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The Practical Aspects of Batch Crystallization:

Design, Optimization & Scale-up

Dr. Paul Barrett, Lasentec

Paulb@lasentec.com

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Monitoring and Quantifing Polymorphic CrystallizationsThe Application of Raman

James WardPaul Barrett MT AutoChem

Polymorphism & Crystallization Forum 2003 November 12, 2003

Internet -jamesw@lasentec.com

Phone (484) 343-5514

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Presentation overview

• Brief introduction of raman and overview of particle size

• Case studies that highlight the benefit and considerations of Raman

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PVM Images: Particle shape and crystallization

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FBRM: Lab to Production

Lab to Plant installations

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Introduction to Raman

Phenomena documented in 1928 – Raman & KrishnanC.V. Raman and K.S. Krishnan Nature 501 (1928), p. 3048.

Until relatively recently considered purely as an academic technique

Several key technologies changed that perspective; - compact lasers scientific CCD detectors - volume holographic element

- easy-to-use computing platforms

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FBRM/Raman in 1 probe

Source: Laser

Illumination Fiber

Collection Fiber

Probe

CCD Detector

Echelle Grating

MirrorProbe Diameter : 19 mm

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What is Raman?“We’re not talking noodles here”

Raman - Based on measurements of inelastic scattering of monochromatic light from moleculesMonochromatic light striking a molecule changes the electron distribution resulting in scattering (release of energy) of radiation.

hn0

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Raman Spectroscopy

Anti-Stokes

Infrared Raman

Electronic levels

Vibrational levels

Virtual levels

RayleighFluorescence

Stokes

Molecule of

interest

Elastically Scattered light

Majority of scattered light is elastically scattered light

Raman scattering is a low probability event

Approx 0.0001% of photons show a shift in frequency – i.e. Raman scattering

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What does Raman measure in polymorphism?

Polymorphs => Different intermolecular bonding

Slightly different electron distributions in ‘molecular enviroment’ & ‘lattice enviroment’

=> Shift in Raman spectra

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Spectrum Comparison-Polystyrene

FT-IR Transmission Spectrum

FT-Raman Spectrum

20

40

60

80

%T

ran

smit

tan

ce

1

2

3

4

Ram

an In

ten

sity

1000 2000 3000 4000

Wavenumbers (cm-1)

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Hydration of Carbamazepine (CBZ) Background

Carbamazepine (CBZ) Tegretol-Xr® Carbatrol® Atretol® Tegretol®

Indicated for the treatment of epilepsy, trigeminal neuralgia, bipolar affective disorder and acute mania

Four known Forms - Marketed as Form I

FDA recalled the product from the market for dissolution problems 5 times in the last 5 years

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Recent References

Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder,

International Journal Of Pharmaceutics, Volume 246, Issue 1-2, October 10, 2002, Pages 121-134

Murphy, D; Rodríguez-Cintrón, F; Langevin, B; Kelly, R C; Rodríguez-Hornedo, N

Solid-state study of polymorphic drugs: carbamazepine,

Journal Of Pharmaceutical And Biomedical Analysis, Volume 23, Issue 1, August 1, 2000, Pages 41-54

Rustichelli, C; Gamberini, G; Ferioli, V; Gamberini, M C; Ficarra, R; Tommasini, S

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Hydration of CBZ

Objectives

– Follow Hydration of CBZ with FBRM & PVM

Form I

Form IICBZ dihydrateSlurry in Water

Heat

Slurry in EtOH

Heat

Slur

ry in

Wat

er

Polymorphism of CBZ

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#/Sec (1-5 Microns)

#/Sec (10-25 Microns)

#/Sec (30 - 100 Microns)

#/Sec (100-500 Microns

The Hydration - Particle Dynamics via FBRM & PVM

Anhydrous CBZ

Charged

PVM ImageTrended FBRM particle counts

Ch

ord

s P

er S

eco

nd

(n

ot

to s

cale

)

TimeMicrons

Mic

ron

s

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#/Sec (1-5 Microns)

#/Sec (10-25 Microns)

#/Sec (30 - 100 Microns)

#/Sec (100-500 Microns

The Hydration - Particle Dynamics via FBRM & PVM

Anhydrous CBZ

Charged

PVM ImageTrended FBRM particle counts

Ch

ord

s P

er S

eco

nd

(n

ot

to s

cale

)

TimeMicrons

Mic

ron

s

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#/Sec (1-5 Microns)

#/Sec (10-25 Microns)

#/Sec (30 - 100 Microns)

