About Continuous Flow Technology
Continuous flow chemistry (or flow chemistry) is the process of moving reactive components (e.g., substrates, reagents, and catalysts) in solution together through a reactor. One of the key aspects of flow chemistry is that the reactions are performed continuously, so only a fraction of the reactive components undergoes a reaction as these components are being combined in the reactor, allowing for far greater control than that with conventional batch methodology. Moreover, reaction products can be taken onto successive flow reactions, allowing for multi-step syntheses to be done in one integrated, continuous process.
A flow chemistry reactor is temperature-controlled (i.e., may be heated or cooled), can allow for the introduction of UV or visible light in a controlled manner, and may contain fixed beds with solid supported catalysts or reagents. When the combined flows of reactants/reagents reach the end of the reactor, another flow (i.e., quench solution) can be introduced to stop the reaction. The internal diameter of the reaction line is typically in the micron to low millimeter range.
KEY ADVANTAGES OF FLOW CHEMISTRY
RELIABLE ACCESS TO POWERFUL, UNDERUTILIZED CHEMISTRY
Flow technology enables reliable access to chemical reactions (such as photochemical and high-temperature reactions) that are difficult to harness via conventional batch methodology. This technology can moderate powerful carbon-carbon, complexity-building transformations that (1) provide rare chemical structures to use for discovery and (2) reduce the number of transformations required to synthesize a molecule of interest.
BETTER SELECTIVITY FOR TARGET PRODUCTS
Flow methodology allows for fine control of reaction conditions, such as residence time, temperature, and pressure. Moreover, with a continuous process, starting materials and reagents have limited exposure to reactive intermediates and products, which can negatively impact selectivity and lead to product/starting material degradation. As a result, flow reactions are often cleaner and higher-yielding and lead to greater product selectivity than reactions using batch chemistry.
Scale-up of an optimized reaction can be achieved rapidly with minimal process development, either by changing the reactor volume or by running several reactors in parallel.
Flow has many safety advantages over batch chemistry. First, exotherms are much easier to control, as only a small amount of material undergoes a reaction at a given time and has limited exposure to the rest of the system. Similarly, explosive or other hazardous reagents (e.g., O2 and HN3) can be introduced in small quantities to the system, thereby limiting their potential for undesired or dangerous reactivity.
GREATER MANUFACTURING EFFICIENCY
Flow reactions can be automated with far less effort than that necessary for batch reactions. This allows for unattended operation and experimental planning, which ultimately creates a much more efficient manufacturing process. Manufacturing footprints incorporating continuous flow processes are often smaller than their corresponding conventional batch processes.
More Environmentally Friendly
Reactions done in flow are often faster than their corresponding batch reactions (partly attributed to better mixing and finer pressure/temperature control exerted over the reaction) and thus have improved energy efficiency and reduced operating time. Further, the continuous aspect to flow can considerably reduce the manufacturing footprint. At scale, flow chemistry can have a significant impact on greener manufacturing practices in the pharmaceutical and animal health industries.
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For additional resources, see the white papers developed based on the International Symposium on Continuous Manufacturing of Pharmaceuticals in May 2014, sponsored by MIT and CMAC.