In-situ wet milling for particle size control in continuous crystallization: Expanding the attainable region

• Published in: Chemical engineering science Vol. 300; p. 120542
• Main Authors: Svoboda, Vaclav, Burcham, Christopher L., McClary Groh, Jennifer, Johnson, Martin D., Merritt, Jeremy M., Myers, Steven S., Stout, James R.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 05.12.2024
• Subjects: Attainable regions; Continuous processing; Cooling and antisolvent; Crystallization; MSMPR; Particle engineering; Particle size distribution; Process intensification; Wet milling; Particle size distribution; Attainable regions; Particle engineering; Crystallization; Process intensification; MSMPR; Continuous processing; Wet milling; Cooling and antisolvent
• ISSN: 0009-2509
• DOI: 10.1016/j.ces.2024.120542

[Display omitted] In-situ high-shear wet milling was used to:•Expand the attainable particle size region in an MSMPR cascade.•Produce a significantly narrower particle size distribution.•Intensify the process. Continuous mixed-suspension mixed-product removal crystallizer cascades are robust and proven options for continuous manufacturing. However, when applied to a late-stage drug substance the desired particle size could not be achieved due to rapid crystal growth and slow secondary nucleation kinetics. This necessitated a batch terminal milling operation to achieve particle size control (Johnson et al., 2021). To overcome this and to intensify the process, an in-situ high-shear wet mill was integrated into the continuous equipment train to achieve the target physical properties of the drug substance that met the quality and manufacturability criteria needed for the drug product. This article describes the workflow used to optimize the equipment set and operational parameters. Incorporation of a high-shear wet mill operated intermittently in the continuous drug substance process greatly expanded the attainable particle size region, improved product quality, reduced cycle time, and simplified process development and scale-up compared to the process of batch milling after continuous crystallization. Small scale batch milling experiments were used to characterize milling performance at lab and production scales and inform operational space. Several lab-scale continuous runs were then used to define the process operating space and validate the process parameters necessary to meet the particle specifications of the product. Scale-up of the equipment set for in-situ milling was also demonstrated. This approach was tested at lab-scale on representative material operating for 70 h while changing the particle size of the product in real time. This illustrated the potential of intermittent milling for model-free particle size control.