Scaling continuous API synthesis from milligram to kilogram: extending the enabling benefits of micro to the plant

The signature benefits of continuous flow are largely a result of a reactor's micro-sized features. However, as the technology gains industrial traction in the synthesis of active pharmaceutical ingredients (API), the reactors must be scaled to larger size to meet production demands. Often, the micro-features cannot be preserved, and thus the challenge is in transferring the benefits of micro to the pilot plant and beyond. This review presents solutions to typical problems encountered in plug flow reactors (PFR) related to heat transfer, mixing, handling biphasic reactions, and photochemistry. Lessons are taken from kilogram level syntheses developed in pharmaceutical process chemistry groups.