Crystallisation
Gavin Duffy
DIT, Kevin St.
Learning Outcomes
After this lecture you should be able to…..
 Describe crystal growth and nucleation
 Define the constituents of a solution and degrees of saturation
 Describe the solubility curve
 List three methods of achieving supersaturation/crystallisation
 Describe nucleation and crystal growth
 Give an example of crystallisation
 Analyse a crystallisation process in a pharmaceutical plant
 Explain how to crystallise by cooling
Crystallisation - Introduction
 Crystallization refers to the formation of solid crystals from
a homogeneous solution.
 It is a solid-liquid separation technique
 Used to produce
 Sodium chloride
 Sucrose from a beet solution
 Desalination of sea water
 Separating pharmaceutical product from solvents
 Fruit juices by freeze concentration
 Crystallisation requires much less energy than evaporation
 e.g. water, enthalpy of crystallisation is 334 kJ/kg and
enthalpy of vaporisation is 2260 kJ/kg
What is a crystal?
 A crystal is a solid form of substance (ice)
 Some crystals are very regularly shaped and can be
classified into one of several shape categories such rhombic,
cubic, hexagonal, tetragonal, orthorhombic, etc.
 With pharmaceuticals, crystals normally have very irregular
shapes due to dendritic growth which is a spiky type
appearance like a snowflake. It can be difficult to
characterise the size of such a crystal.
 Crystals are grown to a particular size that is of optimum use
to the manufacturer. Typical sizes in pharmaceutical
industry are of the order of 50m.
Crystallisation
In general, crystallisation should be a straightforward
procedure. The objective is to grow crystals of a particular
size or crystal size distribution (CSD). If this is not
successful, problems that can occur are:
 Inconsistency from batch to batch
 Difficult to stir and filter
 Crystals damaged in filtration/agitation
 Creation of polymorphs
 Difficult to dry
Crystal Size Distribution - CSD
A crystal
Paracetamol crystals
precipitated from acetone
solution with compressed
CO2 as antisolvent using
the GAS technique
Source
http://www.ipe.ethz.ch/laboratories/spl/researc
h/crystallization/project05
Accessed 131106
Solutions, Solubility and Solvent
 A solid substance (solute) is termed soluble if it can dissolve
in a liquid (the solvent) to create a solution
 The solution is a homogenous mixture of two or more
components
 Solubility is normally (but not always) a function of
temperature
 Solubility can change if the composition of the solvent is
changed (e.g. if another solvent is added)
 Solubility is usually measured as how many grams of
solvent can be dissolved in 100 grams of solute
Solubility curve – sucrose
Ref: http://www.nzifst.org.nz/unitoperations/conteqseparation10.htm
Solubility curve – NaCl
Solubility Curve NaCl in H2O
100
90
Solubility g/100g H2O
80
70
60
50
40
30
20
10
0
0
10
20
30
40
50
60
Tem p Deg C
70
80
90 100
Saturation
 An Unsaturated or Undersaturated solution can dissolve
more solute
 A saturated solution is one which contains as much solute as
the solvent can hold
 A Supersaturated solution contains more dissolved solute
than a saturated solution, i.e. more dissolved solute then can
ordinarily be accommodated at that temperature
 Two forms of supersaturation
 Metastable – just beyond saturation
 Labile – very supersaturated
 Crystallisation is normally operated in the metastable region
Concentration
Kg solute/100kg solvent
Solubility curve - Saturation diagram
Supersaturated
Or Labile
Metastable
Stable
Temperature
Stable zone – crystallisation not possible
Metastable zone MSZ – crystallisation possible but not spontaneous
Labile – crystallisation possible and spontaneous
We need a supersaturated solution for crystallisation
Concentration
kg solute/100kg solvent
Supersaturated
Or Labile
Metastable
Stable
Undersaturated
Temperature
3
2
4
1
X
5
Metastable
Stable
Undersaturated
Temperature
Concentration
kg solute/100kg solvent
Concentration
kg solute/100kg solvent
Supersaturated
Or Labile
Supersaturated
Or Labile
3
4
2
1
X
Metastable
Stable
Undersaturated
Temperature
Concentration
kg solute/100kg solvent
Supersaturated
Or Labile
3
2
4
1
X
Metastable
Stable
Undersaturated
Temperature
Concentration
kg solute/100kg solvent
Determination of MSZW
Cool
1
Heat
2
Dilute
3
4
Temperature
 MSZW is a function of kinetics (wider for faster cooling)
Achieving Supersaturation
Concentration
Labile
E
D
C
B
A
Metastable
Stable
Temperature
ABC - If A is cooled, spontaneous nucleation not possible
until C is reached. No loss of solvent
ADE – If solvent is removed, nucleation occurs at E
Can combine cooling and evaporation
Crystallisation Techniques
 In general crystallisation is achieved by
 Cooling a solution
 If supersaturation is a function of temperature
 Removal of the solvent by evaporation
 Where supersaturation is independent of temperature
(e.g. common salt)
 Addition of another solvent to reduce solubility
 When solubility is high and above methods are not
desirable, or in combination with above methods
 The new solvent is called the anti solvent and is
chosen such that the solubility is less in this new
solution than it was before
Change in Concentration
Concentration
kg solute/100kg solvent
Supersat, C = C – C*
Nucleation
C
Crystal Growth
C*
Temperature
Crystallisation
Ref: http://www.cheresources.com/cryst.shtml
Concentration
kg solute/100kg solvent
Activity
B
A
C
D
Temperature
Explain what is happening in each stage from A to D in the
above crystallisation
Supersaturation, C
 Supersaturation is the driving force for
 Nucleation
 Crystal Growth
 Creation and control of supersaturation is the key to
successful crystallisation
 High C  High Crystal Growth + High Nucleation
 High nucleation means a lot of fines (filtration problems)
 High crystal growth means inclusion of impurities
 C is usually maintained at a low level in the
pharmaceutical industry so the right CSD is achieved
Activity – How would you crystallise?
