Microstructured Reactors for Rapid Process Development and Scale-Up - Pharmaceutical Technology

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Microstructured Reactors for Rapid Process Development and Scale-Up
The authors discuss a continuous-flow reactor that avoids parallel channels and enables economic plant setup. This article is part of a special issue on API Development, Formulation, Synthesis and Manufacturing.

Pharmaceutical Technology
pp. s32-s36

Slow reactions with a characteristic time of more than approximately 10 min. (i.e., Type C) can be performed in conventional equipment such as static mixers or tube reactors. However, for rapid reactions, all the reactor plates are microstructured because mixing and heat exchange are the dominant factors. For intermediate reactions, the same plate depth is used for the various plate formats, thereby keeping the surface-to-volume ratio constant. The gradual size increase of reactor plates (i.e., the multiscale approach) and appropriate channel geometry allow the MicroReactor to operate at flow rates as high as 600 mL/min.

The modularity and versatility of the single channel and plate-in-series approach allow the development of plates appropriate to a multitude of applications. Lonza designed, manufactured, and applied plates for rapid mixing, gas–liquid dispersions, and multi-injection applications in various projects, thus demonstrating the technology's suitability for various purposes. The right side of Figure 2 shows the individual reactor plates made from Hastelloy C-22 sandwiched between aluminum plates with high thermal conductivity, a design that yields a compact reactor. In this way, the thermal fluid layer is not directly fixed onto the reactor plates, thus allowing for cost-effective manufacturing, as well as quick and easy adaptation to various reaction conditions. The overall reactor is robust, allows high flow rates of the heat exchange fluid, and can sustain pressures higher than 100 bar on the reaction side.

In many reactions, especially with viscous systems and low-temperature applications, the pressure drop may become important at high flow rates. In addition, the mixing zone often is the plate section that consumes the largest pressure drop. Consequently, an enlargement of mixer elements at higher flow rates drastically reduces the overall pressure drop. In general, no loss of performance is observed as long as the same energy-dissipation rate in the mixing zone is maintained. Thus, the mixing zone is the only scaled factor that is considered in this reactor technology, and it must be properly designed and adapted. It is essential to operate a microreactor with one single channel and completely avoid device parallelization to scale up processes successfully from laboratory to pilot scale.

The stepwise scale-up of the plates is accompanied by a stepwise scale-up of the channel cross section, leading to a scaling factor of approximately 1.4 between each two steps. For example, the typical hydraulic diameters of the mixing channel in the A6 reactor plate are 0.35 and 0.5 mm. The A5 reactor plate therefore contains mixing-channel structures with typical diameters of 0.7 and 1.0 mm. Larger plates are scaled up accordingly, thus creating comparable mixing conditions. To gain residence time, the heat-transfer area and internal volume are increased in corresponding steps of connected plates in series. These measures result in a consistent, versatile, and flexible scale-up strategy that completely avoids parallelization over a wide range of flow rates (10).

In addition to reactor size, the operational conditions are changed accordingly. Small reactors such as the LabPlate and A6 Lonza MicroReactor are well suited for projects in process development. They fulfill the needs of early-phase studies in a consistent and straightforward manner. Larger A5 MicroReactors are suitable for small-scale and pilot-production campaigns.


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