Interdependency among Crystal Quality

Parameters

The crystal quality parameters are dictated by the

fundamental crystallization phenomena involved in a
process.

The process design and operation conditions govern

which of these fundamental phenomena are dominant
under given conditions.
Consequently, by controlling the process design and
operation conditions, we can influence the crystallization
phenomena active in a crystallizer, which in return
dictates the crystal quality parameters.

However, altering the process design and operation often

affects more than one of the quality parameters in an
interdependent manner.
This interdependency is best illustrated with a closer
look at polymorphic forms of a pharmaceutical
compound commonly known as ROY, 5-Methyl-2-[(2-
nitrophenyl)amino]-3-thiophenecarbonitrile (L.Yu et al
JACS 122 (2000) 585).

Altering the process conditions results in three

different polymorphic form of ROY (Form A, B & C
shown in Figure 8.9) with drastically different
morphologies and size distributions.
For instance, Form B is more aggregated than other
forms, its inter-grown morphology facilitates
undesired engulfment of solvent pockets)

Form B is consequently of lower purity. The needle-

shaped form C can cause problems in filtering forcing
alterations in the process design as needle form often
causes clogging in filtration process.
The ROY case shown in Figure 8.9 is a good example of
interdependency amongst crystal quality parameters.

It demonstrates that the product quality parameters are

intimately related to each other.

Moreover, crystal quality parameters depend on the

interplay among crystallization phenomena and process
design.
This network of interdependencies makes
crystallization the most complex and difficult to
control process among separation techniques
Interdependency of crystal quality, crystallization
phenomena and process design.
 PHASE DIAGRAMS

Understanding the crystallization starts with exploring

the equilibrium behavior or thermodynamics of
solutions.

Solution thermodynamics can be thought of as a balance

between intermolecular interactions.
By changing the thermodynamic state, we are
changing how molecules interact with each other and
their preferred phase.

For instance, a mixture of compounds A and B will

form a homogeneous one-phase solution if the
intermolecular interactions between A and B at a
thermodynamic state (at given Temperature and
Pressure and composition) are much stronger than the
interactions between A-A and B-B. In other words, A
will dissolve in B and form a homogeneous solution as
both A and B molecules prefer to be in the presence of
each other rather than their own kind.
This situation can change if the thermodynamic
state parameters are altered.

In crystallization, we change the thermodynamic

state parameters (temperature and/or pressure); so
that the system phase separates and forms two
phases (solid and liquid) from one homogeneous
solution or melt phase.

In crystallization, at least one of the phases is

crystalline with high purity.
Crystallization is the formation of a solid crystalline
phase from a supersaturated mother phase.

The success of crystallization process depends on the

phase diagram and the thermodynamic state is chosen
as operating conditions.

A phase diagram can be thought of a map describing

the thermodynamic conditions for stable phases. Figure
8.10 shows a binary eutectic at constant pressure.
Points phase diagram, Tm,A and Tm,B, correspond to
melting temperatures of pure crystalline compounds
of A and B.

Curves Tm,A-E and Tm,B-E indicate equilibrium

between the solution and the crystalline solid of A
and B, respectively.

Point E is the eutectic point where crystalline

compounds A and B and solution phases exist in
equilibrium.
Eutectic phase diagrams are encountered in most
inorganic compounds and many organics produced in
industrial crystallization.

In a binary eutectic, shown in Figure 8.10a, a pure

solid component is formed by cooling an unsaturated
solution until solids appear.

Continued cooling will increase the yield of pure

component.
At the eutectic point, both the components solidify and
additional purification is not possible.

Figure 8.10b shows another phase diagram for solid

solutions commonly encountered in melt
crystallization.

These phase diagrams are interpreted as the two

compounds A and B fit into each other’s crystal lattice
so that crystallization does not produce pure compound
A or B.
a) Solid–liquid phase diagram of a eutectic system and (b) a
binary solution system.
 Types of crystallizers

Factors that affect the choice of a crystallizer include:

 the production capacity,

 method of supersaturation generation and

 the desired crystal quality parameters, particularly,

crystal size and purity
Stirred tank and cooling disk crystallizer
The most widely used cooling crystallizer with a cooling
jacket due to its simple construction.