 Have a look at the solubility curves provided
 List the three techniques for achieving supersaturation
 Which would you use and why?
Nucleation
 Crystallisation starts with Nucleation
 There are two types of nucleation – Primary and Secondary
 Primary relates to the birth of the crystal, where a few tens
of molecules come together to start some form of ordered
structure
 Secondary nucleation can only happen if there are some
crystals present already. It can occur at a lower level of
supersaturation than primary nucleation.
 Often, industrial crystallisers jump straight to secondary
nucleation by ‘seeding’ the crystalliser with crystals
prepared earlier
Primary Nucleation
 The birth of a new crystal is complex and involves the
clustering of a few tens of molecules held together by
intermolecular forces
 Homogeneous – small amounts of the new phase are formed
without any help from outside
 Heterogeneous – nucleation is assisted by suspended
particles of a foreign substance or by solid objects such as
the wall of the container or a rod immersed in the solution –
these objects catalyse the process of nucleation so it occurs
at lower levels of supersaturation
 Homogenous conditions are difficult to create so
heterogeneous nucleation is more normal in industrial
crystallisation (if it is not seeded)
Primary Nucleation
Nucleation rate
Heterogeneous
Homogeneous
Supersaturation
Secondary Nucleation
 Secondary nucleation is an alternative path to primary nucleation and
occurs when seed crystals are added
 Nucleation occurs at a lower supersaturation than primary when crystals
are already present
 Secondary nucleation is due to:
 Contact nucleation – crystals are created by impact with agitator or
vessel wall. Nuclei are created by striking a crystal – the number
created is related to the supersaturation and the energy of impact.
Can occur at low supersaturation.
 Shear nucleation – shear stresses in the boundary layer of fluid flow
create new crystals/nulcei. Embryos are created and swept away that
would have been incorporated into an existing crystal
 Very important in industrial crystallisers as this is the main type of
crystal growth used
 Difficult to predict or model nucleation rates
Supersaturation and Crystal Growth
 For low supersaturation primary nucleation is not
widespread. Secondary nucleation on existing crystals is
more likely. Result is small numbers of large crystals
 For high supersaturation primary nucleation is widespread.
This results in many crystals of small size.
 Slow cooling with low supersaturation creates large crystals
 Fast cooling from high supersaturation creates small crystals
 Agitation reduces crystal size by creating more dispersed
nucleation
 Rate of cooling can affect purity of product - see handout on
slow cooling v rapid cooling
Seeding
 The type or quality of seed used can influence the
crystallisation process
 Good seed results in a good crystallisation, i.e. a particle size
distribution that does not include fines
 Bad seed can increase the amount of fines produced
 Good and Bad can be defined by the seed crystal size
 Source of seed can be
 Material left from the last batch (no tight control on
particle size)
 Specially prepared material or material from a good
batch (tight particle size distribution)
When to Seed?
 Seed can be added dry to the crystalliser
 Allow time for dispersion throughout the crystalliser – this
can take several hours
 Never seed to the right of the solubility curve – the solution
is not yet ready
 Never seed to the left of the solubility curve – nucleation is
already happening
 Seed half way between the two
No. of Particles
Seeded V Unseeded
Unseeded
Seeded
Time
 With unseeded nucleation does not occur till later when
supersaturation is higher. High rate of nucleation follows.
Seeding – advantages, disadvantages
 Advantages include
 Point of nucleation from batch to batch is repeatable
 Reduces the number of fines
 Improves predictability of scale up
 Can prevent polymorphism
 Disadvantages
 Experience has shown that not any seed will do, good
quality seed is needed
 Extra addition point on vessel or hand hole is usually
opened to manually add seed which could create health
and safety issues
Crystal Growth
 Once nucleation has occurred crystal growth can happen
 The objective of crystallisation is to produce the required
crystal size distribution (CSD)
 The actual CSD required depends on the process
 Crystal growth rate has proved difficult to model and
empirical relationships developed from laboratory tests are
generally used
 Two steps to crystal growth
 Diffusion of solute from bulk solution to the crystal
surface
 Deposition of solute and integration into crystal lattice
CSD
Counts
 The following CSD is very common. 50 m crystals are the desired
outcome in this crystallisation. However, some fines are created also.
Fines problem
50m
Crystal Size
Impurities and Crystal Growth
 Impurities can prevent crystal growth
 If concentration of impurities is high enough crystals will
not grow
 Should not be an issue in the pharmaceutical industry
 For example, the production of non crystalline sweets such
as lollipops (sugar crystals give an unwanted grainy texture)
 Addition of acid breaks sucrose into fructose and glucose
 This makes it difficult for sucrose crystals to form
because the impurities damage the structure
 Addition of other sugars creates the same result