Rapid optimisation of API crystallisation in a segmented flow reactor with a continuous, variable temperature gradient

Robertson, Karen; Seeberger, Peter H.; Gilmore, Kerry

Abstract

The reproducible crystallisation of small molecules can be difficult due to the myriad of factors influencing crystallisation events and growth as well as the inhomogeneity of traditional approaches. While continuous flow approaches can increase reproducibility in sensitive chemical processes, the controlled formation of solids in flow is technically challenging due to issues with fouling. Further, while one of the simplest means of inducing crystallisation is the slow decrease of temperature, smooth temperature gradients across a long distance have not been achievable in flow reactors. Herein we disclose a segmented flow reactor employing a controlled continuous temperature gradient that allows for continuous crystallisation at temperature profiles ranging from 80 to 15 °C. The temperature gradient can be altered (input and output temperatures independently) during operation to rapidly optimise crystallisation conditions. Fine control of crystallisation conditions for the reproducible growth of single paracetamol crystals serves to illustrate the potential of this continuous crystallisation method.

Citation

Robertson, K., Seeberger, P. H., & Gilmore, K. (2022). Rapid optimisation of API crystallisation in a segmented flow reactor with a continuous, variable temperature gradient. Reaction Chemistry and Engineering, https://doi.org/10.1039/d2re00183g

• Journal Article Type: Article
• Acceptance Date: Sep 20, 2022
• Online Publication Date: Sep 21, 2022
• Publication Date: Sep 21, 2022
• Deposit Date: Oct 26, 2022
• Publicly Available Date: Oct 26, 2022
• Journal: Reaction Chemistry and Engineering
• Print ISSN: 2058-9883
• Electronic ISSN: 2058-9883
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1039/d2re00183g
• Keywords: Fluid Flow and Transfer Processes; Process Chemistry and Technology; Chemical Engineering (miscellaneous); Chemistry (miscellaneous); Catalysis
• Public URL: https://nottingham-repository.worktribe.com/output/12036109
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2022/RE/D2RE00183G