Crystallisation

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/research/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

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 Or Labile Concentration Kg solute/100kg solvent 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 Concentration kg solute/100kg solvent Metastable Stable Undersaturated Temperature

Supersaturated Or Labile Supersaturated Or Labile 3 2 3 2 1 Concentration kg solute/100kg solvent Concentration kg solute/100kg solvent X 4 4 1 X 5 Metastable Metastable Stable Undersaturated Stable Undersaturated Temperature Temperature

Supersaturated Or Labile 3 2 4 1 Concentration kg solute/100kg solvent X Metastable Stable Undersaturated Temperature

Cool 1 Heat 2 Dilute Concentration kg solute/100kg solvent 3 4 Temperature Determination of MSZW • MSZW is a function of kinetics (wider for faster cooling)

Labile E Concentration D C A B Metastable Stable Temperature Achieving Supersaturation 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 Supersat, C = C – C* Nucleation C Crystal Growth Concentration kg solute/100kg solvent C* Temperature

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

B A Concentration kg solute/100kg solvent C D Temperature Activity 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)

Heterogeneous Homogeneous Nucleation rate Supersaturation Primary Nucleation

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. Unseeded No. of Particles Seeded Time

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

Crystallisation