Continuous Flow Chemistry

Improve Safety, Reduce Cycle Time, Increase Quality and Yield

Flow chemistry, also known as continuous flow chemistry or continuous processing, begins with two or more streams of different reactants pumped at specific flow rates into a single chamber, tube, or microreactor. A reaction takes place, and the stream containing the resultant compound is collected at the outlet. The solution may also be directed through subsequent flow reactor loops to generate the final product.

This approach requires only small amounts of material, which dramatically enhances process safety. Because of the inherent design of continuous flow technology, reaction conditions that are unsafe or unattainable in batch processing become possible. The result is a product with higher quality, fewer impurities, and faster reaction cycle times.

Flow chemistry has been used for decades in the chemical industry. More recently, the pharmaceutical and fine chemical industries have increasingly adopted this methodology. The inherent safety improvements, enhanced product quality, cost efficiency, and overall production flexibility drive the growing use of continuous flow chemistry.

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Flow chemistry equipment generally consists of pumps that transport reactants, reagents, and solvents into reaction loops, which introduce small volumes of reagents. These feed into a mixing junction where reagent streams are combined and passed into a coil reactor to provide the necessary reaction residence time. The reaction mixture may then be fed into a column reactor containing solid reagents, catalysts, or scavengers. An inline back pressure regulator controls the system pressure, and inline analytics are often used to provide information about reaction performance.

Additionally, in-situ FTIR spectroscopy can provide real-time feedback to proactively improve the reaction. For example, data from in-situ FTIR spectroscopy can be used to mitigate the effects of imperfect flow and control the addition rate of reagents, resulting in a better mixing profile.

Advantages of Flow Chemistry

Better control and reproducibility of reactions	Key reaction parameters such as mixing, heating, and residence time are more precisely controlled, leading to improved product yield and impurity control.
Wider range of reaction variables are accessible	Running continuous reactions under pressure allows higher temperatures than typical batch reactions limited by solvent reflux at ambient pressure, providing higher product yields.
Modular, customizable workflow	Flow chemistry equipment is highly modular, making it easy to configure systems to meet specific reaction requirements. A range of task-specific modules are commercially available and readily assembled into user-customized workflows.
Improved process safety	Reactions considered too hazardous in batch—such as highly exothermic or energetic processes—are often safer in continuous flow due to smaller reactant volumes. Exposure to toxic substrates and reagents is minimized by smaller volumes and elimination of manual sampling.
Rapid analysis, optimization, and scale-up of chemical reactions	Flow processes enable faster testing of reaction variables using fewer substrates and reagents. Inline, real-time analysis provides immediate feedback on reaction performance.
Increase product quality and yield	Precise control over variables and safe execution under broader reaction conditions improve overall yield while minimizing impurity levels.

In recent years, the scope and variety of reactions performed using continuous flow chemistry have expanded significantly, particularly in the pharmaceutical, fine chemicals, green chemistry, catalytic reactions, and polymer chemistry sectors. Much of this growth involves chemistries that pose challenges for scale-up in traditional batch processes, especially those that are potentially hazardous. Examples include:

Hydrogenation reactions
Oxidations
Halogenations
Nitrations
Diazotizations
Grignard reactions
Reactions involving toxic gases

Flow chemistry enhances safety by enabling safer handling of reactants that may present human health hazards. Another important application is the control of stereochemistry, as flow systems allow precise adjustment of reaction variables to manage epimerization effectively.

Additionally, flow chemistry is well-suited for reactions with limited starting materials, where conducting small-scale reactions is preferable.

When integrated with process analytical technology (PAT), flow chemistry enables rapid analysis, optimization, and scale-up of chemical reactions. Continuous, real-time monitoring allows researchers to track steady-state conditions, quickly troubleshoot process deviations, and identify reactive intermediates.

Utilizing techniques such as attenuated total reflectance (ATR) spectroscopy, each functional group within a substance exhibits a unique spectral fingerprint that can be monitored over time. This provides continuous measurement of component concentrations relative to process conditions, offering valuable insights into the time and parameters required to achieve and sustain steady state.

Continuous Flow Reaction of a Highly Exothermic Reaction

In this example, inline FTIR technology was employed to analyze a continuous process forming thiomorpholine dioxide through the reaction of ethanolamine (EA) and divinylsulfone (DVS). Inline FTIR played a critical role both during the development of the continuous process and in monitoring the reaction at larger scales.

