Continuous flow chemistry has traditionally been used as a safer and more efficient way of handling high energy products and reagents when batch operations were deemed too dangerous. To undertake these in batch mode often requires bunkered production facilities away from main manufacturing areas, while vessel sizes and inventories would be kept low so that in an uncontrolled event, any damage could be easily contained and the risk to personnel and the surrounding area would be limited. However, constructing and maintaining these facilities, together with the small scale of the reactions, can be prohibitively costly.

Continuous flow processing reduces the effective volume of a unit operation, enhances control and minimizes the exposure and risk so that energetic chemistries or hazardous reagents can be handled safely. It does not eliminate safety concerns entirely, but does reduce the risk factors to levels that are easier to manage and mitigate. Furthermore, by enabling these operations to take place in a regular manufacturing plant they can be linked directly to other downstream processes, giving the advantage of integration of operations.

Chemical syntheses which have benefited from continuous flow on a commercial level include nitration, where the rapid reaction can be monitored and controlled to ensure the process is efficient and yields high quality product.

Case Study: Conversion of batch nitration to continuous flow process
A nitration process that Cambrex converted from batch to continuous processing demonstrates the safety benefits that the technology affords: at its Karlskoga, Sweden facility, the company developed a commercial scale continuous flow process with an annual capacity of more than 50 tons within its regular production facility.

The intermediate in the reaction itself is highly energetic (more than 2,000 kJ per kilogram), so the process to transfer it into a regular manufacturing facility involved rigorous safety assessments and precautions. Additionally, the nitration reaction is exothermic and requires high cooling capacity to strictly control the temperatures during the reaction.

Based on the risk profile, a focus of process development was carefully managing both heat and mass transfer to achieve a safe and predictable operation of the process. A formal Design of Experiments (DoE) study was carried out to investigate the impact of key parameters, such as residence time and reaction temperature, on yield and purity to ensure the process can not only be conducted safely but also without sacrificing efficiency or quality.

Based on the DoE results in conjunction with early development work in the laboratory, the effort to design the nitration reactors began, again with the focus being on maximizing heat and mass transfer. Two continuous stirred tank reactors (CSTRs) were chosen, each with a volume of 15L so that at any single time in the process, the amount of material in each reactor was limited to 5 kg. The arrangement also offered a relatively high surface to volume ratio, which is of course beneficial for the heat transfer. To minimize the risk of any pressure build-up in the event of a runaway reaction, the design of the pressure relief on the reactors was oversized.

The reaction vessels by design allow high cooling capacity, and the use of small reactors in series limits the amount of product present in each reactor, and thereby the amount of energy stored at any one time.
To further minimize the risk of explosion, the stoichiometric ratio between the substrate, the solvent and the nitrating agent had to be controlled by monitoring and controlling the ratio between the two feed streams into the nitration reaction, and by interlocking the control system. In an event where the temperature could not be controlled, an emergency quench system was incorporated, utilizing a pre-pressurized tank that could release water into the nitration vessel. As yet another level of process safety, the equipment was also designed to withstand the gas evolution associated with a complete decomposition of the reactants in the vessel.

Development of continuous flow processes: overcoming challenging conditions
The previous case study is an excellent example of the importance of both heat transfer and mass transfer (mixing) for chemical processes, with respect to both quality and process safety. It also illustrates the enabling power that continuous flow can provide in managing or even enhancing these key process attributes. Looking into this further, controlling temperature is critical to a successful scale-up within a process development or commercialization cycle, and this is particularly true when dealing with exotherms within a reaction. The impact of scale is seen when looking at the ratio of heat transfer surface area to the overall reactor volume. In general, the ratio drops by at least an order of magnitude when a process is scaled up from a laboratory or pilot demonstration batch to a modestly sized production run.

This drop in the ratio hinders the ability to remove the excess heat from the reaction mixture, possibly putting the material at risk as it reaches a temperature limit. It can also lead to localized hot spots within the mixture, which can cause inconsistency and non-homogeneity.

The reduction in the surface area to volume ratio is still present in the scale-up of a flow process, however that ratio is considerably larger for a tube reactor. For example, a 4-inch diameter tube has approximately the same ratio as a typical 0.5 liter laboratory reactor; while more typical tube or pipe reactor diameters will have considerably higher values, ensuring that temperature control and exotherm management can be handled in a straightforward manner.

In some cases, it may be advantageous to purposely increase the process temperature. With regard to reaction kinetics, in general, the reaction rate doubles for every increase in 10 degrees of absolute temperature, but at larger scale in batch processing there are several pitfalls to elevated temperatures. Firstly, as with elevated process pressure, elevated process temperatures often require a much more expensive infrastructure which will be exacerbated by inefficient mixing in large reactors, extending reaction times and negating any process time gains resulting from the accelerated kinetics of a higher temperature.

Secondly, after a reaction is completed at elevated conditions the process is typically returned to ambient or near-ambient conditions for quenches, work-ups and subsequent process steps. The large thermal mass in a batch reactor takes a considerable amount of time to adjust, which not only further erodes process time gains but also exposes the reaction mixture to extreme conditions for an extended period of time.

Finally, higher temperatures may have undesirable effects on reaction selectivity, while also significantly increasing the risk profile and potential dangers with solvents being raised to or above flash points and reaction mixtures purposely being raised to the point where runaway conditions or over-pressure conditions are a real possibility.

