Crystallisation Part II
Gavin Duffy
DIT, Kevin St.
Activity - A crystallisation
Read the crystallisation procedure taken from a
pharmaceutical company
In groups of two, discuss the purpose of each step in
the process
Identify where the following events occur
Nucleation
Supersaturation
Crystal growth
Crystallisation by Cooling
Supersaturation by cooling is the most popular
method of crystallisation
Most components have a strong solubility
dependence on temperature
Normally the crystallisation is achieved by following a
cooling cycle where the crystalliser is cooled at a
constant rate for a certain time
Typical rates of cooling are slow, 0.1 or 0.2 °C/min
Although the rate is slow, the physical dimensions of
the reactor and jacket capacity limit the maximum
rate possible
The rate may be changed after a certain time period
(e.g. 2 hours)
This creates a linear temperature profile over time
Typical Crystallisation by Cooling
C, Temp
The following linear temperature profile is often
encountered
Temp
C
time
Optimal Cooling
An alternative is to use a non linear temperature
profile where rate of cooling is slow at the start and
speeds up as the crystallisation progresses
The rationale for this is as follows:
Cool slowly at the start to keep C low to prevent
high rates of nucleation. At this stage the rate of
mass transfer from liquid to solid phase is slow
As the surface area of the crystals increase, they
can adsorb solute at a higher rate so the rate of
cooling can be increased
Supersaturation is in theory a constant over the
entire duration of the crystallisation
This results in a non linear temperature profile
Optimal Cooling
Non linear temperature profile
C, Temp
Temp
C
time
Cooling and Seeding
Addition of seed on its own creates crystallisation
Therefore, there is no need to force crystallisation at
the time of seeding as it is going to happen anyway
Cooling at the same time may create high rates of
crystallisation and a lot of fines
Hold the temperature after seeding, do not cool
This is known as an isothermal age
Before supersaturation is lost completely, start
cooling
Optimal Cooling with Seeding
Seeding
Concentration
MSZ
Isothermal age
Optimal Cooling
Temperature
Anti Solvent Additon
Anti Solvent reduces solubility
Creates the same result as cooling
Can be treated like cooling, i.e. add slowly at the
start and increase rate of addition with time
Mixing is extremely important with anti solvent
addition
We want a homogenous mixture in the crystalliser
but if mixing is not good, we will get regions of high
anti solvent conc. and, as a result, high rates of
crystallisation. Other areas will have little anti
solvent and low rates of crystallisation
C may vary throughout the crystalliser
Anti Solvent Addition
Anti solvent concentration and C will be highest
near the anti solvent addition point
Add anti solvent near the impeller
Add anti solvent at a high velocity – use a thin pipe
to increase velocity and dispersion of anti solvent
throughout the vessel
Add anti solvent at a number of points in the vessel
Activity – Compare two SOPs
Have a look at the two SOPs for crystallisation of the same API
Compare the initial SOP to the one that was created to address
the prevention of fines
Solubility curve for this material:
Solubility Curve
80
70
g solute/litre
60
50
40
30
20
10
0
0
10
20
30
40
50
Temp deg C
60
70
80
90
Crystallisation without thermal cycle
Crystallisation with thermal cycle
Mixing
In a small lab scale vessel, mixing is good and
homogeneity is quickly achieved
This is not so in a large vessel. It takes a lot of
mixing or a long time to create a homogenous
mixture
This can create scale up issues where problems that
were never noticed in the lab become evident in the
plant
Fines prevention is important in crystallisation but
high rates of agitation don’t tend to break up
particles
Low rates of mixing can also allow heavy particles to
fall out of suspension
Don’t be conservative with mixing – poor mixing is
bad for crystallisation
Measuring crystallisation
Crystallisation is a mass transfer of solute from the
liquid phase to the solid phase
As crystallisation progresses
The liquid phase concentration of the solute
decreases
The particle size and number of particles increase
We can track crystallisation by measuring
Liquid phase concentration
Solid phase particle size
Off line V In line measurement
Off line involves removal of a sample from the vessel
at regular intervals and transfer to a lab for
measurement
Issues
Is the sample representative?
Is it still crystallising?
Can corrective action be taken?
In line measurements (not temperature) are known
as Process Analytic Technology or PAT
Methods include
FBRM
React IR
PVM
USS
FBRM
Focused Beam Reflectance Measurement
Focused laser beam in a rotating lens pointed into
the crystalliser
Focused just outside window
Backscatter of light gives particle size
Number of particles are counted also
CSD data can be produced
A large number of particles are counted and
measured per revolution of laser (thousands)
Location of probe important – usually in impeller
region
Lasentec Probe
A laser beam focused just outside the probe window
rotates around its circumference
The beam intersects the edges of particles and light
is backscattered until the beam reaches the far edge
of the particle
The distance measured is a chord length
It can measure tens of thousands of chords per
second
Materials that do not backscatter such as opticalgrade glass beads cannot be measured with FBRM.
FTIR Spectroscopy
Fourier Transform Infra Red Spectroscopy
Infra red beam pointed into crystalliser
Reaction analysis in the liquid phase
Can identify and monitor reaction species
Needs an air purge to keep the view of the process
free of solution material
Air purge must be CO free as CO absorbs IR
PVM and USS
Particle Vision and Measurement
Video microscope
Image analysis of solid phase
Ultra Sonic particle Sizing
Sample stream taken from vessel and passed
through the USS on a continuous basis
Crystallisation Equipment
CSTR is the most common in pharmaceuticals
Tank crystalliser – non agitated vessel. Solution is
allowed to cool by natural convection without
interference
Scraped surface crystalliser - a trough about 2 feet
wide with a semi-circular bottom. The outside is
jacketed with cooling coils and an agitator blade
gently passes close to the trough wall removing
crystals that grow on the vessel wall.
Vacuum crystalliser – hot saturated solution is fed to
a vessel which is under vacuum. At the new
pressure, the solution is above boiling point. This
helps in two ways.
1. The solution cools to the boiling point.
2. The solvent boils/evaporates.
Activity – Process Variables
Identify the process variables of Crystallisation
What are the main process variables
What are the connected process variables
Draw a block diagram of a crystallisation system with
feedback control. Identify
Instrument
Controlled Device
Process