Compact reaction-module on a pad for scalable flow-production of organophosphates as drug scaffolds


Synthesis of chemical compounds in chemical and pharmaceutical industries have undergone significant improvements, the latest being the development of continuous micro-reactors. This simple and cost-effective technology has offered numerous advantages, including enhanced process safety, and rapid mass- and heat transfer capabilities desirable for scaling up the production levels. Despite the high transfer rates in the microreactors, achieving high throughput (time taken to convert raw materials into final desired products) has remained a challenge. This can be attributed to numerous challenges such as high cost of stacking reaction units. Moreover, maintaining identical operation conditions in all the reaction units, necessary to enhance the overall reactor performance, is rather complicated and required complex control systems.

The modular feature of microreactor facilitates the scaling-up because the throughput can be increased by simply numbering-up microreactor units in parallel with appropriate channel size. Furthermore, the scale-up microreactor system can be operated at the same conditions as optimized in a single microreactor, without complex redesign or reoptimization unlike the conventional batch process. Equipped with this knowledge, a team of researchers at the Pohang University of Science and Technology:  Se Jun Yim (Ph.D. Student), Dr. Bandaru T. Ramanjaneyulu, Shinde Vidyacharan, Yu Dong Yang (Ph.D. Student), Professor In Seok Kang, and Professor Dong-Pyo Kim developed a compact reaction-module on a pad (CRP) for enhanced throughput flow-production of drug precursors. Their work is currently published in the research journal, Lab on a Chip.

In their work, the research team adopted two strategies: fast synthetic methodology and three-dimensional micro-flow circuits integration, sufficient to deliver adequate drug products in a small footprint. The system generally comprised of nine patterned polyimide films and 16-sets of numbering-up microreactors. Lastly, they demonstrated the scale-up production capability of this newly developed CRP system by using it to synthesis α-phosphonyloxy ketone, a type of drug scaffold.

The authors reported that the integrated micro-flow circuits efficiently achieved an even flow distribution to all the 16 reactor units, thus significantly enhancing the system production throughput. Notably, complete mixing of the feeds was achieved within milliseconds while a fully synthesized product was obtained within seconds. Similarly, the fabricated system was successfully used to demonstrate high throughput single-step production of organophosphates with a retention time of 3.93s. For instance, under the pre-optimized operation conditions, 19.2 g h-1 drug precursor (α-phosphonyloxy ketone) was obtained for a 66% yield. Moreover, this approach could be applied to other drug precursors.

In summary, the study by Pohang University of Science and Technology scientists successfully developed a simple and cost-effective compact numbering-up microreactor system for scalable continuous-flow production of drug precursors. The simple stack-up of the microflow layout increased the production throughput by increasing the reaction volume. Thus, single-step synthesis of α-phosphonyloxy ketone could be achieved within seconds. Furthermore, the approach demonstrated the ability to synthesis several drug precursors. In a statement to Medicine Innovates, Professor Dong-Pyo Kim, corresponding author said their study provides important insights that would result in large-scale production of pharmaceutical and chemical products efficiently and cost-effectively.


Yim, S., Ramanjaneyulu, B., Vidyacharan, S., Yang, Y., Kang, I., & Kim, D. (2020). Compact reaction-module on a pad for scalable flow-production of organophosphates as drug scaffolds. Lab on a Chip, 20(5), 973-978.

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