Small-scale batch testing revealed that this reaction is highly exothermic and may pose challenges when scaled up. Furthermore, divinylsulfone is a toxic alkylating agent, and exposure should be strictly avoided.

Continuous Flow Reaction Of Highly Exothermic Reaction

Real-Time Monitoring and Scale-Up of Continuous Flow Reaction

To develop the continuous process, the reaction of ethanolamine (EA) with divinylsulfone (DVS) was carried out in a 12 mL reactor. ReactIR with a flow cell was used to monitor the disappearance of DVS (1390 cm⁻¹ band) and the appearance of the target compound (1195 cm⁻¹ band). Water was used as the solvent, which did not interfere with the IR bands monitored for DVS and the target compound.

As the IR spectral trace over time shows, the 1390 cm⁻¹ band corresponding to DVS appears when pump B is started. Upon actuation of pump A, introducing EA, the DVS band disappears while the target compound band appears and reaches steady state. This continuous flow reaction was subsequently scaled up to kilogram-scale production, with ReactIR flow technology employed for real-time process monitoring.

Strotman, N. A., Tan, Y., Powers, K. W., Soumeillant, M., & Leung, S. W. (2018). Development of a Safe and High-Throughput Continuous Manufacturing Approach to 4-(2-Hydroxyethyl)thiomorpholine 1,1-Dioxide. Organic Process Research & Development, 22(6), 721–727. https://doi.org/10.1021/acs.oprd.8b00100

accelerated process development with flow chemistry

Flow Chemistry for Exothermic Reactions in a CRO

NALAS Engineering, a Contract Research Organization (CRO), demonstrated a safer continuous flow method for a strongly exothermic chemical reaction using data-rich experimentation (DRE). The project employed calorimetry to evaluate heat balance and utilized in-situ mid-infrared spectroscopy to monitor reaction components in real time and develop kinetic models.

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.

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.

View how NALAS Engineering Accelerated Process Development

ReactIR 702L

ReactIR 702L™ is ideal for real-time monitoring of continuous flow chemistry. Its in-situ FTIR spectroscopy provides continuous tracking of key reaction species, enabling measurement of kinetics, mechanisms, and pathways, especially where offline sampling and analysis are challenging.

Small and Lightweight
With a streamlined profile, the instrument fits easily into physically constrained spaces, allowing placement along the reaction sequence wherever monitoring is needed.

No Liquid-Nitrogen Required
Infrared measurements can be performed continuously and unattended for extended periods, accommodating lengthy synthesis processes.

iC IR 8 Software
Setup and trend monitoring are straightforward and intuitive. Data from the ReactIR 702L integrates seamlessly with control systems, enabling proactive management of the chemistry.

Micro Flow Cell Optimized For Continuous Flow Chemistry

A flow cell is a valuable tool for monitoring liquid streams in process environments. This non-destructive analytical technique uses infrared light to scan samples and identify their chemical properties.

In collaboration with leading scientists in continuous flow chemistry*, we have engineered a flow cell optimized specifically for this critical application.

ReactIR Flow Cells are compatible with both micro- and mesoscale flow chemistry equipment, can be attached directly into reaction flow streams, and enable monitoring of reagent consumption and product formation.

Carter, C. F., Lange, H., Ley, S. V., Baxendale, I. R., Wittkamp, B., Goode, J. G., & Gaunt, N. L. (2010). ReactIR Flow Cell: a new analytical tool for continuous flow chemical processing. Organic Process Research & Development, 14(2), 393–404. https://doi.org/10.1021/op900305v

Online HPLC Analysis

With DirectInject-LC™, HPLC can now be used for near real-time reaction, process, and crystallization understanding. Fully automated rapid reaction sampling and injection transforms HPLC into a powerful new process analytical technology (PAT) for online reaction monitoring.

Continuously collect representative samples in batch or flow, enabling real-time analysis of complex, multiphase, and challenging chemistry.
Hands-free and reproducible reaction sampling, preparation, and immediate injection onto HPLC eliminates sample aging and provides data in real time.
Analyze data with world-leading iC Software Suite, specifically designed for reaction analysis and modeling, to enable accelerated process and product development.

