Yang, Y., Ahmed, B. orcid.org/0000-0002-4419-8392, Mitchell, C. et al. (5 more authors) (2021) Investigation of wet milling and indirect ultrasound as means for controlling nucleation in the continuous crystallization of an active pharmaceutical ingredient. Organic Process Research & Development, 25 (9). pp. 2119-2132. ISSN 1083-6160
Abstract
This study compares the use of wet milling and indirect ultrasound for promoting nucleation and controlling the particle size during the continuous crystallization of a hard-to-nucleate active pharmaceutical ingredient (API). Both an immersion and an external wet mill installed on a recirculation loop were investigated. It was found that all methodologies significantly improved the nucleation kinetics, and the effects of key process parameters (e.g., mill speed, temperature, and ultrasound intensity) on particle size were experimentally investigated. A minimum d50 of 27 and 36.8 μm was achieved when using the wet mill and ultrasound, respectively. The effectiveness of wet milling was demonstrated in a three-stage mixed suspension mixed product removal continuous crystallization of the API that was operated continuously for 12 h (eight residence times), achieving a steady state with minimal fouling. Strategies for improving the overall robustness of the setup in routine manufacturing are discussed.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. Published by American Chemical Society. Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
Keywords: | wet milling; ultrasound; continuous crystallization; fouling; mixed suspension mixed product removal crystallizer; crystallization |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Engineering (Sheffield) > Department of Chemical and Biological Engineering (Sheffield) |
Funding Information: | Funder Grant number ENGINEERING AND PHYSICAL SCIENCE RESEARCH COUNCIL EP/P006965/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 24 Nov 2021 18:42 |
Last Modified: | 24 Nov 2021 18:42 |
Status: | Published |
Publisher: | American Chemical Society (ACS) |
Refereed: | Yes |
Identification Number: | 10.1021/acs.oprd.1c00209 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:180845 |