Continuous flow reactions, using smaller, instantaneous volumes drastically minimize mixing impacts and concentration or temperature gradients, and also bring the amount of material that has an elevated risk status to a much more manageable level. Furthermore, the reduced thermal mass makes the process of temperature quenching orders of magnitude quicker, allowing for a rapid introduction to elevated conditions to drive kinetics, followed by a rapid return to ambient conditions for further processing or to protect the integrity of the products or intermediates that are being formed.

At the other end of the spectrum, traditional batch equipment is limited when cryogenic conditions are necessary, for example when stereoselectivity needs to be controlled, or to protect unstable intermediates. Maintaining cryogenic temperatures efficiently and consistently is difficult and multiple low temperature thermal cycles can have a detrimental impact on the equipment itself and lead to stress cracking and premature equipment failure. Using a liquid nitrogen injection as an alternative to drive cryogenic conditions is difficult to control and can become very costly at scale.

An example of an industrially relevant process that typically requires cryogenic conditions is lithiation chemistry. The previously discussed advantages of continuous flow can certainly be utilized to improve the performance of lithiations, but another alternative is replacement by Grignard reactions to avoid the problems of maintaining low temperatures. However, these bring different challenges as they are energetic and extremely air and moisture sensitive, and often necessitate the use of pyrophoric and short shelf-life reagents. Converting Grignard reactions to a continuous process allows much more efficient and safe synthesis, as the reagents can be manufactured in a just-in-time manner.

Just as with temperature, pressure can also be a powerful process parameter that can be harnessed with continuous flow processes. Hydrogenation is a widely used synthetic tool thats use can be limited by batch processing and restrictions of standard plant equipment. The pressure requirements for hydrogenations can typically be 100-150 psig (although pressures higher than 300 psig are not uncommon), and often involve expensive catalysts and lengthy reaction times.

Flow hydrogenation has become an increasingly investigated and accepted technology to solve these issues, and strategies and technologies are available allowing for both homogeneous and heterogeneous catalyst processes. Tube reactors and packed bed columns are readily adaptable to much higher processing conditions, easily achieving pressures 10 times that of standard batch reactors. Strategies also exist for replenishing supported catalysts that are consumed over the course of a process, utilizing multiple columns with diverters or automating a semi-batch/semi-continuous process with multiple catalyst charges. By these means, a throughput of several kilograms in a day is readily achievable with a modest equipment footprint.

Improved product quality
While the case study focused on process safety concerns, the need to maintain quality standards was also a key consideration. Certainly, consistent quality performance during a transition from a batch to a continuous process must be maintained, at a minimum. However, an important benefit that continuous flow can afford in some situations is improved quality of the final product. Frequently, a process chemist or engineer is forced to accept a less than ideal synthetic route due to infrastructure constraints, such as achievable pressures, temperatures, addition rates or equipment availability within a plant. These processes can generate impurities that must be removed, and in some situations the majority of an industrial process may be more focused on removing impurities rather than actually making the desired product.

In some cases, flow chemistry can avoid these impurities, or at least reduce them significantly, as the process can be designed to minimize their formation, and analysis can be integrated into the process rather than functioning as a separate operation.

In a continuous flow process, introducing process analytical technology (PAT) for more sophisticated analysis is generally easier than for batch production: often only temperature probes and flow meters are required to ensure that the process remains within the acceptable parameters to afford product of a known quality. Sophisticated PAT probes can be easily integrated into a flow process to allow for rapid detection of deviations, in addition to nearly continuous monitoring of instantaneous quality, as opposed to waiting on a single batch sample and corresponding measurement.

These PAT probes can be used to monitor process performance attributes, such as reaction conversion, with the data being utilized to make real-time adjustments, correcting for process variations. Fourier-transform infrared (FTIR) spectroscopy can be used to map reaction kinetics during process development, and then subsequently incorporated into flow streams for real-time monitoring of conversion. Peak depletion or peak growth can be used during development to define optimal conditions, with standardized peak intensity, then being used online during campaigns to monitor for deviations and to develop an online process control response. Similarly, with Raman spectroscopy, tracking wave numbers can be used to monitor reaction conditions; however, it adds an intriguing functionality, as different polymorphs of a substance have unique spectra, enabling its use in a crystallization or precipitation process to ensure that the desired form is produced.

However, chromatographic analysis remains the standard for analytical measurements, and as a result, equipment has been developed to perform these analyses as close to real-time as possible.  An added feature is that when a sample is pulled, it is typically representative of the entire flow stream, which, by definition is a complete representation of the reaction mixture in that instantaneous moment, eliminating potential concerns over a sample being truly representative.

The PAT data can be used to ensure the process is operating within its targeted window and often allows for a process incorporating a single flow step to be embedded in a larger process, while still fitting comfortably within well-established quality systems that exist in most manufacturers.

Although it might not be applicable for all reactions and all conditions, for continuous flow to achieve successful widespread implementation, it must be seen as a technology of choice and not just a niche problem-solving option for energetic reactions. Along those lines, a number of pharmaceutical companies have invested in, and are actively investigating the use of continuous flow. Moving forward, as products come to market that have utilized the technology, undoubtedly there will be greater adoption to leverage the advantages that it brings.