FAQ

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).