#/Sec (100-500 Microns

The Hydration - Particle Dynamics via FBRM & PVM

Dry material disperses

Increase in coarse

particles as material

aggregates and dip in

fines

PVM ImageTrended FBRM particle counts

Ch

ord

s P

er S

eco

nd

(n

ot

to s

cale

)Time

Microns

Mic

ron

s

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#/Sec (1-5 Microns)

#/Sec (10-25 Microns)

#/Sec (30 - 100 Microns)

#/Sec (100-500 Microns

The Hydration - Particle Dynamics via FBRM & PVM

PVM ImageTrended FBRM particle counts

Ch

ord

s P

er S

eco

nd

(n

ot

to s

cale

)

TimeMicrons

Mic

ron

s

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#/Sec (1-5 Microns)

#/Sec (10-25 Microns)

#/Sec (30 - 100 Microns)

#/Sec (100-500 Microns

The Hydration - Particle Dynamics via FBRM & PVM

Platelets disappear (drop in coarse)Needles appear

(increase in fine counts)

PVM ImageTrended FBRM particle counts

Ch

ord

s P

er S

eco

nd

(n

ot

to s

cale

)

TimeMicrons

Mic

ron

s

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#/Sec (1-5 Microns)

#/Sec (10-25 Microns)

#/Sec (30 - 100 Microns)

#/Sec (100-500 Microns

The Hydration - Particle Dynamics via FBRM & PVM

PVM ImageTrended FBRM particle counts

Ch

ord

s P

er S

eco

nd

(n

ot

to s

cale

)

TimeMicrons

Mic

ron

s

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#/Sec (1-5 Microns)

#/Sec (10-25 Microns)

#/Sec (30 - 100 Microns)

#/Sec (100-500 Microns

The Hydration - Particle Dynamics via FBRM & PVM

PVM ImageTrended FBRM particle counts

Ch

ord

s P

er S

eco

nd

(n

ot

to s

cale

)

TimeMicrons

Mic

ron

s

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#/Sec (1-5 Microns)

#/Sec (10-25 Microns)

#/Sec (30 - 100 Microns)

#/Sec (100-500 Microns

The Hydration - Particle Dynamics via FBRM & PVM

PVM ImageTrended FBRM particle counts

Ch

ord

s P

er S

eco

nd

(n

ot

to s

cale

)

TimeMicrons

Mic

ron

s

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#/Sec (1-5 Microns)

#/Sec (10-25 Microns)

#/Sec (30 - 100 Microns)

#/Sec (100-500 Microns

The Hydration - Particle Dynamics via FBRM & PVM

Coarse increase

again- Needle

lengthening

PVM ImageTrended FBRM particle counts

Ch

ord

s P

er S

eco

nd

(n

ot

to s

cale

)

TimeMicrons

Mic

ron

s

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#/Sec (1-5 Microns)

#/Sec (10-25 Microns)

#/Sec (30 - 100 Microns)

#/Sec (100-500 Microns

The Hydration - Particle Dynamics via FBRM & PVM

Steady state is achieved

No additional significant change in

dimension, shape or

number of crystals

PVM ImageTrended FBRM particle counts

Ch

ord

s P

er S

eco

nd

(n

ot

to s

cale

)

TimeMicrons

Mic

ron

s

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How can Raman be utilized for the CBZ example?

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Spectral changes during CBZ hydration

A) PEAK INTENSITY CHANGES

B) PEAK SHIFTS

TIME

TIM

E

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Raman & FBRM – Complementary technologies

Form 1

Dihydrate

HOWEVER,

We know that particle number, dimension

and shape are changing over time.

Can this effect the Raman interpretation?

Chemometrics utilized to trend ‘concentration of each form

over time

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Why is Raman signal influenced by particles?

Consider backscatter turbidity:

Light striking a particle is scattering in all directions

Vast majority of light collected coming back towards the probe has the same wavelength as the outgoing light.

This phenomena is termed elastic light scattering

How does light interact with a particle system?

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Turbidity: Time/Intensity

The turbidity measurement is a convoluted function of:

Solids Concentration

Particle Size

Particle Shape

Particle Size/Shape Distribution

If three of these four properties are held constant, the fourth can be quantified.

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Turbidity: same reading,different particle systems

= = =

Same Projected area, different size and different solids concentration.

Same Turbidity Measurement

Same Turbidity Measurement

= = =

Same Projected area, different shape and possibly different solids concentration.

FBRM can be utilized to detect differences based on dimension, number and shape of particles under investigation

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What about Raman?

From a theory perspective, it appears that the backscatter intensity, for a given material at a given wavelength as measured by a bulk measurement instrument like turbidity, is directly proportional to the Raman intensity.

It is evident from experimental data that particle concentration, particle dimension and particle shape can effect the Raman intensity.

