(708a) From Batch to Continuous: Mitigating Strong Exotherms in Multiphase Pharmaceutical Reactors

The small-molecule pharmaceutical and specialty chemical industries are undergoing a transition from batch to continuous flow operation for processes that can benefit from fast transport in microfluidic reactors. For the case of exothermic and biphasic reactions such as direct oxidation with molecular gases, high surface-to-volume ratio of microreactors provides fast heat transfer, thereby enabling safe and enhanced operation at elevated temperature and pressure. Higher temperatures exponentially increase kinetics, while pressure keeps the solvent in its condensed phase and increases the dissolved gas concentration, thus kinetics. Despite such opportunities, the successful implementation of flow chemistry is occurring at a slow pace, requiring relevant case studies and approaches based on fundamentals of transport and kinetic phenomena to efficiently evaluate transition and determine optimal operating conditions from bench to production scale.

In this work, we have intensified the highly exothermic, biphasic decomposition of hydrogen peroxide from batch to flow by combining heat transfer characterization with transport-kinetic modeling and experiments. Transitioning to continuous microreactors was shown to be a strong process intensification strategy due to orders of magnitude faster cooling, eliminating the risk of thermal runaway. The experimentally observed instability in batch and isothermal behavior in continuous-flow were accurately modeled by incorporating experimentally-determined parameters into a transport-kinetic model that accounts for non-idealities like gas hold-up and deviations in heat transfer coefficients. The plug-flow reactor unlocked isothermal operation at extreme reaction conditions that cause major exotherms in batch, resulting in safer and higher throughput processes at scale-up compared to batch reactors of the same volume. We propose a nondimensional regime map based on the conservative Semenov criteria for thermal runaway as a tool to identify operating windows for stable and high throughput production when evaluating batch to continuous process conversion.