Process Development and Scale-Up of a Photochemical Reaction for Drug Substance Intermediate

Recent advances in light-emitting diode (LED) technology and development of visible-light photoredox catalysis have led to a resurgence of interest in photochemical transformations for drug substance development. Photochemical approaches can streamline the manufacturing of active pharmaceutical ingredient (API) by providing reaction selectivity that cannot be achieved with traditional synthetic methods. Despite the intrinsic synthetic value of these approaches, applications in the pharmaceutical industry have largely been focused in the early stages of drug development, with very few examples of photochemistry implemented beyond lab scale.

This presentation will discuss various strategies that have been used to develop and scale up a photochemical bromination. Small, benchtop experiments were used to identify the reaction mechanism and understand reaction sensitivities. By establishing photon equivalence as the scaling factor, the bromination was scaled up to larger batch reactors and tech transferred to continuous flow reactors. The process was scaled up to the kilo-scale with two different flow reactor configurations to understand the impact of reactor design on photochemical reaction performance before selecting a plug flow reactor for manufacturing. To further understand the bromination reaction in a production environment, the process was explored at various residence times, irradiation levels, and temperatures in the pilot plant. This data, along with kilo-scale process characterization investigations, enabled successful tech transfer of the process to manufacturing to produce metric tons of drug substance intermediate.