Cstr Continuous Stirred Tank Reactor Model Report

What Is a Continuous Stirred Tank Reactor?

A Continuous Stirred Tank Reactor (CSTR) is a reaction vessel in which reagents, reactants and often solvents flow into the reactor while the product(s) of the reaction concurrently exit(s) the vessel. In this manner, the tank reactor is considered to be a valuable tool for continuous chemical processing.

CSTR reactors have effective mixing and perform under steady-state with uniform properties. Ideally, the output composition is identical to composition of the material inside the reactor, which is a function of residence time and reaction rate.

In situations where a reaction is too slow or when two immiscible or viscous liquids are present requiring a high agitation rate, several Continuous Stirred Tank Reactors (CSTRs) may be connected together forming a cascade.

A Continuous Stirred Tank Reactor (CSTR) assumes ideal mixing and thus, is the complete opposite of a Plug Flow Reactor (PFR).

Batch Reactors vs. Continuous Stirred Tank Reactors (CSTRs)

In general, reactors can be classified as either batch or semi-batch reactors (Fig. 2) or continuous reactors. Batch reactors have adequate volume, temperature control and mixing to enable reagents, reactants and solvents to be introduced and the reaction completed inside the vessel in a timely manner.

Continuous reactors are generally smaller in volume and allow the uninterrupted introduction of reagents and reactants and outflow of product to be continuous. While batch reactors are ubiquitous in the chemical industry and versatile, there are numerous advantages to lower volume flow reactors. Advantages include the ability to handle higher reactant concentrations, as well as more energetic reactions due to their superior heat transfer properties. In this manner, a CSTR (Fig. 1) is considered a tool supporting flow chemistry.

Design and Use of a CSTR

Continuous Stirred Tank Reactors (CSTRs) consist of:

• A tank reactor
• Stirring system to mix reactants (impeller or fast flowing introduction of reactants)
• Feed and exit pipes to introduce reactants and remove products

CSTRs are most commonly used in industrial processing, primarily in homogeneous liquid-phase flow reactions where constant agitation is required. However, they are also used in the pharmaceutical industry and for biological processes, such as cell cultures and fermenters.

CSTRs may be used standalone (Fig. 4) or in a cascade manner (Fig. 3).

What Is the Difference Between CSTRs and Plug Flow Reactors (PFRs)?

CSTRs (Fig. 5) and PFRs (Fig. 6) are both used in continuous flow chemistry. Sometimes, CSTRs and PFRs are stand-alone reaction systems, and at times in combination as part of a continuous flow process. While mixing plays an important role in CSTRs, PFRs are tubular reactors where distinct moving plugs contain reactants and reagents, acting as individual mini batch reactors. Each of these plugs in a PFR have a slightly different composition and the concept is that the plug mixes internally, but not with the nearby plug ahead of or behind it. In an ideally mixed CSTR, the composition of products is uniform across the entire volume, whereas the product composition in a PFR varies with its position within the tubular reactor. Each type of reactor has its advantages and disadvantages relative to the other.

A CSTR can produce large amounts of product per unit time and operate for long periods of time, but is not as useful for reactions with slow kinetics. For this type of synthesis, batch reactors are typically the preferred solution.

PFR reactors tend to be more space efficient and have higher conversion rates. However, they are not typically used for highly exothermic reactions since rapid increases in temperature are difficult to control. In addition, PFRs have higher operation and maintenance costs than CSTRs.

Advantages of CSTRs vs. PFRs

• Temperature control is easily maintained
• Continuous Stirred Tank Reactor behavior is well understood, including in mixing, reaction calorimetry, dosing options and chemical kinetics
• Less expensive and easier to construct than dedicated specialty flow systems
• Interior of reactor is accessible for Process Analytical Technology (PAT)
• Multiple units can be easily joined for cascade operation or integration in more complex flow systems with PFR, etc.

Disadvantages of CSTRs vs. PFRs

• Overall throughput per unit volume typically lower than tubular flow reactors
• Steady state needs to be maintained so system needs to be well understood
• Single units not optimal for reactions with slow kinetics

Residence Time Distribution in CSTR Reactors

An ideal CSTR shows ideal mixing and well-defined flow behavior that can be characterized by Residence Time Distribution (RTD). Tank reactors do not satisfy the conditions associated with idealized flow patterns. Deviation from ideality can result from channeling of fluid through the vessel, recycling of fluid within the vessel or the presence of poorly mixed or stationary regions in the vessel. As a result, a probability distribution function, RTD, is used to describe the amount of time that any finite portion of the fluid resides in the reactor. This helps to define the mixing and flow characteristics in the reactor and to compare the behavior of the reactor to ideal models. For example, a cascade of CSTRs exhibits tighter residence time and reaction resolution as the number of reactors increases in the cascade setup.

The RTD of a fluid in a vessel can be experimentally determined by the addition of a non-reactive tracer substance into the system inlet. The concentration of this tracer is varied by a known function and overall flow conditions in the vessel are determined by tracking the concentration of the tracer in the effluent of the vessel.

