InCatT’s scale up studies using DoE and kinetics – a powerful combination

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The scale up of a reaction from gram to multi-kilogram scale is not always straightforward and requires crucial knowledge about the reaction. One way of upscaling is to perform One Factor At a Time (OFAT) but this only provides very limited information about the reaction space. More appropriate is the statistical DoE (design of experiment) approach which will also give the interactions between the different parameters and thus can be used to identify the region of the chemical space where the yield and selectivity are optimized.

At InCatT, we believe that upscaling should be performed using a proper DoE to understand the effect of different parameters but also identify kinetic processes such as substrate/ product inhibition and catalyst decomposition/ fouling. Such combined approach is not solely based on end-point analysis but also shows how the reaction behaves during the process. Using our AMTECH SPR16 parallel reactor system we can perform both DoE and kinetic studies on the same set of experiments as the gas uptake curve of each individual reactor is recorded. This unique approach will speed up the upscaling process and also provides the most reliable results.

Application of DoE at InCatT

In the framework of InCatT’s’ own catalyst development, we sought to optimize the hydroformylation reaction of a bis-alkene into a dialdehyde. Among the different parameters that can have an influence on the reaction we decided to investigate the following factors:

• Rh content
• Pressure of syngas
• Temperature
• Ligand/Rhodium ratio

For the purpose of upscaling, we decided to focus on optimizing the yield of aldehyde and minimizing higher-ends which are side products of the reaction. A center point (i.e. point at the middle of the range for each parameters) was added to the design to check for discrepancy over time and assess the error in the response. This procedure allows for a higher reproducibility of the process. The non-linear responses are clear from the graph below and shows the strength of the DoE approach.

The DoE revealed that the temperature was the most important factor on the yield while the ligand/Rh ratio had the strongest influence on the formation of higher end products. In addition, the recorded gas-uptake curves show that the two hydroformylation steps show different kinetics. From a safety point of view, the rate (exothermicity) of the first step needs to be controlled in the upscaling study. Eventually the process was designed to run efficiently using just 30 ppm rhodium catalyst loading and provides an economically viable process.

Scale up of the reaction

With the data in hand, the reaction can be smoothly scaled up in InCatT’s 20 Liters Buchi Kiloclave. The high control of reaction temperature, stirring speed allows for a smooth transfer from gram to kilogram quantities within 2-3 weeks timeframe. Again, the gas-uptake can be recorded and can be compared to the kinetic data obtained from the scale-up study proving a feedback to the upscaling process.

Our Buchi Kiloclave 316SS can be pressure up to 80 bar and a Huber thermostat allows for the precise control of the reaction’s temperature in the range -50 to +170°C.

In summary, our procedure for the scale up of reaction consists of a DoE followed by the scale up of the reaction using a 20L Kiloclave and is perfectly adapted for the development of reaction to multi-kilogram batches of products with high reproducibility and affording high quality products. Our team is ready to work with you on the development of your products on multi-kilogram scale. For more information, contact us at info@incatt.nl .

About InCatT (www.incatt.nl): InCatT B.V. is a company specialized in catalyst screening and catalyst development from initial catalyst-lead finding to process optimization. Over the years we have worked with different industries ranging from Flavor & Fragrance, Bio-based industry, Pharmaceutical and Bulk chemical industry to solve their most challenging projects.