(624e) Development of Novel in-Line Purification Operations for Flow Chemistry and Continuous Pharmaceutical Manufacturing

Capabilities in terms of flow chemical processes and continuous manufacturing for fine chemical and pharmaceutical sectors have seen rapid innovation in the past 20 years. This has provided scope for significant process intensification, new modes of supply and has been a facilitator for scale up of novel reaction modalities such as photochemistry.

Despite significant development in the field of continuous crystallization for pharmaceutical applications over the past decade it remains a relatively challenging operation to design and operate for the purpose of intermediate purification. Intermediated purification via continuous crystallization has the requirement to handle supersaturated streams with long residence times, transfer slurries, filter, in some cases convey wet filter cake, wash, and dissolve for further processing. As such, conventional continuous crystallizers cannot easily fulfill the workhorse role for intermediate purification and solvent swapping as batch crystallization in pharmaceutical synthesis. Batch synthetic routes often define “steps” by the intermediate isolations, which provide operational flexibility and offer significant intermediate purification, allowing each step to start with ideal conditions. It is therefore potentially desirable to maintain the flexibility of batch crystallization/purification in telescoped, integrated continuous routes to meet the high-purity specifications for APIs.

To provide this capability in multi-step telescoped continuous synthesis a number of novel continuous operations have been proposed, prototyped, and demonstrated with the needs of relatively small scale, multistep pharmaceutical and organic synthesis operations the focus of the design. This presentation will focus and performance of these operations: Continuous Spatially Distributed Diafiltration¹, Parallel Agitated Bed Crystallization², Continuous Spatially distributed Distillation and Concentric Annular liquid-liquid extraction³. Example deployments of the purification strategies in integrated continuous flow manufacturing of complex chemical products such as active pharmaceutical ingredients will be presented and discussed.

Acknowledgements:

This publication is supported by Science Foundation Ireland (SFI) through; SSPC, The SFI Research Centre for Pharmaceuticals, co-funded under the European Regional Development Fund under grant number 12/RC/2275_P2. I-Form, the Science Foundation Ireland Centre for Advanced Manufacturing, co-funded under the European Regional Development Fund under grant number (16/RC/3872) and Enterprise Ireland (IP20160474).

References:

1. Khan, Z., Long, X. Casey, E., Dowling, D. , Ferguson, S. Development of Continuous Spatially Distributed Diafiltration Operations, React. Chem. Eng., 2023. (in press).
2. Stocker, M.W.; Harding, M.J.; Todaro, V.; Healy, A.M.; Ferguson, S. Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing.Pharmaceutics 2022, 14, 1058. https://doi.org/10.3390/pharmaceutics14051058.
3. Matthew J Harding, Bin Feng, Rafael Lopez-Rodriguez, Heather O'Connor, Denis Dowling, Geoff Gibson, Kevin P Girard, Steven Ferguson. Concentric annular liquid–liquid phase separation for flow chemistry and continuous processing. React. Chem. Eng., 2021,6, 1635-1643. https://doi.org/10.1039/D1RE00119A