Monitoring and quantifing polymorphic crystallizations (james ward 111203)compressed
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Transcript of Monitoring and quantifing polymorphic crystallizations (james ward 111203)compressed
LASENTEC
The Practical Aspects of Batch Crystallization:
Design, Optimization & Scale-up
Dr. Paul Barrett, Lasentec
LASENTEC
Monitoring and Quantifing Polymorphic CrystallizationsThe Application of Raman
James WardPaul Barrett MT AutoChem
Polymorphism & Crystallization Forum 2003 November 12, 2003
Internet [email protected]
Phone (484) 343-5514
LASENTEC 2
Presentation overview
• Brief introduction of raman and overview of particle size
• Case studies that highlight the benefit and considerations of Raman
LASENTEC 3
PVM Images: Particle shape and crystallization
LASENTEC 4
FBRM: Lab to Production
Lab to Plant installations
LASENTEC 5
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
LASENTEC 6
FBRM/Raman in 1 probe
Source: Laser
Illumination Fiber
Collection Fiber
Probe
CCD Detector
Echelle Grating
MirrorProbe Diameter : 19 mm
LASENTEC 7
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
LASENTEC 8
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
LASENTEC 9
What does Raman measure in polymorphism?
Polymorphs => Different intermolecular bonding
Slightly different electron distributions in ‘molecular enviroment’ & ‘lattice enviroment’
=> Shift in Raman spectra
LASENTEC10
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)
LASENTEC11
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
LASENTEC12
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
LASENTEC13
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
LASENTEC14
#/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
LASENTEC15
#/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
LASENTEC16
#/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
LASENTEC17
#/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
LASENTEC18
#/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
LASENTEC19
#/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
LASENTEC20
#/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
LASENTEC21
#/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
LASENTEC22
#/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
LASENTEC23
#/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
LASENTEC24
How can Raman be utilized for the CBZ example?
LASENTEC25
Spectral changes during CBZ hydration
A) PEAK INTENSITY CHANGES
B) PEAK SHIFTS
TIME
TIM
E
LASENTEC26
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
LASENTEC27
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?
LASENTEC28
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.
LASENTEC29
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
LASENTEC30
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.
LASENTEC31
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.,
LASENTEC32
Example 3:
The influence of Particle Dimension and Particle Number on Raman Spectra
LASENTEC33
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
LASENTEC34
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
LASENTEC35
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
LASENTEC36
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
LASENTEC37
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.
LASENTEC38
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
LASENTEC39
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
LASENTEC40
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
LASENTEC41
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
LASENTEC42
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.
LASENTEC43
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
LASENTEC44
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