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

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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

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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

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35000

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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

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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