Crystallisation

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 50m.

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/research/crystallization/project05Accessed 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 – NaClSolubility Curve NaCl in H2O

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

Temp Deg C

So

lub

ility

g/1

00g

H2O

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

Temperature

Con

cent

rati

onK

g so

lute

/100

kg s

olve

nt SupersaturatedOr Labile

Metastable

Stable

Stable zone – crystallisation not possibleMetastable zone MSZ – crystallisation possible but not spontaneousLabile – crystallisation possible and spontaneousWe need a supersaturated solution for crystallisation

Temperature

Con

cent

ratio

nkg

sol

ute/

100k

g so

lven

t

SupersaturatedOr Labile

Metastable

StableUndersaturated

Temperature

Con

cent

ratio

nkg

sol

ute/

100k

g so

lven

t SupersaturatedOr Labile

Metastable

StableUndersaturated

X123

4

5

Temperature

Con

cent

ratio

nkg

sol

ute/

100k

g so

lven

t SupersaturatedOr Labile

Metastable

StableUndersaturated

X1

23

4

Temperature

Con

cent

ratio

nkg

sol

ute/

100k

g so

lven

t

SupersaturatedOr Labile

Metastable

StableUndersaturated

X1

23

4

Determination of MSZW

Temperature

Con

cent

rati

onkg

sol

ute/

100k

g so

lven

t Cool

Heat1

Dilute2

3

4

MSZW is a function of kinetics (wider for faster cooling)

Achieving Supersaturation

Temperature

Con

cent

rati

on

Labile

MetastableStable

A

D

B

C

E

ABC - If A is cooled, spontaneous nucleation not possible until C is reached. No loss of solventADE – If solvent is removed, nucleation occurs at ECan 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 solubilityWhen solubility is high and above methods are not

desirable, or in combination with above methodsThe 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

Temperature

Con

cent

rati

onkg

sol

ute/

100k

g so

lven

tSupersat, C = C – C*

Nucleation

Crystal Growth

C

C*

Crystallisation

Ref: http://www.cheresources.com/cryst.shtml

Activity

Temperature

Con

cent

rati

onkg

sol

ute/

100k

g so

lven

t B

D

A

C

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

Supersaturation

Nuc

leat

ion

rate

Heterogeneous

Homogeneous

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

With unseeded nucleation does not occur till later when supersaturation is higher. High rate of nucleation follows.

No.

of

Par

ticl

es

Time

Seeded

Unseeded

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.

Crystal Size

Cou

nts

Fines problem

50m

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