(701h) Pharmaceutical Synthesis in Flow – Process Intensification of Albuterol

The active pharmaceutical ingredients (APIs) found in most modern drugs are traditionally synthesized via batch-style methods as opposed to continuous processing in flow reactors. While batch synthesis allows production of APIs in bulk quantities, it limits the tools and process efficiencies at the disposal of pharmaceutical engineers. Batch API synthesis requires large volume vessels in order to scale up a process; this raises safety concerns, increases capital costs, and generates variability between batches. In recent years, a new wave of pharmaceutical engineering has sought to translate batch pharmaceutical processing into continuous methods of manufacturing. While still a developing field, continuous synthesis in flow allows an API to be synthesized in plug flow reactors and offers the option of employing packed catalytic beds to efficiently drive reactions to completion via non-equilibrium conditions.

This talk examines the conversion of traditional batch API synthesis to continuous flow manufacturing for the production of albuterol. Albuterol is a beta-agonist bronchodilator used for the treatment of asthma and a current listing on the Food and Drug Administration’s (FDA’s) drug shortage list. Specifically, we highlight new methodologies of process intensification via flow chemistry to optimize amination and hydrogenation reactions. Practical aspects related to appropriate synthon selection to enable flow chemistry and process intensification will be discussed. Current results offer improved efficiencies versus batch synthesis as measured by liquid chromatography area percent (LCAP), nuclear magnetic resonance (NMR), and spectroscopic techniques (Raman, IR, UV-Vis). Additionally, we demonstrate how packed bed catalytic reactors (Pd/Carbon) can be used to replace commercial batch reactors. This work will ultimately be utilized in a continuous end-to-end albuterol manufacturing plant in order to streamline API synthesis and help the U.S. mitigate critical drug shortages.