Advanced Real-Time Process Analytics for Multistep Synthesis in Continuous Flow

IntroductionContinuous flow processing is now widely accepted asa disruptive technology in the synthesis of active pharmaceutical ingredients (APIs) as well as other fine and commodity chemicals.[1] This processing method has provenparticularly useful in multiple synthetic transformations insequence, known as multistep flow synthesis. This approachhas been utilized to synthesize a number of APIs, oftenproviding significant improvements in processing time, safetyand yield.[2] As the chemical industries move towardsincreased digitization in development and manufacturing,establishing data-rich multistep synthesis is of prime importance.[3]Process analytical technology (PAT)[4]now plays anincreasingly central role in continuous flow processing,[5]enabling real-time reaction monitoring for a range ofapplications, such as self-optimization,[6]reaction kineticanalysis,[7] dynamic experimentation,[8] online chiral analysis[9]and process control.[10] Furthermore, there is clear supportfrom regulatory agencies within the pharmaceutical industryfor the incorporation of PAT in continuous manufacturingprocesses to ensure a high standard of safety and productquality.[11]Until now, such instruments have relied on rathersimplistic data processing to determine reaction progress, orrelative product distribution (i.e. % content). However, usingmore powerful data processing techniques, the concentrationof products and impurities can be precisely discerned, whichsubstantially improves process control. This is especiallyimportant where intermediate workup/separation steps areconcerned and for complex reaction mixtures with numerousoverlapping species.The combination of multistep flow synthesis with multiplePAT tools is an area in which surprisingly little progress hasbeen made, although it has the potential to substantiallyenhance process control, optimization and reaction understanding. A recent report from our laboratories detailed thebasic use of three separate PAT tools in an organometallicreaction, facilitating monitoring of each process step individually.[12]Here we report an integrated reaction and analysisplatform, monitored and controlled by a single computer program. The implemented PAT strategy employs threedifferent advanced data processing methods and is capableof quantifying numerous species (including intermediates andimpurities) at different points along the process. Furthermore,the developed system communicates with all process peripherals (PAT tools, pumps, sensors, thermostats, mass flowcontrollers etc.). The capabilities of this system were exemplified in the multistep flow synthesis of mesalazine (5-ASA),a commonly prescribed drug for treating CrohnQ s disease andcolitis.[13] To our knowledge, such a level of PAT integration ina multistep synthesis has not been previously reported, andleads toward a strong level of process understanding andcontrol.