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In flow chemistry, chemical reactions occur in a flowing fluid rather than a stirred tank (batch). This generally requires pumps and a reactor that can be monitored for specific temperatures and pressures. This type of production is developed to replace the batch production as well as to facilitate continuous manufacturing.

What are advantages of flow chemistry over batch chemistry?

• Safer
  
  In batch, reagents are loaded into a reactor at once. A large volume of hazardous chemicals can be unsafe. This is opposed to flow chemistry, where reagents are gradually and continuously sent to a reactor. The smaller volumes provides a safe environment to carry out aggressive reactions. Also, headspace is absent in flow reactions, and thereby the reactor can be easily pressurized by a back pressure regulator (BPR).
• More efficient
  
  With smaller sizes, flow reactors promote heat and mass transfers by providing a high surface area to volume ratio. This increases overall kinetics of the reactions. For some processes, multiple reactions need to be operated in series. In flow, they can be telescoped so that unstable intermediates can be sent to another flow reactor before chemical decomposition.
• Better control
  
  Residence time can be precisely controlled by matching a reactor’s volume with a flow rate. Also, with better heat transfer, the reactor can be maintained uniformly at a specified temperature. Heat can dissipate out effectively from the reactor in case of exothermic reactions.
• Easier to scale
  
  Fluid hydrodynamics (e.g. mixing) is much simpler in flow than in batch. Agitation in batch typically generates non-uniform droplet sizes, which are difficult to predict across different scales.

What are known examples of chemical syntheses that are done in flow?

There have been many chemical syntheses that benefit from flow, such as highly exothermic reactions that require efficient cooling and photochemistry that require a large surface upon exposure to light. Multistep synthesis containing sensitive metal-hydride or potentially explosive organic azides can be telescoped in a closed flow system such that those chemical species can be consumed as soon as they are generated from the previous step.

• Reduction with metal hydride (e.g. DIBALH reduction)
• Exothermic oxidation
• Organic azide chemistry, click reaction
• Photochemistry
• Solid-supported synthesis
• Organometallic chemistry (e.g. Grignard reaction)
• Nanoparticle synthesis
• Coupling reaction

A membrane or a semi-permeable material is commonly used for separation because it consumes less energy than such other techniques as distillation and crystallization. Almost all industries, ranging from food to pharmaceutical to biotechnology, use membrane technology in at least one of their unit operations. The separation in a membrane can be driven by pressure or by a concentration gradient. The membrane can be fabricated from organic material (e.g., polymers), or inorganic materials (e.g., ceramic, zeolite, emulsion liquid).

Fundamentally, the applications of membranes can be divided into three major categories:

Particle exclusion by pore size

This approach uses a membrane to physically capture particles or molecules that are larger than the pore sizes or the molecular-weight cut off of membranes. The examples of this technique include microfiltration, ultrafiltration, and nanofiltration.

Diffusion facilitating barrier

Components are first absorbed into a membrane. The separation factor depends on the difference in solubility and diffusion among different components. The examples using this type of approach include gas permeation, pervaporation, and supported-liquid membrane.

Membrane extraction

In this application, a membrane acts as a barrier for two immiscible phases. One of the phases will be preferentially wetting the membrane while the other is non-wetting. Each phase carries a certain amount of species of interest.

Liquid-liquid extraction refers to contact between two immiscible liquid phases. One of the phases is a feed containing components to be separated while the other is generally a solvent. The latter sometimes contains an extractant, a chemical species that facilitate extraction by binding or forming molecular complexes with components of interest.

The two liquid phases that come out of the extractor are called the raffinate and the extract. The raffinate refers to the phase rich in the same carrier solvent as the feed, while the extract refers to the phase rich in the extraction solvent. One example is the extraction of succinic acid from water using ethyl acetate: the feed is the aqueous solution of succinic acid, the extraction solvent is ethyl acetate, the raffinate is the remaining aqueous solution of succinic acid, and the extract is the succinic acid in ethyl acetate.

How to quantify performance of extraction?

We can assess whether the chosen solvent is suitable by examining the partition ratio. The partition ratio (K), or interchangeably termed as partition coefficient or distribution ratio, is defined as the ratio of the solute concentration in the extract phase to that in the raffinate phase after one equilibrium extraction. The partition ratio is dimensionless, but it is important to note that concentration units used in the calculation of K as different units could produce different values of K.

