(426d) Efficient Process Development in the Micromixing-Mesomixing Space: The Bourne Protocol and Beyond

Reaction and crystallization processes often need to balance competing rates in order to achieve the desired results. Mixing can affect certain rate processes, so understanding the role of mixing is a critical part of process development and scaling. Process developers in the chemical and pharmaceutical industries need efficient ways to understand how mixing matters to their processes.

Since it was introduced in 2003, the Bourne Protocol has been used to efficiently understand the effect of impeller speed, feed time, and feed location on semi-batch or gradual-addition processes. Bourne’s simple experimental plan creates a framework to understand if micromixing (mixing at the molecular or particle length scale) or mesomixing (mixing at feed plume length scale) or macromixing (mixing at the length scale of the vessel) matters in a process. Applications and enhancements to the Bourne Protocol have been discussed in a variety of venues over the past decade (see References).

Most recently, we obtained more appropriately visualized regions of acceptable process performance by plotting Bourne Protocol results in a micromixing-mesomixing space (Sarafinas, 2019). That study looked at examples from the literature and showed how regions of different process failures could be characterized in the micromixing-mesomixing space, enabling improved and efficient understanding of the acceptable process operating window for scale-up or scale-down. There are many potential undesirable process responses that can be affected by mixing: low yield or conversion, poor selectivity, unacceptable purity, unmanageable particle size, poor crystal morphology, inappropriate polymorph, etc. Understanding how a process responds to different levels of micromixing and mesomixing can enable more successful scaling, suggest potential process improvements, and speed troubleshooting of industrial processes.

This paper continues the exploration of the micromixing-mesomixing space to characterize our processes. Beginning with how to apply the Bourne Protocol to efficiently show how mixing matters in a process, we explore how process practitioners can expand the Protocol to better understand their process for scaling (up or down) in development and troubleshooting. This approach results in achieving more robust processes and more optimal equipment designs, more quickly. Further literature examples and some new examples will be shown.

References:

Bourne J.R., “Mixing and the Selectivity of Chemical Reactions”, Org. Process Res. Des. Dev.; 2003; 7(4) pp. 471-508.

Sarafinas, A. “Efficiently Characterize Process Scalability in the Micromixing-Mesomixing Space Using the Bourne Protocol,” AIChE 2019 Annual Meeting, Orlando, FL, November 2019.

Sarafinas, A. “Test Process Mixing Sensitivities Using the Bourne Protocol,” Scientific Update Webinar, 13 November 2018.

Sarafinas, A. “Using the Bourne Protocol to test mixing sensitivities in the lab,” DynoChem Guest Webinar, 8 August 2018.

Sarafinas, A. “A further look at the Bourne Protocol for efficient investigation of mixing sensitivities during process development,” AIChE 2017 Process Development Symposium, Toronto, Canada, June 2017.

Sarafinas, A. and C.I. Teich in Kresta, S.M., A.W. Etchels III, D.S. Dickey, V.A. Atiemo-Obeng, Advances in Industrial Mixing: A Companion to the Handbook of Industrial Mixing, John Wiley and Sons, 2016.

Teich, C.I., A. Sarafinas, P.M. Morton, AIChE 2010 Annual Meeting, Salt Lake City, UT, November 2010 (2 papers):

• “Can this process be saved? A search for understanding using the Bourne Protocol and advanced process development tools”
• “Taking the min to the max: a case study in small scale process development using on-line reaction calorimetry and in-situ particle characterization”