While chemo-, bio-, and photocatalysis are well-established methodologies, integrating them into continuous flow processes remains still a major challenge. Similarly, there is a shift in pharmaceutical crystallization from isolated batch operation to an integrated element of end-to-end processing. While batch processing dominates due to operational flexibility, continuous flow crystallization offers enhanced batch-to-batch reproducibility, increased control over particle size and morphology, seamless scalability, and superior resource efficiency.
This contribution outlines various strategies for integrating different catalytic methodologies within continuous flow processes, as well as the synergy between continuous crystallization and enabling technologies such as automation, real-time analysis, and process optimization. First, photobiocatalytic applications using cyanobacteria in tubular1 and 3D-printed reactors2 are highlighted. Next, a continuous multistep cascade combining chemo-, photo-, and biocatalysis is detailed, featuring the synthesis of an α-CF3-substituted ketone substituted ketone in a self-designed photoreactor followed by enzymatic ketoreduction to yield chiral trifluoromethylated alcohols.3 The interface between catalysis and particle formation is further extended to a three-step biocatalytic process for polycaprolactone (PCL) production.4 Finally, additive manufacturing for tailored crystallizer designs in cooling crystallization is showcased5, alongside an in-house optical flow cell6 serving as an in-line PAT tool for automated monitoring and process optimization.
1 Valotta, A., Malihan-Yap L., Hinteregger K., R. Kourist R., Gruber-Woelfler H., ChemSusChem, 2022, 15, e202201468
2 Malihan-Yap, L.; Schmedler, L.; Pint, D.; Medipally, H.; Lackner, L.; Fedrigotti, S.; Kargl, R.; Stana Kleinschek, K.; Kourist, R.; Gruber-Woelfler, H. ACS Sustainable Chem. Eng. 2026 14 (14)6599–6612,
3 Valotta A., Maderbacher J., Stelzer D., Reiter T., Kroutil W., Gruber-Woelfler, H., Chemical Papers, 2024, 78, 7973-7986
4 Valotta, A., Stelzer, D., Reiter, T., Kroutil, W., Gruber-Woelfler, H., React. Chem. Eng., 2024, 9, 713-727
5 Nys N., Koenig M., Neugebauer P., Jones M.J., Gruber-Woelfler H., Org. Process Res. Dev, 2023, 27, 1455 – 1462
6 Soritz S., Nys N., Thierrichter M., Buchgraber L., Amering R., Neugebauer P., Gruber-Woelfler H., Org. Process Res. Dev., 2024, 28, 3940–3949