Last month Adamo et al published a hot Science paper on a compact continuous flow synthesiser for four drugs: luoxetine hydrochloride, lidocaine hydrochloride, Diazepam and diphenhydramine hydrochloride. The group had previously reported an end-to-end manufacture of aliskiren hemifumarate (see Angew. Chem. Int. Ed., 2013, 52, 12359–12363), which included the synthesis, purification, and tableting of the drug. The Science paper represents a significant advance in terms of reducing plant footprint and showing that a continuous processing setup can also achieve the similar flexibility as a batch manufacturing plant, it includes the upstream (reaction) and downstream (purification and formulation) processing. Researchers at MIT have also published an economic analysis of a batch vs flow integrated flow process (see Ind. Eng. Chem. Res., 50, 10083-10092 (2011) doi:10.1021/ie2006752), presenting a persuasive argument for the drive to continuous manufacturing.
Opening the supporting information really does highlight the that this truly is an integrated and uninterrupted processing strategy, with real-time process monitoring. The reactor unit is modular in the size of a refrigerator, thus enabling a plug-and-play platform and the flexibility needed for flow to be competitive with established batch manufacturing. Many of the components used in the configuration were custom built, including PFA tubing within aluminium casing and membrane separators with high pressure ratings. The system includes in-line, real time analysis using FlowIR from MettlerToledo for qualitative reaction analysis, automated gravity separators were incorporated for monitoring the organic and aqueous phase separation, and in-line ultrasonic monitoring for measuring ultrasound velocity for formulation.
There is a table within the ESI which shows the processing time for the different unit operations with the upstream processes all taking less than 2 hours for each API and the downstream processing taking significantly longer (about 10 hours for each drug), and it is the downstream processing achievements is where this contribution is the most powerful.
I don’t envisage a future of having a TV size reactor inside everyone’s house dispensing personalised medicines as this would be a regulatory nightmare, and in reality too many stock chemicals are necessary to access the drug catalogue. I think the portability of flow is needed in hospitals for personalised medicines and for on-demand delivery in hospitals, such as for the generation of radiopharmaceuticals. To dream further, another application would be in the human spaceflight to Mars anticipated to take place by 2035.
The researchers are now attempting to reduce the footprint further and widen the drug catalogue. It will be interesting to see how much re-optimisation of the reactor unit and chemistry will be needed to access more drugs. I look forward to seeing the future results.
Read the Science article online: Adamo et al., Science, 2016, 352, 61-67, DOI: 10.1126/science.aaf1337