Continuous Flow Process for Preparing Budesonide

Researchers at the CSIR in India have published a paper in the Journal of Flow Chemistry titled "Continuous flow process for preparing budesonide", involving the Coflore ACR flow reactor.

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The abstract of the paper states:

Budesonide, a glucocorticosteroid, is used as anti-asthmatic drug that became generic in 2019. Existing preparation methods of budesonide require utilization of corrosive acids and involve expensive purification process. Thus, a new cost-effective continuous flow process for the synthesis of budesonide which belongs to the class of 16,17 acetals of pregnane core, is discussed in the present research findings. Flow reactor parameters such as flow rate, temperature, residence time, solution volumes, anti-solvents and reactor frequency are subjected to investigation on the preparation of molar ratio of budesonide epimers. Further, the suitable parameters entail for obtaining the desired molar ratio of epimers. In another aspect, particle size optimization studies are also performed to get the desired budesonide solid product. A continuous flow process for preparation of budesonide is identified from the present research investigation which can be readily transferred to industrial scale up.

The schematic view and continuous flow synthesis of budesonide
The schematic view and continuous flow synthesis of budesonide, taken from the publication.

AM Technology spoke to Dr Manjinder Singh, first author on the publication, to discuss the research in more detail. Currently, the preparation of budesonide via batch methods has several undesirables, such as requiring costly purification steps to yield the desired ratio of epimers as required by regulatory bodies and effluent generation. Given the importance of budesonide as a treatment for asthma and other conditions affecting the respiratory system, demand for the drug is anticipated to increase over the coming years and therefore there is industrial interest for improved manufacturing processes.

As part of the work, researchers set out to develop a continuous flow process for the synthesis of budesonide that offered significant benefits over the pre-existing batch processes. The group focused on the reaction of 16α-Hydroxy Prednisolone (16-HPS) in HBr with butyraldehyde, with the handling of HBr at industrial scale in batch requiring significant hazard mitigation.

Initial reaction parameter screening was performed with a variety of flow reactor technologies before the researchers settled on the Coflore ACR as the preferred reactor taken forward for final experimental runs, due to the scalability offered by Coflore systems. A scheme detailing how the Coflore ACR was set up to react compound 16-HPS in HBr and butyraldehyde to form budesonide is shown in Figure 1. As can be seen in figure 1, both reagents were fed into the first cell of the ACR, with water introduced at the ACR outlet to quench further reactivity followed by filtration, purification and HPLC analysis. The optimised reaction residence time was determined to be 5 minutes, showing significant improvements compared to a reaction time of 3 hours via batch methods. Furthermore, the researchers were able to control the reaction conditions to yield the desired ratio of epimers as would be required by regulatory bodies.

The Coflore ACR is a bench-top flow reactor for developing scalable flow chemistry solutions in a laboratory environment. The ACR is ideal for establishing and developing continuous processes prior to scale up, or when only limited quantities of material are available or required. Processes developed on an ACR platform have a straight-forward path to scale up via the larger volume Coflore ATR and Coflore RTR pilot and production scale flow reactors.

The open access paper is available for download from the following DOI link: