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Drug Substance

Scientific Poster Spotlight: Kilo-Scale Synthesis in Daisy-Chained Flow Reactors

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Continuous flow manufacturing is becoming increasingly popular across the pharmaceutical industry as an alternative to traditional batch manufacturing for active pharmaceutical ingredients (APIs), providing significant benefits for rapid and robust delivery of drug substances to support downstream drug product development. Through a collaboration with the University of Nottingham funded by Innovate UK, Quotient Sciences is actively focused on flow chemistry research and has developed a modular continuous manufacturing technology platform.

As part of this collaboration, Felicity Roberts, Flow Chemist at Quotient Sciences, presented a poster at the American Association of Pharmaceutical Scientists (AAPS) 2022 PharmSci 360 Meeting, investigating a continuous flow process for the kilo-scale synthesis of norketamine from 2-chlorophenylcyclopentyl ketone using daisy-chained reactors. Norketamine is an intermediate in the synthesis of (2R,6R)-hydroxynorketamine, a pharmaceutical undergoing trials as an antidepressant.

While manufacturing of norketamine had previously been carried out in batch, converting to a continuous flow process could provide several advantages, including safer handling of hazardous reagents on scale-up, access to process conditions that are difficult to achieve in batch, and reduced time between stages to minimize the risk of impurity formation.

A system of four daisy-chained flow reactors was constructed for the synthesis of norketamine from 2-chlorocyclopentyl ketone, including bromination, amination, solvent swap, and thermal rearrangement stages. The process was run at steady state for over 24 hours, producing over 1 kg of norketamine at good purity.

Overall, this project demonstrated that continuous flow approaches continue to present time, cost, and quality benefits for small-molecule drug substance synthesis.

Poster authors
Felicity Roberts, Rowena Howie, Rory MacDonald, Gareth Jenkins, Marcos Veguillas Hernando, Jonathan Moore, Peter Licence, Martyn Poliakoff, and Michael George

Find out more about Quotient Sciences’ drug substance manufacturing capabilities.