(721c) Scaling Down to Scale up: Advances in Using the Bourne Protocol and Optimization in the Micromixing-Mesomixing Space

Reaction and crystallization processes often need to balance competing rates 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. 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. 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 and Sarafinas, 2020). Those studies 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. In addition, we showed approaches to make practical choices of small-scale operating conditions to mimic the micromixing and mesomixing space for large scale vessels.

The Bourne Protocol was a popular topic in the AIChE 2020 Virtual Annual Meeting, as four papers discussed different applications and advances (Sarafinas, 2020; Ataíde et al, 2020; Baudouin et al, 2020; Jordan et al, 2020). Two of the papers at the AIChE 2020 Virtual Annual Meeting discussed the importance of appropriately characterizing the local energy dissipation and local velocity in the vicinity of the feed for the proper application of the micromixing-mesomixing operating space (Sarafinas, 2020 and Jordan et al, 2020).

This paper continues the exploration of the micromixing-mesomixing space to characterize our processes. After giving a quick review on how to apply the Bourne Protocol to efficiently show how mixing matters in a process, we explore how differences between estimates of local energy dissipation and local velocity can affect proper characterization of the micromixing-mesomixing operating space. We will look at how good is “good enough” for a screening study, and how our information needs change when working on a troubleshooting or optimization study. Further literature examples and some new examples will be shown. We will consider how process practitioners can expand the Protocol to better understand their process for scaling. This approach results in achieving more robust processes and more optimal equipment designs more quickly, which should enable faster commercial success.

References:

Ataíde, F., J. Sardinha, R. Mendonça, E. Gonçalves, A. Monteiro, and S. Nascimento, “Coupling Reaction Kinetics, Calorimetry and Mixing Studies for Successful Scale-up of Exothermic Reactions,” AIChE 2020 Annual Meeting, Virtual, November 2020.

Baudouin, O., E. Clavel, S. Dechelotte, and B. Wincure, “Modeling for the Scale-up of Processes: Illustration on the Aspects of Heat Transfer for a Batch Reactor,” AIChE 2020 Annual Meeting, Virtual, November 2020.

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

Jordan, C., C. Marton, Y. Agustinus, C. Wilbert, J. Perona, K. Ragazzo, and B. Holloway, “Scaling Down a Reactive Crystallization using Various Mixing Models,” AIChE 2020 Annual Meeting, Virtual, November 2020.

Sarafinas, A., “Efficient Process Development in the Micromixing-Mesomixing Space: the Bourne Protocol and Beyond,” AIChE 2020 Annual Meeting, Virtual, November 2020.

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”