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SINHA ROY, P. (2017). Advantages and disadvantages of continuous flow processing in fine chemicals manufacture. PHILICA.COM Article number 1155.

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Advantages and disadvantages of continuous flow processing in fine chemicals manufacture

PARTHA SINHA ROYunconfirmed user (Pharmaceutical Science and Engineering (Process Chemistry & Chemical Technology), University of Leeds)

Published in chemo.philica.com

To understand the flow processing in the manufacture of fine chemicals it is necessary to make out the chemistry, development time-scale along with the “product cost-structure” involved in it. Continuous flow processing involves controlled process conditions with high flow-rates and mass throughput. Simple methodology and experimental apparatus should be introduced to scale up from laboratory bench-scale to pilot to plant scale. Such methodologies can potentially be utilized for the innovation of newer drug compounds. This would surely influence towards purity of the product in a controllable manner, improved sophisticated economical performance and less environmental impacts.

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For a particular molecule plenty of possible routes of synthesis, individual route with number of reaction steps, variable reactive-sites being possessed by the intermediates and the products are important. Selection of the potentially best route of synthesis curtailing off environmental hazards, covering health and safety guidelines and establishing a fruitful manufacturing system are necessary. [1]

Example : Pyrethroid

Numbers of impurities are there which have structural resemblance of the target compound. They must be separated. Thus it leads to waste. [1]

Problems: Even in the most convenient route for the synthesis of organic molecules, it is hardly found that the reactions involved are entirely specific. In case of the reaction shown below, higher selectivity goes 95% to the para-product, 5% towards the ortho-product and the meta-product receives a tracer amount. Synthesis going through nine reaction steps results with only 62-64% yield which practically becomes even much lesser predominantly due to purification. Other factors which affect on lower yield are design and type of the reactor, concentration of the reagents used, effects of mixing, inhomogeneous nature. [1]


Through the final stages of development the processing for fine chemicals manufacture converges to a research route associated with pre-formulation and components of the delivery system. This generates establishing other possible alternative routes. Only feasible and economically fit routes are selected for further analysis, others are discarded. Considerations are made based on reaction-conditions, various solvents used for extraction, specific reactors and process-integrity. [1] 


Ø  Cost:  Fine chemicals manufacture that needs comparatively lower rate of production proves batch-operations much cost-friendly as it runs through “fewer but larger items” [1].

Ø  Capacity to handle uncertainty: Simple, convenient and economical over design of batch-reactor along with its other subservient equipments makes it advantageous. For a chemical reaction leading to form other by-products and an intermediate step which primarily determine the rate of reaction can significantly undergo a change via “mass transfer, mixing and chemical rate control” [1]. In such case, minimum mixing capacity, maximum rheology and minimum mass-transfer co-efficient can easily be presumed. But still the wise thing is to assume these parameters being increased. This uncertainty justifies the actual distinctive features associated with the exact manufacture while reactor being critically installed in order to differentiate the initial development process. Thus overall development time is shortened.

Ø  Flexibility: Continuous flow processing in a batch-agitated vessel forms a reaction-stage that can be typically arranged for a definite and particular cluster of physical parameters like mechanical properties, reaction kinetics, etc. This eventually gives way to grasp a variety of materials thereby giving privilege for modification and handling of new conditions. Batch operations are thus simple, price-friendly and robust. [1]

Limitation: As the Batch-agitated vessel has a fixed pressure which runs maximally, it cannot be further increased. For a continuous flow processing it is critically hard, rather beyond being possible to exceed concentration/reduce the solvent/exceed viscosity which solely depends on the particular design of the reactor. [1]


This is one of the most newest and innovative approaches which simply adapts and permits “batch protocols” [3] through micro-wave heating which gives rise to generation of organic solids that are  needed to be scaled up where reaction-conditions remain unaltered and re-optimization is not required. The product-stream on being emerged from the hot area is cut-off with an outflow of organic solvent. This solvent helps the product get solubilized thereby giving a provision to reach the collection vessel avoiding formation of aggregates of the particulate substances. [3]

This approach has a signifiacnt application on synthesis of 3-acetyl coumarin.

In this synthesis reaction, salicylaldehyde is the reagent, ethyl acetate is the solvent, piperidine is the catalyst, reaction temperature is 130°C, time-period is around 8-10 minutes. Knowing the solubility of coumarin, it was intentionally done so that product-stream could admix with acetone which would allow coumarin to get solubilized and then could easily be isolated. Finally 3-acetylcoumarin was formed with a yield of aorund 72-74%. Microwave heating in batch resulted with yield of 76-78%. [3]



Equipment 1:

The equipment consists of:

a)      Double-tube assembly: inner side of this tube is formed by the catalyst bed

b)      Annual section of the tube: rotation of the heat-transfer fliud

c)      Grant GP200 oil-bath: rotation maintains a static temperature

Reagents which have already been mixed  with the solvent in a container give rise to a solution that is pumped out to a reactor by dint of HPLC pump with an optimum flow-rate. Pressure is checked from the base as well as from the top of the reactor. 16-turn needle valve typically adjusts the back-pressure of the reactor. When fluid temperature decreases sharply, it is analysed on being collected. [2]

Equipment 2:

The equipment ideally shows the reactors used in laboratory (0.06-1.2L) and bench (1.5-3.0L) scale for continuous flow processing in fine chemicals manufacture (kinetic measurement). The reactors as designed are ideal for batch/semibatch operations. High Pressure Liquid Chromatography (HPLC) and Gas Chromatography (GC) are the two main principles based on which the samples are analysed and thus the reaction-rate is monitored. [4]

Disadvantages: sample instability, analytical time limiting the number of data. 


