Model-based comparison of batch and flow syntheses of an active pharmaceutical ingredient using heterogeneous hydrogenation

Abstract

This work presents a model-based comparison of the batch and flow syntheses for doripenem, which is an antibiotic active pharmaceutical ingredient. The targeted reaction is heterogeneous hydrogenation, the most widely used method for reduction reaction in drug syntheses. We developed rigorous physical models considering the decrease in catalyst activity and the leaching of catalyst as the critical factors in the actual operation. Experiments were performed to estimate model parameters for reaction and catalyst poisoning. Conditions of leaching were observed, and an indicator for estimating leaching possibility was developed. A multiobjective evaluation regarding yield and leaching possibility indicated that the flow synthesis gives the optimal solution. However, the flow synthesis exhibited a significant weakness at low hydrogen pressure due to poor mass transfer of hydrogen in the reaction system. This result suggests the importance of careful selection and control of the operational conditions in flow synthesis before implementation.