Sometimes, the extraction involves more than one component. A separation factor, αi, j, is used to assess how selectively the extraction can separate different components. The separation factor, αi, j, is typically defined as the partition ratio of component i divided by that of component j.

What are major types of extraction?

Extraction can be classified by different criteria:

Standard extraction is aimed to extract one solute from the feed to the solvent while fractional extraction is aimed to separate two or more components such that a fraction of components are leaving with the raffinate and others are leaving with the extract phase. The analogies of standard and fractional extractions are gas stripping and fractional distillation, respectively.

Extraction can be set up to be performed multiple times to increase separation levels. The extraction can be operated with single-stage, crosscurrent, and countercurrent. The crosscurrent extraction involves sequential extractions. The raffinate from a previous stage will be in contact with the fresh solvent. The countercurrent extraction requires an arrangement such that the feed and the extraction solvent have countercurrent (i.e., opposite) flows.

Selection of extractors can vary from one industry to another. Many decisions depend on feed and solvent properties such as density difference, viscosity, stability of solute, and interfacial tensions. Sometimes, the extractor is chosen because of the industry’s experience and knowledge of the equipment and scale-up procedure.

Simplified drawings show major types of liquid-liquid extraction equipment: (far left) static column, (second from left) agitating column, (top right) mixer settler, (bottom right) membrane technology.

Static extraction column

This type of equipment refers to a column containing trays or packing materials. They are often used in petrochemical industries. The application is limited to systems with low viscosity, low to moderate interfacial tension, and only a few number of stages. The disadvantages are low mass-transfer efficiency due to the absence of active agitation.

Agitated extraction column

For systems with moderate to high interfacial tensions, agitation may be needed to create dispersion with better control of drop size and distribution. Examples are rotating-impeller, Scheibel, and reciprocating-plate columns. The scale-up procedure involves rough hydrodynamic and geometric similarity estimation between pilot-plant and production-scale designs. Occasionally, individual stages are structured differently to accommodate variation across the column.

Mixer-settler

Mixer settlers are similar to batch-wise separatory funnels. They are commonly used in hydrometallurgical and high-value chemical productions because of its flexibility and ability to handle solids. It generally provides high stage efficiency, as the mixing speed and settling time can be precisely controlled. Nevertheless, the excessively strong mixing is problematic because it creates small droplets that are difficult to separate by settling.

Centrifugal extractors

In this type of extractors, centrifugal force is used to simultaneously facilitate the mass transfer and liquid-liquid phase separation. This equipment is particularly useful for systems with small density difference or with unstable solutes that require short contact time. However, the centrifugal machine is expensive, and requires high maintenance costs.

Membrane-based extractors

Membrane-based extractors separate two liquid-liquid phases using selective wettability. So, it is more suitable for systems containing liquids with similar densities. It can be done for a wide range of flowrates. The separation is completed within short time and with minimal energy consumption.

Axial mixing

This refers to the behavior of the dispersed and continuous phase flows that deviate from an ideal plug flow. This increases a residence time distribution and minimizes the solute concentration driving force throughout the equipment. Therefore, the overall performance is decreased. To resolve the problem, the equipment is designed to accommodate a larger capacity or to guide the direction of the liquid phase.

Flooding

This phenomenon refers to a breakthrough of one liquid phase to an outlet of the other liquid phase in a countercurrent flow operation. Flooding often occurs because of excessive solvent-to-feed ratio, throughput and agitation intensity. A plot between a certain process variable and the maximum throughput before the flooding begins to occur is called a flooding curve. Many columns are operated at 40-60 % of the flooding point because the actual process may contain surface-active impurities and variations in the design.

Short residence time required

Many systems contain unstable solutes that require short contact time. Gravity-based columns and mixer-settlers are not suitable because of the slow coalescence. Centrifugal and membrane-based extractors allow high mass-transfer and phase-separation rates.

Emulsions

Stable dispersion cause problems like flooding. Formation of emulsions can be promoted by low interfacial tension and density differences and the presence of surfactants. According to Perry’s handbook, systems with < 3 mN/m or Δρ < 0.05 are likely to form stable dispersions, which take several hours or longer to collapse.

Reference: Perry, Robert H., D. W. Green, and J. O. Maloney. “Perry’s handbook of chemical engineering.” Perry’s Handbook of Chemical Engineering (1997).