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Application to Drug Application to Drug Substance CrystallizationSubstance Crystallization
Marino NebuloniREDOX – MonzaParma University
Objectives of the presentationObjectives of the presentation
1.Crystallization principles
2.What are QbD (Quality by Designe) and PAT (Process Analytical Technique)?
3.Analytical Techniques for PAT Application
4.Examples of PAT in Crystallization of API
5.Summary
Crystallization ProcessesCrystallization Processes1 Crystallization is a core technology of
many sectors in the chemical processand allied industries
2 Involves a variety of business sectors, e.g. .Agrochemicals, catalysts, dyes/pigments, electronics, food/confectionery, health products, nano-materials,nuclear fuel, personal products & pharmaceuticals
3 Processes can involve complex process chemistry together with non-ideal reactor hydrodynamics.Hence can be difficult to understand and scale-up from laboratoryto production scale operation
4 Crystallization also forms part of a wider process system
Crystallization Process SystemsCrystallization Process Systems
CRYSTAL CHARACTERISTICSCRYSTAL CHARACTERISTICS
Phase EquilibriaPhase EquilibriaUnderstanding phase equilibria is crucial to Understanding phase equilibria is crucial to
crystallizer operationcrystallizer operation
Solubility-supersolubility diagram
SupersaturationSupersaturation
Supersaturation, ∆c, is sometimes called the “concentration driving force”
Crystallization KineticsCrystallization Kinetics
particle formation processes depend upon supersaturationparticle formation processes depend upon supersaturation
Process Analytical TechnologyProcess Analytical Technology(PAT)(PAT)
in the assessment and control theCritical VariablesCritical Variables
in Crystallization Processes
The application of PAT to the The application of PAT to the crystallization meanscrystallization means
understandunderstand
IDENTIFICATIONIDENTIFICATION
MEASUREMENTMEASUREMENT
PREDICTIONPREDICTION
PATPAT
PATPAT
Analytical
Analytical
SensorSensor
Process
Process Control
ControlDa
ta
Data
Anal
ysis
Anal
ysis
Qual
ity a
nd
Qual
ity a
nd
Haza
rd
Haza
rd
desi
gnde
sign
Scientific Contributions for the Scientific Contributions for the application of the PATapplication of the PAT
Fundamental Approach in DevelopmentFundamental Approach in Development
Real Time Controlfor ContinuousImprovement
Quality by Design
Data Derived From Trial & Error Experimentation
Decision Based On Univariate Approach
Causal Links Predict Performance
Traditional Approach
Identification of PCCP*
DOE (Multivariate Systems Approach)
Modeling forMechanistic Understanding PAT
Scale UpPrediction
PCCP* – Process Critical Control Parameter
Impact of OnImpact of On--line Process Analyzersline Process Analyzers- Crystallization Crystallization --
Quality/ProductivityQuality/ProductivityMechanistic & kinetic knowledgeParametric boundaryAccess to extreme conditionsReal time monitoring & controlContinuous quality assurance
Raw Material Reaction Purification Crystallization
Isolation & Drying
PAT
API
Application for OnApplication for On--line Process Monitoringline Process Monitoring- Crystallization Crystallization --
Physical properties
intrinsicintrinsic externalexternal
SOLID STATESOLID STATE
••Reaction CalorimetryReaction Calorimetry
••FTFT--IR/ATR spectroscopyIR/ATR spectroscopy
••Raman SpectroscopyRaman Spectroscopy
•• FBRM FBRM --Focuse BeamReflectance Focuse BeamReflectance MeasurementsMeasurements
IInstrumentnstrument characteristic requirementscharacteristic requirementsfor for onon--lineline process monitoringprocess monitoring
Spectroscopic TechniquesSpectroscopic Techniques• NIRNIR Light Scattering (laser)Light Scattering (laser)•• FTFT--IR/ATRIR/ATR MassMass--SpectrometrySpectrometry•• RamanRaman XX--ray ray (Diffraction & Fluorescence)(Diffraction & Fluorescence)
Analytical Techniques available on Analytical Techniques available on the marketthe market
Turbidimetric and Rifractometric TechniquesTurbidimetric and Rifractometric Techniques••TurbidimetryTurbidimetry••Densitometry Densitometry –– rifractometry rifractometry
Particles physical and morphologic propertiesParticles physical and morphologic properties••Particle Size (FBRM)Particle Size (FBRM)••PhotoacusticPhotoacustic••EtcEtc..
