Crystallisation Part II

Gavin DuffyDIT, Kevin St.

Activity - A crystallisationRead the crystallisation procedure taken from a pharmaceutical companyIn groups of two, discuss the purpose of each step in the processIdentify where the following events occur

NucleationSupersaturationCrystal growth

Crystallisation by CoolingSupersaturation by cooling is the most popular method of crystallisationMost components have a strong solubility dependence on temperatureNormally the crystallisation is achieved by following a cooling cycle where the crystalliser is cooled at a constant rate for a certain timeTypical rates of cooling are slow, 0.1 or 0.2 °C/minAlthough the rate is slow, the physical dimensions of the reactor and jacket capacity limit the maximum rate possibleThe rate may be changed after a certain time period (e.g. 2 hours)This creates a linear temperature profile over time

Typical Crystallisation by CoolingThe following linear temperature profile is often encountered

Temp

CC, T

emp

time

Optimal CoolingAn alternative is to use a non linear temperature profile where rate of cooling is slow at the start and speeds up as the crystallisation progressesThe 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 slowAs the surface area of the crystals increase, they can adsorb solute at a higher rate so the rate of cooling can be increasedSupersaturation is in theory a constant over the entire duration of the crystallisation

This results in a non linear temperature profile

Optimal CoolingNon linear temperature profile

Temp

CC, T

emp

time

Cooling and SeedingAddition of seed on its own creates crystallisationTherefore, there is no need to force crystallisation at the time of seeding as it is going to happen anywayCooling at the same time may create high rates of crystallisation and a lot of finesHold the temperature after seeding, do not coolThis is known as an isothermal ageBefore supersaturation is lost completely, start cooling

Optimal Cooling with Seeding

Isothermal age

Optimal Cooling

Con

cent

rati

on

Temperature

Seeding

MSZ

Anti Solvent AdditonAnti Solvent reduces solubilityCreates the same result as coolingCan be treated like cooling, i.e. add slowly at the start and increase rate of addition with timeMixing is extremely important with anti solvent additionWe 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 crystallisationC may vary throughout the crystalliser

Anti Solvent AdditionAnti solvent concentration and C will be highest near the anti solvent addition pointAdd anti solvent near the impellerAdd anti solvent at a high velocity – use a thin pipe to increase velocity and dispersion of anti solvent throughout the vesselAdd anti solvent at a number of points in the vessel

Activity – Compare two SOPsHave a look at the two SOPs for crystallisation of the same APICompare the initial SOP to the one that was created to address the prevention of finesSolubility curve for this material:

Solubility Curve

0

10

20

30

40

50

60

70

80

0 10 20 30 40 50 60 70 80 90

Temp deg C

g s

olu

te/l

itre

Crystallisation without thermal cycle

Crystallisation with thermal cycle

MixingIn a small lab scale vessel, mixing is good and homogeneity is quickly achievedThis is not so in a large vessel. It takes a lot of mixing or a long time to create a homogenous mixtureThis can create scale up issues where problems that were never noticed in the lab become evident in the plantFines prevention is important in crystallisation but high rates of agitation don’t tend to break up particles Low rates of mixing can also allow heavy particles to fall out of suspensionDon’t be conservative with mixing – poor mixing is bad for crystallisation

Measuring crystallisationCrystallisation is a mass transfer of solute from the liquid phase to the solid phaseAs crystallisation progresses

The liquid phase concentration of the solute decreasesThe particle size and number of particles increase

We can track crystallisation by measuringLiquid phase concentrationSolid phase particle size

Off line V In line measurementOff line involves removal of a sample from the vessel at regular intervals and transfer to a lab for measurementIssues

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 PATMethods include

FBRMReact IRPVMUSS

FBRMFocused Beam Reflectance MeasurementFocused laser beam in a rotating lens pointed into the crystalliserFocused just outside windowBackscatter of light gives particle sizeNumber of particles are counted alsoCSD data can be producedA large number of particles are counted and measured per revolution of laser (thousands)Location of probe important – usually in impeller region

Lasentec ProbeA laser beam focused just outside the probe window rotates around its circumferenceThe beam intersects the edges of particles and light is backscattered until the beam reaches the far edge of the particleThe distance measured is a chord lengthIt can measure tens of thousands of chords per secondMaterials that do not backscatter such as optical-grade glass beads cannot be measured with FBRM. 

FTIR SpectroscopyFourier Transform Infra Red SpectroscopyInfra red beam pointed into crystalliserReaction analysis in the liquid phaseCan identify and monitor reaction speciesNeeds an air purge to keep the view of the process free of solution materialAir purge must be CO free as CO absorbs IR

PVM and USSParticle Vision and Measurement

Video microscopeImage analysis of solid phase

Ultra Sonic particle SizingSample stream taken from vessel and passed through the USS on a continuous basis

Crystallisation EquipmentCSTR is the most common in pharmaceuticalsTank crystalliser – non agitated vessel. Solution is allowed to cool by natural convection without interferenceScraped 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.

Activity – Process VariablesIdentify the process variables of Crystallisation

What are the main process variablesWhat are the connected process variables

Draw a block diagram of a crystallisation system with feedback control. Identify

InstrumentControlled DeviceProcess