Researchers develop novel technology to automate the production of active pharmaceutical ingredients

The discovery and development of new small molecule compounds for therapeutic use requires an enormous amount of time, effort and resources. A team of researchers from the National University of Singapore (NUS) has given conventional chemical synthesis a new twist and developed a way to automate the production of small molecules suitable for pharmaceutical use. The method can potentially be used for molecules that are typically manufactured in manual processes, thereby reducing the manpower required.

The research team that achieved this technological breakthrough was led by Assistant Professor Wu Jie from the NUS Department of Chemistry and Associate Professor Saif A. Khan from the NUS Department of Chemical and Biomolecular Engineering.

During the demonstration of the new technology on Prexersatib, a pharmaceutical molecule for the treatment of cancer, the NUS team achieved a fully automated six-step synthesis with 65 percent isolated yield within 32 hours. In addition, their technique successfully produced 23 prexasertib derivatives in an automated manner, underscoring the method’s potential for drug discovery and design.

The results, which were first published in the journal Nature Chemistry on April 19, 2021, have the potential to be applied to the manufacture of a wide variety of pharmaceutical molecules.

Simplification of the production of active pharmaceutical ingredients

Recent advances in end-to-end, continuous flow synthesis are rapidly expanding the capabilities of automated synthesis of low molecular weight pharmaceutical compounds in flow reactors. There are well-defined manufacturing processes for molecules such as peptides and oligonucleotides that have repeating functional units. However, due to problems such as solvent and reagent incompatibilities, it is difficult to conduct a multi-step continuous flow synthesis of active pharmaceutical ingredients.

The new automated technique developed by the NUS research team combines two chemical synthesis techniques. These include continuous flow synthesis, in which chemical reactions are carried out in a seamless process, and solid-supported synthesis, in which molecules are chemically bound and grown on an insoluble carrier material.

Their novel technique, known as solid phase synthesis flow or SPS flow, enables the target molecule to develop on a solid support material while the reaction reagent flows through a fixed bed reactor. The entire process is controlled by computer automation. Compared to existing automated techniques, the SPS-Flow process enables broader reaction patterns and a longer linear end-to-end automated synthesis of pharmaceutical compounds.

The researchers tested their technology on the cancer-inhibiting molecule Prexasertib due to its suitability for attachment to solid resin that was used as a carrier material. Their experiments showed a 65 percent yield after 32 hours of continuous automated execution. This is an improvement over the existing method of making prexasertib, which is estimated to take about a week and requires an extensive six-step manual process and cleaning process to achieve up to 50 percent yield.

The new method also enables early synthetic modifications and thus enables greater structural diversification compared to conventional methods, which only allow late diversification of the common core structure of a molecule. Using a computer-based chemical recipe file, the team successfully produced 23 derived molecules of Prexasertib. The derivatives produced are molecules in which parts of the molecular structure differ slightly from the original molecule.

“The ability to easily obtain these derivatives is critical during the drug discovery and design process as understanding the relationship between molecular structures and their activities plays an important role in selecting promising clinical candidates,” said Assoc Prof. Khan.

Creating new opportunities in drug development

The NUS team plans to further demonstrate the versatility of its SPS flow technique by doing more research on the best-selling pharmaceutical molecules.

“Our new technology offers a simple and compact platform for the automated on-demand synthesis of a drug molecule and its derivatives. We estimate that 73 percent of the 200 best-selling small molecule drugs could be manufactured using this technology, ”said Asst Prof. Wu.

Future studies by the team aim to develop a fully automated and portable system for large-scale manufacturing of active ingredients that is suitable for manufacturing. The system will use the newly developed lead optimization technique to accelerate the drug discovery process.