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

Project approach for continuous-flow processes

The main goal in laboratory development is to achieve a robust process because chemical systems are often metastable and tend to form deposits that are more or less stable over time. Precipitation or fouling within the channels creates unpredictable pressure drop behavior over the reactor. The reactor technology must facilitate timely and flexible process development and minimize the need to consider chemical engineering during process development. Thus, the use of one single channel, together with robust, pulsation-free high-pressure pumps, ensures correct feed balance and stoichiometry, as well as the ability to clean the reactor during and after operation.

The MicroReactor concept also indicates a certain project-management strategy for converting a batch protocol into a continuous-flow process. The base is a detailed mass balance with stoichiometry, including all starting materials, intermediates, and products, as well as major side products. A preliminary short feasibility study with a LabPlate or A6 MicroReactor indicates the potential advantages of performing a given chemistry in a continuous-flow process. Typical parameters such as concentration and mixing ratios, mixing and residence times, reactor temperature, and pressure can be tested. A decision at the end of each step allows good project control and shortens the time needed to make a decision.

If results are positive, operators can perform a parameter-optimization study to develop a robust process with sufficiently high yield and selectivity. A flexible and modular reactor setup with pumps, sensors, control system, and residence-time loops allows the investigation of a wide range of process parameters and will give a huge amount of data from kinetics and chemistry. These data are important for the design of the final production process. A long run of several hours in the laboratory at the end of the optimization step ensures the achievement of a robust and reliable process that can be scaled up to pilot scale.

The production campaign on pilot or large scale can be performed with the same reactor equipment used in the laboratory, but with longer operation times and appropriate peripheral equipment. The high flow rates typical of production can be tested in the laboratory for a short period to guarantee appropriate reactor performance. This approach enables operators to avoid a parallelization of reactor equipment, including in production campaigns. The approach also provides flexibility and manageable cost scenarios and time limits. In additionally, it avoids the risk of a technology jump from laboratory to production scales.

Scale-up example


Figure 3: Reaction scheme of a two-step reaction, corresponding process scheme with two reactors, and image of the plant setup in a pilot-plant environment. Three feed lines and the MicroReactor (Lonza, Basel) with iced surface (–35 C reactor temperature) are visible. (IMAGE IS COURTESY OF LONZA)
All reactor types displayed in Figure 2 are used frequently in Lonza's laboratories and production environment. A real-case example of a two-step organometallic reaction (i.e., lithium–hydrogen exchange and coupling) demonstrates the scale-up of microreactors. The reaction had three feeds: Feed-1 with substrate, Feed-2 with the first reagent, and Feed-3 with the second reagent. The reaction was stoichiometric and operated at two temperature levels. Feed-1 and Feed-2 were precooled to the cryogenic reactor temperature (i.e., –35 C), and the second reaction was performed without cooling at room temperature. The flow diagram and reaction scheme are depicted in Figure 3.

The first reaction was of Type A with an adiabatic temperature rise of more than 75 C. This reaction was performed in four units: a static mixer, a glass microreactor, and the Lonza A6 and A5 MicroReactors. The second reaction was of Type B and less demanding in terms of heat exchange (ΔT ad < 25 C) and mixing. A microreactor and static mixer performed equally well.

Personnel observed no adequate temperature control within the static mixer for the first reaction. Roughly the entire adiabatic temperature rise was detected at a medium flow rate (i.e., 148 g/min). Many unwanted side products were formed, and yield dropped visibly compared with that at lower flow rates (i.e., 84% versus 89% on average).

The glass microreactor showed a loss of temperature control at high flow rates, but it was not reflected in the product yield. The short residence time also was important for this process.

Lonza's smaller (i.e., A6) and larger (i.e., A5) MicroReactor technology showed equivalent performance. It was possible to operate the A5 reactor at a speed of 237 g/min with a total flow rate higher than 700 g/min for the second reaction by keeping the pressure drop well controlled. A yield of 88% was achieved. A pilot campaign produced 700 kg of isolated material, thus yielding more than 10 m3 of processed solution through the reactor setup. A second campaign was performed to produce more than 2 tons of isolated material. Both campaigns demonstrated the long-term robustness of the process and the reliability of the installed reactor equipment. Further chemical examples from Lonza's experience demonstrate the versatility of the reactor toolbox described with various kinds of chemistry such as phosgene, ketene or diketene, ozone, or the production of nitrogen-containing compounds (5, 10).


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