Nirav J Bhavsar

DDU
Nadiad
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

80
Solubility g/100g H2O
70

60

50

40

30

20

10

0
0 10 20 30 40 50 60 70 80 90 100
Tem p Deg C
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
Solubility curve - Saturation
diagram Supersaturated
Kg solute/100kg solvent
Concentration 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
 Supersaturated
Or Labile
kg solute/100kg solvent
Concentration

Metastable

Stable
Undersaturated

Temperature
 Supersaturated Supersaturated

kg solute/100kg solvent
kg solute/100kg solvent

Or Labile Or Labile
3
2
3 2 1
X

Concentration
Concentration

4 4 1
5
X
Metastable Metastable
Stable Stable
Undersaturated Undersaturated

Temperature Temperature
 Supersaturated
Or Labile
kg solute/100kg solvent
3 2

4 1
Concentration

X
Metastable
Stable
Undersaturated

Temperature
Determination of MSZW

Cool
kg solute/100kg solvent

1
Heat
2 Dilute
Concentration

Temperature
MSZW is a function of kinetics (wider for faster cooling)
AchievingLabile
Supersaturation
E
Concentration

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 inSupersat,
Concentration
C = C – C*
Nucleation
kg solute/100kg solvent
C

Crystal Growth
Concentration

C*

Temperature
Crystallisation

Ref: http://www.cheresources.com/cryst.shtml
Activity
B A
kg solute/100kg solvent
Concentration

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
Heterogeneous
Nucleation rate

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
Seeded V Unseeded
Unseeded
No. of Particles

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
 The following CSD is very common. 50 m crystals are the desired
outcome in this crystallisation. However, some fines are created also.
Counts

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