Crystallisation Part II

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Crystallisation Part II

• Gavin Duffy
• DIT, Kevin St.

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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

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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

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Typical Crystallisation by Cooling

• The following linear temperature profile is often
  encountered

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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

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Optimal Cooling

• Non linear temperature profile

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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

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Optimal Cooling with Seeding
Seeding
Isothermal age
MSZ
Concentration
Optimal Cooling
Temperature
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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

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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

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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

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Crystallisation without thermal cycle
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Crystallisation with thermal cycle
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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 dont tend to break
  up particles
• Low rates of mixing can also allow heavy
  particles to fall out of suspension
• Dont be conservative with mixing poor mixing
  is bad for crystallisation

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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

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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

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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

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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
  optical-grade glass beads cannot be measured with
  FBRM. 

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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

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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

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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.

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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