Researchers from the National University of Singapore (NUS) have discovered a novel method to fully automate the chemical synthesis of pharmaceutical molecules, effectively boosting yield and shortening production time.
Given the wide array of medications available for just the common cold, it is reasonable to assume that drugs are easily and quickly mass-produced. However, despite the massive commercialisation of various medicines, streamlining end-to-end continuous-flow manufacturing of pharmaceuticals remains to be one of the biggest challenges in the pharma industry.
Technical challenges have long hindered the possibility of realising efficient, continuous automation, and chemical incompatibilities have made seamless synthesis seem like a distant dream. That is, until recently.
Deviating from conventional chemical manufacturing, a group of researchers from the National University of Singapore (NUS) has constructed a novel method to automate the production of small molecules needed for pharmaceutical use. Spearheaded 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, the team merged two chemical synthesis methods, namely continuous-flow synthesis and solid-supported synthesis. Their computer-automated approach, known as solid phase synthesis-flow (SPS-flow), is foreseen to reduce manual labour processes, thus effectively shortening the time needed to develop these molecules.
Continuous-flow synthesis refers to a seamless process of chemical reactions, while solid-supported synthesis requires molecules to be chemically bonded and cultivated onto an insoluble support material. The SPS-flow develops target molecules by producing them on a solid support material and concurrently passing the reaction reagent through a packed-bed reactor, effectively widening reaction patterns and extending linear end-to-end automated synthesis of pharmaceuticals.
The team proved the value of their findings through an experiment involving the production of a small molecule kinase inhibitor used in cancer treatment, known as prexasertib. The inventive technique successfully produced prexasertib in a fully automated six-step synthesis, yielding 65 per cent yield in 32 hours. Conventional techniques, in contrast, require about seven days and extensive manual processing and purification to yield only 50 per cent.
Besides efficiency and yield, the new method also boasts greater structural diversification as compared to traditional methods. Synthetic modifications can be made during the early stages of the new process unlike traditional methods, which only allow diversification much later. By using a computer-based chemical recipe file, the team was able to produce 23 prexasertib derivatives, demonstrating its powerful potential for drug discovery and design.
“The capability to easily obtain these derivatives is crucial during the drug discovery and design process as understanding the relationship between molecule structures and their activities play an important role [in] the selection of promising clinical candidates,” said Assoc Prof Khan.
The highly versatile SPS-flow will be further refined and tested using other pharmaceutical molecules to validate its applicability for industrial use.
“Our new technique presents a simple and compact platform for on-demand automated synthesis of a drug molecule and its derivatives. We estimate that 73 per cent of the top 200 bestselling small-molecule drugs could be produced using this technique,” explained Asst Prof Wu.
In future, the team hopes to build a fully automated, portable, and scalable system to produce pharmaceutical ingredients, and in doing so, lay the groundwork for faster drug discovery and development.
Source: Liu et al. (2021). Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis. Nature Chemistry, 13(5), 451-457.