Shining a Light on the Advances, Challenges and Realisation of Utilising Photoredox Catalysis in Pharmaceutical Development

Abstract

Photoredox catalysis has advanced significantly over the last fifteen years, with improvements in technology facilitating implementation in both academic and industrial settings. Despite these advances, the uptake of photoredox catalysis in pharmaceutical development and manufacture has been slow, in part due to the challenge of developing a robust, transferable process. This perspective provides insight on the successes and difficulties encountered when applying photoredox catalysis to pharmaceutical development. It is hoped greater understanding of the challenges faced by the pharmaceutical industry will inform future research and encourage collaboration.

Photochemistry in Pharmaceutical Development: A Survey of Strategies and Approaches to Industry-wide Implementation

“…The literature of the last 100 years discusses the issues with photochemistry and how to overcome them, highlighting merits of both batch and flow reactors. ,− With the advent of the publication of “A Practical Flow Reactor for Continuous Organic Photochemistry” by Booker-Milburn and Berry in 2005 coupled with widely available nearly monochromatic light sources in the 310–800 nm range, i.e., light emitting diodes (LEDs), − this has transformed photochemistry from a seldom-used bond-forming strategy into an innovative technology . Recently, Bonfield et al (2020), Cohen et al (2023), and Callard-Langdon et al (2023) discussed scaling photochemistry in the pharmaceutical industry. With significant advances in scaling up photochemical reactions, we expect that more pharmaceutical companies will bring more types of reactions into their process development groups in the future.…”

“…Cross coupling reactions (20%, three examples) and halogenation (27%, four examples) still account for approximately 50% of transformations. However, a greater proportion of halogenation reactions ,,, have been scaled compared to cross couplings. − Next are trifluoromethylations, cycloadditions, , and isomerization (14% each, two examples each), and finally rearrangements and HAT reactions (7% each, one example each).…”

“…However, a greater proportion of halogenation reactions 15,26,74,75 have been scaled compared to cross couplings. 76−78 Next are trifluoromethylations, 79 cycloadditions, 80,81 and isomerization 73 (14% each, two examples each), and finally rearrangements and HAT reactions 80 (7% each, one example each).…”

Development of a Horizontal Dynamically Mixed Flow Reactor for Laboratory Scale-Up of Photochemical Wohl–Ziegler Bromination

“…In 2005, a landmark publication from Booker-Milburn and Berry (GSK) et al described a photochemical plug flow reactor (PFR) using readily available fluorinated ethylene propylene (FEP) tubing and mercury broad-spectrum lamps and subsequently sparked a renaissance in photochemistry . Coupled with the advent of cheaper monochromatic light sources, i.e., light emitting diodes (LEDs), there has been an explosion in new chemical transformations reported in the literature, from both academia and the pharmaceutical industry. − As these new transformations are implemented into the construction of active pharmaceutical ingredients (APIs), a perennial question arises: how do you scale photochemical transformations? Continuous flow chemistry has received much attention for scaling photochemistry due to the increased surface area to volume ratio which satisfies issues around the penetration of light (Beer–Lambert law) and the intensity of light (Bunsen–Roscoe law). , As intimated above, there are added complexities to reactor design for photochemistry, and both light penetration and the use of heterogeneous catalysis remain unresolved issues when designing reactors. In recent years, different types of reactors have been described in the literature as a solution to performing photochemistry on scale. − These reactors tend to follow a PFR design (Figure a), although the design of immersive modular photoreactors with static mixing has recently been reported to increase mass transfer in the system .…”

“…7−11 As these new transformations are implemented into the construction of active pharmaceutical ingredients (APIs), a perennial question arises: how do you scale photochemical transformations? 12 Continuous flow chemistry has received much attention for scaling photochemistry due to the increased surface area to volume ratio which satisfies issues around the penetration of light (Beer−Lambert law) and the intensity of light (Bunsen−Roscoe law). 13,14 As intimated above, there are added complexities to reactor design for photochemistry, and both light penetration and the use of heterogeneous catalysis remain unresolved issues when design-ing reactors.…”