Practical Scale-Up of Trickle Bed Continuous Hydrogenation for Pharmaceuticals

Abstract

There is a growing trend in the pharmaceutical industry toward the adoption of continuous processing for the synthesis of active pharmaceutical ingredients (APIs) and intermediates. This enables access to novel synthetic routes by operating at high temperatures and high pressures. Hydrogenation is a key transformation that particularly benefits from continuous processing, offering enhanced volumetric productivity and improved safety profiles. This study presents the development and scale-up of a continuous hydrogenation process, progressing from bench scale to pilot plant operation while addressing challenges associated with material limitations. The scale-up achieved a production rate of 12 kg/day for a pharmaceutical intermediate, with online HPLC employed for real-time process monitoring at both scales. Additionally, this work offers a strategic framework for catalyst selection in continuous hydrogenation and provides a scale-up methodology that can be readily applied when material constraints are present in pharmaceutical manufacturing.