Learn more about online HPLC solutions

Dynochem: Design and Scale-up of Flow Chemistry Systems

Performing reactions and processes in continuous flow mode can enhance quality, safety, and throughput. Dynochem, a chemical process simulation software,, enables modeling of critical variables such as tube length, volume, temperature, and residence time. It also allows assessment of mixing effectiveness in tubular and static mixing flow reactors.

For improved process safety in energetic reactions, Dynochem assists in designing appropriate plug-flow reactors based on heat flow data obtained from calorimetric measurements. Additionally, it facilitates easy modeling of the degree of conversion to product in continuous stirred tank reactor (CSTR) chains.

Dynochem builds organizational confidence in the selection of the right type of reactor and reaction conditions for a process. Dynochem modeling is ideal for rapid optimization of conditions in flow reactors across product scales.

By providing reliable insights, Dynochem builds organizational confidence in selecting the right reactor type and reaction conditions. It is ideal for rapid optimization of conditions in flow reactors across various product scales.

FAQs

What is flow chemistry?

Flow chemistry, or continuous flow, is a technique that involves running chemical reactions in a continuously flowing stream where pumps move fluid into a reactor, and the fluids contact each other where tubes join. The combined components can react when mixing spontaneously or with heating.

Why is flow chemistry important?

Flow chemistry is a well-established technique for use at a large scale when manufacturing large quantities of a given material.

Some advantages of performing reactions in continuous flow include:

Better control over reaction parameters
Faster reactions
Improved product quality and yield
Improved safety profiles
Process intensification
Sustainable chemical processes

What is the difference between batch and continuous flow?

Flow chemistry differs from conventional batch chemistry in several ways, including:

Flow of reagents: In continuous flow, reagents are pumped under pressure and flow continuously through the reactor.
Control of reaction time: Reaction time is determined by the time the reagents take to flow through the reactor.
Increased control over reaction parameters: This can enhance reactivity or enable new reactions.

Related Publications

FTIR Spectroscopy for Flow Chemistry

Journal Articles to Review Before Developing Your Continuous Process

Real-Time Reaction Analysis Guide

A Guide Reviewing the Advantages and Importance of Real-Time Reaction Analysis—A Key Element in Any PAT Strategy

ReactIR™ Spectroscopy in Peer-Reviewed Publications

Extensive List of References Published from 2020 to May 2023

In-Situ Monitoring of Chemical Reactions

Recent Advances in Organic Chemistry

Rapid Analysis of Continuous Reaction Optimization Experiments

Optimize Chemical Reactions With In Situ Monitoring

On-Demand Webinars

Continuous Flow Process Optimization and Control Using Multiple Orthogonal PAT

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Gérardy, R., Emmanuel, N., Toupy, T., Kassin, V., Tshibalonza, N. N., Schmitz, M., & Monbaliu, J. M. (2018). Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges. European Journal of Organic Chemistry, 2018(20–21), 2301–2351. https://doi.org/10.1002/ejoc.201800149
Strotman, N. A., Tan, Y. S., Powers, K. W., Soumeillant, M., & Leung, S. (2018). Development of a Safe and High-Throughput Continuous Manufacturing Approach to 4-(2-Hydroxyethyl)thiomorpholine 1,1-Dioxide. Organic Process Research & Development, 22(6), 721–727. https://doi.org/10.1021/acs.oprd.8b00100
Fitzpatrick, D. E., & Ley, S. V. (2018). Engineering chemistry for the future of chemical synthesis. Tetrahedron, 74(25), 3087–3100. https://doi.org/10.1016/j.tet.2017.08.050
Galaverna, R., Breitkreitz, M. C., & Pastre, J. C. (2018). Conversion of d-Fructose to 5-(Hydroxymethyl)furfural: Evaluating Batch and Continuous Flow Conditions by Design of Experiments and In-Line FTIR Monitoring. ACS Sustainable Chemistry & Engineering, 6(3), 4220–4230. https://doi.org/10.1021/acssuschemeng.7b04643
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Tshibalonza, N. N., Gérardy, R., Alsafra, Z., Eppe, G., & Monbaliu, J. M. (2018). A versatile biobased continuous flow strategy for the production of 3-butene-1,2-diol and vinyl ethylene carbonate from erythritol. Green Chemistry, 20(22), 5147–5157. https://doi.org/10.1039/c8gc02468e
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