Continuous Flow Chemistry

Continuous processing, or flow chemistry, has been used for decades in the chemical industry. Recently, it has been gaining interest in the pharmaceutical and fine chemical industries due to the inherent increased safety, improved product quality and cost efficiency, and overall production flexibility. Continuous flow chemistry opens options with exothermic synthetic steps that are not possible in batch reactors, and new developments in flow reactor design provide alternatives for reactions that are mixing limited in batch reactors.

Continuous flow chemistry begins with two or more streams of different materials pumped at a pre-determined flow rates into a single chamber, tube or in some cases a microreactor. The product is collected at the outlet in a flask or container of some type or directed to another flow reactor loop for a secondary step and so on for as many steps required to generate the final product. Only small amounts of material are needed, which dramatically enhances process safety. A higher reaction temperature is generally possible thanks to shorter reaction time (residence time). This often results in better product quality and higher yield.

When coupled with process analytical technology (PAT), flow chemistry allows for rapid analysis, optimization, and scale-up of a chemical reaction. With continuous real-time analysis, researchers monitor steady state conditions, troubleshoot process mishaps, and identify reactive intermediates. When flow chemistry is analyzed with ATR-FTIR, each functional group of a given substance has a unique fingerprint which can be trended over time and provides continuous measurement of component concentration as a function or process conditions. This provides a means to track the time and conditions necessary to reach and maintain steady state. 

In an example presented by the Contract Research Organization (CRO), NALAS Engineering, data-rich experimentation was applied in an effort to develop a safer continuous alternative for strongly exothermic chemical reaction. Important laboratory techniques included calorimetry for heat balance evaluation with in situ mid-infrared spectroscopy to monitor reaction components in real time and to develop kinetic models. These tools also provided an understanding of which step controls the overall process rate as well as the effect that mixing and mass transfer and catalyst have on the reaction rate.

Reaction heat assessment was used to determine the optimum experimental conditions (flow rate, temperature, catalyst loading) that best take advantage of the high heat transfer capacity of the Advanced-Flow Reactor. Heat information also allowed modeling of the thermodynamic behavior of each fluidic module and the heat distribution among them all. Real time mid-infrared analysis was to used to define the fraction conversion at each stage of the multiple fluidic module system, as well as the overall conversion and yield as a function of residence time. Key variables such as dosing rate, catalyst loading, and temperature were screened and optimized rapidly based on real time information provided by heat flow calorimetry and in situ mid-infrared spectroscopy.

In this example, the combination of calorimetry and real-time in situ mid-infrared spectroscopy (PAT) were the instrumental "eyes inside the reactor" that allowed these researchers to accelerate the development of a greener, safer, more efficient exothermic process using continuous processing as a superior alternative to batch processing. These technologies enabled the data-rich experiments necessary for modeling to be run early in development. In this presentation, Jerry Salan explains ways to provide his CRO customers with the best combination of high quality chemistry, analytical, engineering.

PAT is essential for developing robust continuous flow chemistry and providing full process understanding.  The utility of the application of continuous processing with various process analytical technologies is discussed, as well as case studies on developing flow chemistry processes.

Infrared spectroscopy is widely used for obtaining information about reaching steady state, stability of intermediates, as well as achieving rapid screening and optimization. These capabilities lead researchers in academia and industry to employ in situ mid-FTIR spectroscopy as a routine technique to gain comprehensive information-rich experimental data that is used to advance research in a shorter time frame.

In situ FTIR spectroscopy provides continuous monitoring of key reaction species and provides continuous measurements of kinetics, mechanism, and pathway where offline sample and analysis difficult.

ReactIR fitted with a micro flow cell easily connects to a continuous flow reactor to provide a real time “video” of the reaction chemistry as it takes place at any point in the flowing stream. 

Whether used for chemical processing or crystallization, mixed suspension and mixed product removal (MSMPR) and cascade stirrer tank reactors (CSTR) are alternative continuous processing technologies to Plug Flow Reactor (PFR) or tubular reactors. Taking advantage of existing batch reactors, EasyMax and OptiMax, these turn-key automated lab reactors can be converter to precisely controlled CSTR systems with fully integrated Process Analytical Technologies (PAT). Multiple stage CSTR can be implemented using pumps, valves, pressure or vacuum for mixture transfer from vessel to vessel. One single software can monitor and control up to 8 consecutive vessels. Precision heat flow monitoring can be applied to detect reaction onset, endpoint, measure the rate of reaction, and establish the reaction calorimetry profile for kinetic understanding or safety assessment.