It is the go-to type for small-scale manufacturing and lab

experiments.

It can be used with all methods of supersaturation

generation.
Stirred tank crystallizers are utilized in cooling,
evaporative and vacuum crystallization approaches.

The stirred tank crystallizer may be as simple as a

shallow open pan heated by an open fire.

Steam-heated crystallizers are widely used to produce

common salt from brine and sugar refining.

These applications often use an evaporative crystallizer

containing calandria (steam chest)
The magma (mixture of crystals and solution)
circulates by dropping through the central
downcomer and then rises as it is heated in the
calandria.

At the top, some of the solution evaporates

increasing the supersaturation causing crystal growth
Forced circulation crystallizers
For large-scale production, more efficient heat transfer
is required to match high volume production rates.

The forced circulation crystallizer is a simple and highly

effective unit designed to provide high heat-transfer
coefficients in evaporative, cooling or vacuum mode.

They are commonly used with indirect heat transfer and

crystallization units, so that the heat transfer rates are
kept high in an external heat exchanger.
Depending on the heat exchanger function, the forced
circulation crystallizer can be operated in cooling
mode or evaporation mode.

Most systems are operated with a high recirculation

rate to provide good mixing inside the crystallizer and
high rates of heat transfer to minimize encrustation.
Schematic of (a) forced circulation cooling crystallizer and (b) force circulation
evaporative crystallization with external heat exchanger
Draft tube baffle crystallizer
Figure 8.23a shows a draft-tube-baffle (DTB)
crystallizer designed to provide preferential removal of
both fines and classified product.

A relatively low speed propeller agitator is located in a

draft tube, which extends to a few inches below the
liquor level in the crystallizer.

The steady movement of magma up to the surface

produces a gentle, uniform boiling action over the
whole cross-sectional area of the crystallizer.
Between the baffle and the outside wall of the
crystallizer, agitation effects are absent.

This provides a settling zone that permits regulation of

the magma density and control of the removal of
excess nuclei.

Flow through the annular zone can be adjusted to only

remove crystals below a certain size and dissolve them
in the fines dissolution exchanger.

Feed is introduced to the fines circulation line to

dissolve nuclei resulting from feed introduction.
Fluidized bed crystallizers
Another type of continuous crystallizer is the Oslo
fluidized-bed crystallizer shown in Figure 8.23b.

In units of this type, a bed of crystals is suspended in

the vessel by the upward flow of supersaturated
liquor in the annular region surrounding a central
downcomer.
The objective is to form a supersaturated solution in
the upper chamber and then relieve the
supersaturation through growth in the lower chamber.

The use of the downflow pipe in the crystallizer

provides good mixing in the growth chamber
a) Draft-tube-baffled crystallizer and (b) Oslo fluidized bed crystallizer. The
arrows show the direction of fluid flow.
Melt crystallizers

Melt crystallization is the process where crystalline

material is separated from a melt of the crystallizing
species by cooling.

Melt crystallization can be conducted via multiple counter

current contacting stages somewhat analogous to
distillation.

The main incentive is to attain higher purity product than

can be achieved in a single stage of conventional
crystallization.
The concept of a column crystallizer is to form a crystal
suspension and to force the solids to flow counter
currently against a stream of enriched reflux liquid by
gravity or rotating blades.

At the end of the crystallizer, the crystals are melted.

A portion of the melt is removed as product and the

remainder is returned to the system as enriched reflux to
wash the product crystals.
Vertical column melt crystallizer.
Vacuum crystallizers

Vacuum crystallizers utilize evaporation to both

concentrate the solution and cool the mixture.

They combine the operating principles of evaporative

and cooling crystallizers.

The hot liquid feed enters the crystallizer at a higher

pressure and temperature, where it flashes and part
of the feed evaporates.
Membrane-assisted crystallizers aim to control
evaporation rate through a membrane consequently
dictate the supersaturation in evaporative
crystallization.

Oscillatory crystallizers utilize structures such as draft

tubes and baffles combined with oscillatory flows to
enhance mixing hence enhance growth rates.

Microfluidic crystallizers can provide enhanced control

over heat and mass transfer within the crystallizer at
the expense of production rates.