Measurement technology Measurement technology reviewreview
REVIEWREVIEW
Polymorphism and Particle Size modification during acrystallization process controlled by
RC1, FT- IR/ATR and FBRM
•During a crystallization process of an API was observed :
•at the first step after seeding :
* crystals with large Particle Size andpolymorphic Form I
•at the second step (cooling phase):
* Increase of small crystals instead ofgrowth and transformation of the solid into polymorphic Form II
First Step : Lab ScaleFirst Step : Lab ScaleFTFT--IR/ATR & FBRM (Lasentec) into RC1 calorimeterIR/ATR & FBRM (Lasentec) into RC1 calorimeter
RC1RC1
FT-IR/ATR
-
FBRMFBRM
Heat developed on the crystallization
-1
0
1
2
3
4
5
50 100 150 200 250 300
time (min)
0
5
10
15
20
25
30
35
40
Reactor Temperature
Heat Flow
Conversion
Crystallization Heat of API recorded by RC1Crystallization Heat of API recorded by RC1
seeding ||-------- Form I Form I -------------------- Form I I Form I I ------||
Esempio I – Valore medioMean Diameter and Particles count by FBRM
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50 100 150 200 250 300 350Time (min)
N°T
otal
e di
Par
ticel
le
0
5
10
15
20
25
30
35
40
Dia
met
ro M
edio
(um
)Tr=36-->19°C
Seeds
(1)
(2)
(3)
(4) (5)
MeanMean diameterdiameter
N° Particles MaximumGrowth Rate
Crystallization Profile and distribution of particles
0
50
100
150
200
250
300
350
400
450
50 100 150 200 250 300 350
Time (min)
N°C
onte
ggi
0
5
10
15
20
25
30
35
40
Dia
met
ro M
edio
(um
)
Tr=36-->19°C
Seeds
(1)
(2)
(3)
(4)(5)
DIAMETRO MEDIO
50 um
250 um
Esempio I – FT-IRPolymorphic Form modification during the crystallizationcontrolled by FT-IR/ATR
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50 100 150 200 250 300 350
Time (min)
N°T
otal
e di
Par
ticel
le
-0.05
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
Con
cent
razi
one
Rel
ativ
a
Tr=36-->19°C
Seeds
(1)
(2)
(3)
(4)
(5)
FormForm II (Final)
N° Particles
FormForm I (initial)
Second Step: labSecond Step: lab--max & mini plantmax & mini plant
Heat developed on the crystallization
-1
0
1
2
3
4
5
50 100 150 200 250 300
time (min)
0
5
10
15
20
25
30
35
40
Reactor Temperature
Heat Flow
Conversion
Crystallization induced by the cosolvent
-2
0
2
4
6
8
10
12
14
16
18
100 120 140 160 180 200 220 240 260 280
time (min)
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
Conversion
Heat flow
Reaction Calorimetry Reaction Calorimetry –– RC1 RC1 profilesprofiles
With only one With only one solventsolvent(standard process)(standard process)
Modify Modify methodmethod(with co(with co--solvent)solvent)
Seeds addition
Third Step: production scaleThird Step: production scale
OnOn--line Control of crystallization line Control of crystallization of polymorphic forms and Particle of polymorphic forms and Particle
Size by FBRM (Lasentec)Size by FBRM (Lasentec)Active Principle (API) can exist into two polymorphic formsActive Principle (API) can exist into two polymorphic forms
Form I - m.p = 222 °C
By slow cooling
Form II - m.p = 219 °C
By rapid cooling
Batch Cooling Crystallizer:Experimental Set-Up
c1IR: Concentration Measurement 1(Oscillating U-Tube Measurement)
c2IR: Concentration Measurement 2(Ultrasound Velocity Measurement)
TuIR: Turbidometer (Backscatter Measurement) CSDIR: Crystal size Distribution Measurement (Chord Length Measurement FBRM)
TICRTICR
c1IR TuIR
c2IR
CSDIR
jacketed crystallizer
nICR
FBRM FBRM (Focused Beam Reflectance Measurement)(Focused Beam Reflectance Measurement)
Probe schemeProbe scheme
Particle Size distribution by FBRM Particle Size distribution by FBRM during the cooling stepsduring the cooling steps
Cooling step from 90 to Cooling step from 90 to 55 55 °°CC
Particle Size Particle Size distribution on the time distribution on the time at 55at 55°°CC
Final Particle Size distribution Final Particle Size distribution in relation to the process temperaturein relation to the process temperature
FBRM application for monitoring an API crystallization process
influenced by pH, concentration, Temperature and Induction time
FBRM on lineFBRM on line
Critical Quality Paramiters
Concentration
Filtrability
pHSolid state
Induction
Time
Information collected on the time during Information collected on the time during the crystallizationthe crystallization
Induction Time
0 time
Time
GrowingNucleation
Scale-upLaboratoryLaboratory
Definition of CQa
F.B.R
.M.