This is a newly innovated reactor used in production of bio-diesel from methanol and soyabean-oil through transesterification reaction.

Ø  Irradiation of ultra sound of higher intensity

Ø  Reaction time generally 4 times reduced than the so-called conventional procedures

Ø  Amount of catalyst 2/3 times reduced than the conventional procedures

Ø  Molar ratios alcohol : oil = 6 : 1

Ø  Reaction performed at 60-65°C. [5]

Advantages: greater efficiency, greater flexibility, minimum consumption of energy, high purity of compounds without tedious work-up and purification stage.


This is the process established by the University College London for the production of titanium di-oxide nano- particles.

Titanium (IV) bis (ammonium-lactate) dihydroxide transforms to Bis ammonium lactate dihydroxide. There is supercritical water fed in the heater. Temperature is maintained at about 400-420°C and the pressure at 20-25 MPa. The flow-rates for three feeding streams are 20, 10 and 10 mL/min. The first stream is for supercritical water (pump1). The second is for TiBALD solution (pump2). The third is for cold water (pump3). The reactor is continuous Mixed Solution Mixed Product Removal (MSMPR) crystallizer. The rate of reaction of the continuous hydrothermal flow synthesis is significantly enhanced when being operated supercritically. Rate-constant k is around 6.2 at 400°C and the reaction typically follows the 1st order reaction-mechanism. [6]

Advantages: high throughput, avoids excessive cost of larger processes, operational conditions of the system optimally maintained.

Disadvantages: pool mixing, chances of blockages of pipes, scale-up might lead to over -heating.

CONTINUOUS R.E.S.S. PROCESS: [Rapid Expansion of Supercritical Solution]

Supercritical carbon di-oxide is one of the most extensively used technologies for the production of micro-and nano- particles of polymer. Compared to other conventional systems like spray-drying, milling, grinding, etc. this technique neither causes surface changes nor undergoes thermal denaturation. Supercritical carbon di-oxide serves the role of a very useful solvent. Solute is allowed to dissolve in it and then it is subjected to remove the pressure with the help of a nozzle under ambient condition which leads to a greater extent of supersaturation of the particles of the solute molecules thereby leading to formation of precipitate, nucleation and growth of the particles. Thus, finally the micro- or nano- particles are formed. [7]


Thus, for continuous flow processing in fine chemicals manufacture the process system must develop a real-time process analytical technique for monitoring the process concentration thereby limiting the hazards and defining the lines of safe operations. The continuous flow process avoids the risk of explosion as the techniques select the route of synthesis of the product in which the non-flammable reagents are chiefly selected. Nonetheless, efficient provision for whole-scale explosion testing is made on the final reactor system. Generally high yield of the product along with the purity of high extent can be achieved. This integrated system does not require any additional purification steps. [8]


1)      Carpenter, K J., 2001. Chemical Reaction Engineering Aspects of Fine Chemical Manufacture, Chemical Engineering Science, 56 (2), pp. 305-322.

2)      Lamb, Gareth W., Al Badran, Firas A., Williams, Jonathan M. J., Kolaczkowski, Stan T., 2010. Production of Pharmaceuticals: Amines from Alcohols in a Continuous Flow Fixed Bed Catalytic Reator, Chemical Engineering Research and Design, 88 (12), pp. 1533-1540.

3)      Kelly, Christopher B., Lee Christopher (Xiang), Leadbeater, Nicholas E., 2011, An Approach for Continuous Flow Processing of Reactions that Involve the In-situ Formation of Organic Products, Tetrahedron Letters, 52 (2), pp. 263-265.

4)      Tirronen Esko, Salmi Tapio, 2003, Process Development in the Fine Chemical Industry, Chemical Engineering Journal, 91 (2-3), pp. 103-114.

5)      Cintas Pedro, Mantegna Stefano, Gaudino, Emanuela C., Cravotto Giancarlo, 2010, A New Pilot-flow Reactor For High-intensity Ultrasound Irradiation: Application to the Synthesis of Biodiesel, Ultrasonics Sonochemistry, 17 (6), pp. 985-989.

6)      Mahmud Tariq, Chen Man, Ma, Cai Y., Darr, Jawwad A., Wang, Xue Z., 2011, Modelling and Simulation of Continuous Hydro-thermal Flow Synthesis Process for Nano-materials Manufacture, The Journal of Supercritical Fluids, 59, pp. 131-139.

7)      Chen, Ai Zheng, Zhao Zheng, Wang, Shi Biu, Li Yi, Zhao Chen, Liu, Yuan G., 2011, A Continuous RESS Process to Prepare PLA-PEG-PLA Microparticles, The Journal of Supercritical Fluids, 59, pp. 92-97.

8)      Workshops.







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SINHA ROY, P. (2017). Advantages and disadvantages of continuous flow processing in fine chemicals manufacture. PHILICA.COM Article number 1155.

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