Such a separation would normally be performed using a gravity separation, or counter‐current extraction. This may be due to the large amount of water necessary to dilute the strongly acidic reaction medium, which consequently requires a phase separation. Although nitration reactions are a prime example of hazardous chemistry benefiting from continuous flow processing, there are relatively few where these are employed in multistep sequences. The first step in the synthetic route is the nitration of 2ClBA. The expected impurities in this sequence, owing to incomplete conversion, or overreaction (Figure 1 b) have been considered for analysis and quantification after each reaction step. The flow process must integrate a quench of the nitrating mixture, along with two phase separations, facilitating an acid‐base extraction before the subsequent hydrolysis step. A final quantification is provided by UHPLC. The nitration is monitored by NMR, the hydrolysis by UV/Vis and hydrogenation is monitored by IR. Intermediates along the desired reaction pathway are depicted in boxes.Įach step of the synthesis is monitored by a different analytical technique, to capitalize on the advantages provided by each. b) Impurity map, showing the main expected impurities in this multistep process. Each step will be analyzed in real‐time using a different PAT tool, as well as a final analysis by UHPLC. To our knowledge, such a level of PAT integration in a multistep synthesis has not been previously reported, and leads toward a strong level of process understanding and control.Ī) The proposed synthetic route for the synthesis of mesalazine ( 5‐ASA) from 2‐chlorobenzoic acid ( 2ClBA), via a 3‐step synthetic process. The capabilities of this system were exemplified in the multistep flow synthesis of mesalazine ( 5‐ASA), a commonly prescribed drug for treating Crohn's disease and colitis. Furthermore, the developed system communicates with all process peripherals (PAT tools, pumps, sensors, thermostats, mass flow controllers etc.).

The implemented PAT strategy employs three different advanced data processing methods and is capable of quantifying numerous species (including intermediates and impurities) at different points along the process. Here we report an integrated reaction and analysis platform, monitored and controlled by a single computer program. A recent report from our laboratories detailed the basic use of three separate PAT tools in an organometallic reaction, facilitating monitoring of each process step individually. The combination of multistep flow synthesis with multiple PAT tools is an area in which surprisingly little progress has been made, although it has the potential to substantially enhance process control, optimization and reaction understanding. This is especially important where intermediate workup/separation steps are concerned and for complex reaction mixtures with numerous overlapping species. However, using more powerful data processing techniques, the concentration of products and impurities can be precisely discerned, which substantially improves process control. Until now, such instruments have relied on rather simplistic data processing to determine reaction progress, or relative product distribution (i.e. Now plays an increasingly central role in continuous flow processing,Įnabling real‐time reaction monitoring for a range of applications, such as self‐optimization,įurthermore, there is clear support from regulatory agencies within the pharmaceutical industry for the incorporation of PAT in continuous manufacturing processes to ensure a high standard of safety and product quality. This approach has been utilized to synthesize a number of APIs, often providing significant improvements in processing time, safety and yield.Īs the chemical industries move towards increased digitization in development and manufacturing, establishing data‐rich multistep synthesis is of prime importance. This processing method has proven particularly useful in multiple synthetic transformations in sequence, known as multistep flow synthesis. 100 W analogue modules + max.Continuous flow processing is now widely accepted as a disruptive technology in the synthesis of active pharmaceutical ingredients (APIs) as well as other fine and commodity chemicals. 100 W digital modules, total load 150 W (200 W temporary*) with 150 W-Option: max. 100 W digital modules, total load 100 W (200 W temporary*)

RI-CAD™ CAD Program for RI Flow DiagramsĦ0 W (100 W temporary*) analogue/digital modules when using LM-FAN: 100 W analogue/digital modules.Customized Fermenter Controlling Systems.

Hitec zang labmanager