CSTR and Process Analytical Technology (PAT)

Automated chemical reactors can quickly convert from batch to CSTR operation.

• EasyMax has two well-controlled independent reactors that can be used individually or together as CSTRs
• OptiMaxand RX-10 can operate as single CSTR systems or coupled to other reactors controlled from same PC
• Syringe pumps, peristaltic and diaphragm pumps are employed to transfer liquids controlled by synthesis workstations
• For crystallizations, pressure difference can be used to transfer slurries

PAT is invaluable in keeping steady state monitored and well controlled

• FTIR Spectroscopy and Raman Spectroscopy provide real-time measurement of critical reaction species. For example, in continuous crystallizations, ReactIR measures and presents steady state concentration of one or more key solutes. ReactRaman measures and monitors crystal form development as a function of time
• ParticleTrack uses Focused Beam Reflectance Measurement (FBRM) to monitor key crystallization parameters, including particle size distribution and chord length
• pHand O₂probes continually monitor conditions in CSTR - as required

Featured Article: Continuous Process For Safe Production of Diazomethane

ReactIR Monitors the Diazoketone Concentration and is Used For RTD Determination

Wernik, M., Poechlauer, P., Schmoelzer, C., Dallinger, D., & Kappe, C. O. (2019). Design and Optimization of a Continuous Stirred Tank Reactor Cascade for Membrane-Based Diazomethane Production: Synthesis of α-Chloroketones. Organic Process Research & Development, 23(7), 1359–1368. https://doi.org/10.1021/acs.oprd.9b00115

The authors report the development of a diazomethane generator consisting of a CSTR cascade with internal membrane separation technology. They used this technology in a three step, telescoped synthesis of a chiral α-chloroketone – an important intermediate compound in the synthesis of HIV protease inhibitors. A coil reactor was used to generate a mixed anhydride that was passed into the CSTR diazomethane cascade. The Teflon membrane allowed diffusion of the diazomethane into the CSTR where it reacted with the anhydride to form the corresponding diazoketone. The diazoketone was then converted to the α-chloroketone by reaction with HCl in a batch reactor.

ReactIR measurements were used to follow the formation of the intermediate diazoketone compound (tracking 2107 cm-1 peak) and also to experimentally determine the residence time distribution for the system by tracking the tracer substance. The tracer experiment monitored by ReactIR determined that five reactor volumes of the second CSTR in the cascade were required to reach steady state, corresponding to a 6 hour start-up time.

Featured Article: Automated Intermittent Flow Suzuki Coupling System with Associated Downstream Operations

OptiMax Used as MSMPR Reaction Vessels in Continuous Crystallization

Cole, K. P., Campbell, B. M., Forst, M. B., McClary Groh, J., Hess, M., Johnson, M. D., Miller, R. D., Mitchell, D., Polster, C. S., Reizman, B. J., & Rosemeyer, M. (2016). An Automated Intermittent Flow Approach to Continuous Suzuki Coupling. Organic Process Research & Development, 20(4), 820–830. https://doi.org/10.1021/acs.oprd.6b00030

The authors report the development of a system to enable a fully automated intermittent flow liquid−liquid Suzuki coupling, as well as handle batch metal treatment and continuous crystallization. With respect to the continuous crystallization, OptiMax reactors were used in series as Multistage Mixed Suspension and Mixed Product Removal (MSMPR) vessels driving the ambient temperature antisolvent crystallization. These MSMPR vessels act as CSTRs that produce and transfer a slurry containing crystals of the product. The authors report that the nominal residence time in the crystallizers was calculated by the fill volume of the crystallizers divided by the total flow rate of incoming feeds. PAT, including Particle Track with FBRM and Attenuated Total Reflectance (ATR), was used in measuring the continuous crystallization.

Featured Article: PFR-CSTR Cascade For Continuous Reactive Crystallization

ReactIR and ParticleTrack Provide PAT Information and Feedback

Hu, C., Shores, B. T., Derech, R. A., Testa, C. J., Hermant, P., Wu, W., Shvedova, K., Ramnath, A., Al Ismaili, L. Q., Su, Q., Sayin, R., Born, S. C., Takizawa, B., O'Connor, T. F., Yang, X., Ramanujam, S., & Mascia, S. (2020). Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs. Reaction Chemistry & Engineering, 5(10), 1950–1962. https://doi.org/10.1039/d0re00216j

The authors report the development of a combined PFR-CSTR cascade flow reactor system that incorporated inline FTIR and FBRM sensors as process analytical technology. This system was used to investigate several continuous reactive crystallizations, determining crystal morphology, crystal size distribution, reaction and crystallization yields and supersaturation levels. Residence time distribution (RTD) for the PFR, CSTR cascade and PFR-CSTR cascade were measured and showed that the combined PFR-CSTR cascade had a slightly longer RTD than that of the CSTR cascade alone. For the reactive crystallization, a higher yield was obtained for the PFR-CSTR cascade system as a result of the PFR's narrower RTD, minimizing both unreacted material and impurity formation.