ProductionProduction
Quality ControlP.A.T.
F.B.R
.M.
Optimization
Experimental Data
0
1000
2000
3000
4000
5000
6000
7000
8000
0.00.00 2.24.00 4.48.00 7.12.00 9.36.00 12.00.00 14.24.00 16.48.00 19.12.00
Tempo (h)
N° p
artic
elle
0
5000
10000
15000
20000
25000
30000
Particelle 1-3 umParticelle 3-5 umParticelle 5-10 umParticelle 10-21 umParticelle 23-50 umParticelle 54-100 umN° totale di particelle
Inizio 2h
pH= 6.7 concentration : A mg/mLPoor filtrability
Filtrazione
pH
ConcentrazioneNO F
6.7
A
F
6.7
A
NO F
7
A
NO F
7
B
NO F
6.7
B
F
6.7
B
F
7
B
F7A
Design Of Experiment
0
1000
2000
3000
4000
5000
6000
0.00.00 2.24.00 4.48.00 7.12.00 9.36.00 12.00.00 14.24.00 16.48.00 19.12.00
tempo (h)
N° p
artic
elle
0
5000
10000
15000
20000
25000
N° p
artic
elle
tota
li
1-2 um3-5 um5-10 um10-21 um21-50 um54-100 umN° totale particelle
Inizio 3h
Filtrability
pH
ConcentrationNO F6.7A
F6.7A
NO F7A
NO F7B
NO F6.7B
F6.7B
F7B
F7A
Final Result
3 h
0.5 h
2 h
0 h
Time
Impact of Agitation on Particle Size DistributionImpact of Agitation on Particle Size Distribution
Effect of Agitated DryingEffect of Agitated Drying
Monitoring in Tumble DryerMonitoring in Tumble Dryer
ContinuousContinuous Crystallization Crystallization controlled by PATcontrolled by PAT
AIMS
1. To deliver consistent crystal quality (morphology, size and sizedistribution), not achieved consistently in large batch operations.
1. To investigate additional manufacturing advantages of COBC for crystallisation in continuous or semicontinuous modes
1. Improved filterability;
1. Reduced crystallisation time, space usage and utility and energyconsumption;
1. Provision of seeding along the flow path.
ContinuousOscillatory Baffled Crystalliser
•• CContinuousMaterial moves continuously through
• OscillatoryAlthough there is a net flow through the unit, the local flow moves back and forth
• BaffledSmall baffles are installed along the length to promoteturbulence and hence mixing
. ReactorOr crystalliser, or extractor, or…
Courteously by Jon-Paul Sherlock, AstraZeneca
How is mixing achieved?
Mixing Mechanism
• Mixing controlled by oscillation• Plug flow at relatively low flows• Each cell is a CTSR• Handles particulates
material moves through thecrystalliser
Well controlled cooling rateWell controlled cooling rate
Product performanceProduct performance
Summary Summary Advantage of PAT applicationAdvantage of PAT application
i) Understanding of the uncertainties of the process;ii) Identification and quantification of the failure
mechanisms on the crystallization process iii) Estimation of the risks associated with each step of
the process.iv) Documentation of physical characteristics for the
Regulatory Requirements
Thank you for your attention !
Marino NebuloniParma University