(664d) From Lab to Plant: Effective Mixing and Scale-up Strategies for Semi-Batch Processes in the Pharmaceutical Industry

Mixing plays an essential role in the development and robust scale up of chemical processes. We apply a hybrid approach that integrates lab-scale semi-batch experiments with mechanistic modeling to analyze how mixing affects process outcomes. This methodology has been successfully used to scale-up unit operations in the chemical synthetic route of an investigational small molecule in clinical development.

In the first case study, we investigate the impact of mixing time scales and anti-solvent addition rate on material attributes, such as particle size distribution and residual solvent content, in an anti-solvent crystallization process. We conducted small scale experiments in a 100 mL EasyMax reactor (Mettler-Toledo). The mixing time scales were calculated using Dynochem mixing utilities (Mettler-Toledo). With this scale-down approach, we were able to target and achieve the desired particle size distribution for a crystallization scaled up to a 300 L reactor at a CDMO site.

In the second case study, we investigate a semi-batch macrolactamization reaction. The starting material is added to the reactor containing the coupling reagent on a 100 mL scale. The starting material addition time and agitation rate are adjusted to evaluate the impact on conversion and selectivity. The process design space is further evaluated to successfully scale up the reaction at a CDMO site.

This experimental approach coupled with mechanistic modeling serves as an important tool for characterizing the design space for a process, ensuring safe scale-up, developing an impurity control strategy, and determining process operating parameters to achieve desired material attributes.

References

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2. Janbon, S., et al. Effects of Scale, Equipment, and Operation on Agglomeration during a Reactive Crystallization. Org. Process Res. Dev. 2019, 23, 302-308.
3. Torbacke, T. and Rasmuson, Å. Influence of different scales of mixing in reaction crystallization. Chem. Eng. Sci. 2001, 56, 2459-2473.
4. Sarafinas, Aaron. "Efficient Process Development in the Micromixing-Mesomixing Space: The Bourne Protocol and Beyond." 2020 Virtual AIChE Annual Meeting. AIChE, 2020.