ReactIR and ParticleTrack probes measured the reactant concentration and crystal chord length during the reactive crystallization process. The reactant concentrations in the mother liquor measured by ReactIR were in good agreement with HPLC results (prediction error < 0.17 %). ParticleTrack measurements revealed a relatively stable chord length of ~ 150 µm.

Continuous Stirred Tank Reactors in Recent Publications

• Agnew, L. R., McGlone, T., Wheatcroft, H. P., Robertson, A., Parsons, A. R., & Wilson, C. C. (2017). Continuous Crystallization of Paracetamol (Acetaminophen) Form II: Selective Access to a Metastable Solid Form.Crystal Growth & Design,17(5), 2418–2427. https://doi.org/10.1021/acs.cgd.6b01831
• Ahmed, B., Brown, C. J., McGlone, T., Bowering, D. L., Sefcik, J., & Florence, A. J. (2019). Engineering of acetaminophen particle attributes using a wet milling crystallisation platform.International Journal of Pharmaceutics,554, 201–211. https://doi.org/10.1016/j.ijpharm.2018.10.073
• Cole, K. P., Campbell, B. M., Forst, M. B., McClary Groh, J., Hess, M., Johnson, M. D., Miller, R. D., Mitchell, D., Polster, C. S., Reizman, B. J., & Rosemeyer, M. (2016). An Automated Intermittent Flow Approach to Continuous Suzuki Coupling.Organic Process Research & Development,20(4), 820–830. https://doi.org/10.1021/acs.oprd.6b00030
• Dobrosavljevic, I., Schaer, E., Commenge, J., & Falk, L. (2016). Intensification of a highly exothermic chlorination reaction using a combined experimental and simulation approach for fast operating conditions prediction.Chemical Engineering and Processing: Process Intensification,105, 46–63. https://doi.org/10.1016/j.cep.2016.04.007
• Feng, R., Ramchandani, S., Salih, N. M., Lim, X. Y. E., Tan, S. W. B., Lee, L. Y., Teoh, S. K., Sharratt, P., & Boodhoo, K. (2019). Process Intensification Strategies and Sustainability Analysis for Amidation Processing in the Pharmaceutical Industry.Industrial & Engineering Chemistry Research,58(11), 4656–4666. https://doi.org/10.1021/acs.iecr.8b04063
• Glace, A. W., Cohen, B. M., Dixon, D. D., Beutner, G. L., Vanyo, D., Akpinar, F., Rosso, V., Fraunhoffer, K. J., DelMonte, A. J., Santana, E., Wilbert, C., Gallo, F., & Bartels, W. (2020). Safe Scale-up of an Oxygen-Releasing Cleavage of Evans Oxazolidinone with Hydrogen Peroxide.Organic Process Research & Development,24(2), 172–182. https://doi.org/10.1021/acs.oprd.9b00462
• Hu, C., Shores, B. T., Derech, R. A., Testa, C. J., Hermant, P., Wu, W., Shvedova, K., Ramnath, A., Al Ismaili, L. Q., Su, Q., Sayin, R., Born, S. C., Takizawa, B., O'Connor, T. F., Yang, X., Ramanujam, S., & Mascia, S. (2020). Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs.Reaction Chemistry & Engineering,5(10), 1950–1962. https://doi.org/10.1039/d0re00216j
• Li, B., Guinness, S. M., Hoagland, S., Fichtner, M., Kim, H., Li, S., Maguire, R. J., McWilliams, J. C., Mustakis, J., Raggon, J., Campos, D., Voss, C. R., Sohodski, E., Feyock, B., Murnen, H., Gonzalez, M., Johnson, M., Lu, J., Feng, X., . . . Wu, B. (2018). Continuous Production of Anhydrous tert-Butyl Hydroperoxide in Nonane Using Membrane Pervaporation and Its Application in Flow Oxidation of a γ-Butyrolactam.Organic Process Research & Development,22(6), 707–720. https://doi.org/10.1021/acs.oprd.8b00083
• Wernik, M., Poechlauer, P., Schmoelzer, C., Dallinger, D., & Kappe, C. O. (2019). Design and Optimization of a Continuous Stirred Tank Reactor Cascade for Membrane-Based Diazomethane Production: Synthesis of α-Chloroketones.Organic Process Research & Development,23(7), 1359–1368. https://doi.org/10.1021/acs.oprd.9b00115
• Yang, X., Acevedo, D., Mohammad, A., Pavurala, N., Wu, H., Brayton, A. L., Shaw, R. A., Goldman, M. J., He, F., Li, S., Fisher, R. J., O'Connor, T. F., & Cruz, C. N. (2017). Risk Considerations on Developing a Continuous Crystallization System for Carbamazepine.Organic Process Research & Development,21(7), 1021–1033. https://doi.org/10.1021/acs.oprd.7b00130
• Yang, Y., Song, L., & Nagy, Z. K. (2015). Automated Direct Nucleation Control in Continuous Mixed Suspension Mixed Product Removal Cooling Crystallization.Crystal Growth & Design,15(12), 5839–5848. https://doi.org/10.1021/acs.cgd.5b01219

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