Compounds - Rotachrom Technologies LLC.