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Utilizing Raman for crystallizations

Is there a relationship between particle dimension and particle concentration and the intensity of the

peaks in the Raman Spectra?

Raman intensities change as material

dimension (and shape) are changed

Some Recent Work:Ensuring Robust Polymorph Isolation Using In-Situ Raman Spectroscopy

George Zhou, Ph.D., Jian Wang*, Ph.D., Zhihong Ge, Ph.D., Yongkui Sun, Ph.D

Merck Research Laboratories, Merck & Co.,

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Example 3:

The influence of Particle Dimension and Particle Number on Raman Spectra

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Two model materials selected

Mannitol and Sucrose

Not polymorphs, but 2 distinct Raman spectra

Mannitol peak at 875 cm-1

Sucrose peak at 845 cm-1

Investigate effect of Particle Concentration and Particle Dimension on Raman Spectra using this simple system

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As the solids concentration of the fine sucrose increases, there is a direct linear relationship between the solids

concentration and the intensity of the Raman Sucrose peak

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

0 2 4 6 8 10 12

Fine Sucrose concentration (g/100 ml Toluene)

Ram

an P

eak

Inte

nsi

ties

Increasing concentration of fine sucrose

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Raman is a function of the particle system

The Raman measurement is a convoluted function of:

A - Solids Concentration

B - Particle Size

C- Particle Shape

D - Particle Size/Shape Distribution

Just like turbidity, if 3 of these variables are held constant the other can be quantified directly.

In this case, B,C,D are constant

=> Directly correlate Raman to solids concentration

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10 g of large Sucrose,

10 g of milled Sucrose

So what if size of material is changed?

Chord Length Microns

Ch

ord

s P

er S

eco

nd

Reduction in coarse

Increase in fines

Milled

Large Sucrose

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Raman Spectra

Peak height of coarse 5025

Peak height of fines 4315

No change in solids concentration, but a 15% change in signal !!!

Particle size changed, solids concentration held constant

Intensity Change

N.B.

Although we have seen behavior in both directions,

( i.e. increase in signal with reduction in size at same concentration, as well as decrease for different materials)

Always the same behavior for the same materials.

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As the solids concentration of the fine sucrose and fine mannitol changes, there is a direct linear relationship between the solids concentration and the intensity of the Raman peaks of each ‘form’

Samples of 2 materials of relatively the same size, but changing their ratios

Fine Mannitol (wt %)

Fine Sucrose (wt %)

0 100 20 80 50 50 80 20

100 0

Increasing Mannitol conc

Decreasing Sucrose conc

0

2000

4000

6000

8000

10000

12000

14000

0 10 20 30 40 50 60 70 80 90 100

Mannitol concentation (wt %)

Ra

ma

n P

ea

k I

nte

ns

itie

s

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The Raman intensities no longer correlate to relationship on slide 56

=> Particle Dimension and Particle Concentration have large influence

Samples of 2 materials of DIFFERENT sizes, and changing their ratios

0

2000

4000

6000

8000

10000

12000

14000

0 10 20 30 40 50 60 70 80 90 100

Mannitol concentation (wt %)

Ra

ma

n P

ea

k I

nte

ns

itie

s

Fine material obscures the

coarseFine Mannitol (wt %)

COARSE Sucrose (wt %)

0 100 20 80 50 50 80 20

100 0

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As illustrated on the previous slide, If particle concentration or particle dimension increase or decrease, intensity

changes in the Raman spectra do not reflect true changes in polymorph ratios

Need to take into account changes in Particle Dimension and Concentration over time

FBRM/Raman and chemometrics

Utilizing Raman for dynamic crystallizations

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Liquid Phase peaks also change with changing particle size and particle concentration

The toluene peak is heavily effected by the dimension and number of particle present.

It is therefore difficult to use Raman to track quantitatively the liquid phase concentration in the presence of solids

Solids concentration is constant, but dimension varies

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Building calibration curve without taking into consideration

effects of dimension and concentration is not

advised

Quantitative information from Raman

We have to go back and check the

reasonable assumptions we

have made in the past.

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Raman is sensitive to solids Concentration, this may be linear or non-linear depending on particle size/shape distribution. More work to be done.

Raman is intensity is a function of particle size, in some cases trends in same direction, some cases inverse, depends on the system, but most likely a constant within a system.

Summary

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If two different solids are present, such as Polymorph A and Polymorph B, the Particle Size distribution and solids concentration of each, and the change of these variables can influence NOT ONLY their own Raman Intensity response, but also the response of the other polymorph.

The liquid concentration measurement shown by Raman, in the presents of particles, must be tracked in relationship to the change in the particle system.

The Particle System is a integral part of the optical system, Raman research in particle systems must take the change in the particle system into account

Summary