Abstract

Continuous flow reactors (CFRs) are flow cells that are optimized for the continuous production of a target chemical compound. Currently, production of pharmaceuticals relies on large-scale batch processes that are intensified from the laboratory scale. Compared to batch reactors, CFRs have greater energy efficiency due to their superior mixing schemes and heat transfer properties. Due to this efficient heat transfer, reactions that require cryogenic temperatures in batch, such as the Swern oxidation, can frequently be performed at much milder temperatures in CFRs, significantly reducing temperature control costs. Though these features make CFRs attractive to process-intensive industries, they are currently limited by a lack of on-line analytical technologies suitable for small-volume, high-throughput measurements.

Recently, a program was initiated to evaluate the use of process analytics (PAT) and NeSSI sampling systems for the validation of CFRs performing a Swern oxidation. A four reagent sampling system is interfaced to a continuous low-flow reactor enabling reaction monitoring using a four channel process Raman spectrometer. Real-time process control of the Swern reaction was achieved by monitoring a series of process control parameters that included flow rate, stoichiometry, reactor temperature and pressure. Establishing control of the process allowed for optimization, minimizing the production of “off spec” product and removing the need for off-line quality control analytics. Real-time chemical modeling was performed to determine product quality using multivariate statistical methods. Results from initial experiments demonstrated that the oxidation, which requires cryogenic temperatures in batch, can be performed at cost effective temperatures in continuous flow.