Post on 25-Jun-2020
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PPXRD-12
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Beijing, China
Fabia Gozzo
Excelsus Structural Solutions SPRL, Brussels -Belgium
Advances in Synchrotron XRPD for the Enhanced
Characterization of Pharmaceuticals
This document was presented at PPXRD -Pharmaceutical Powder X-ray Diffraction Symposium
Sponsored by The International Centre for Diffraction Data
This presentation is provided by the International Centre for Diffraction Data in cooperation with the authors and presenters of the PPXRD symposia for the express purpose of educating the scientific community.
All copyrights for the presentation are retained by the original authors.
The ICDD has received permission from the authors to post this material on our website and make the material available for viewing. Usage is restricted for the purposes of education and scientific research.
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Outlook
I. Role of structural analysis in the pharmaceutical industry
II. Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD)
III. Synchrotron XRPD in the field of pharmaceuticals
IV. Conclusions
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Why is structural analysis relevant to the
pharmaceutical industry?
Polymorphism and the relation between structure ↔ properties
Microstructural properties (e.g. influence of stress and strain, particle size
and domain)
Form B at 112 ◦C, monoclinic
P 21
a= 20.05795 Å
b= 11.12509 Å
c= 10.13290 Å
b= 116.18377 °
Form D at 20 ◦ C, orthorhombic
P 21 21 21
a= 14.90622 Å
b= 11.73977Å
c= 11.08386Å
n-Bu
Me
Me
N H
O
N
S
HCl·
Example of
Bupivacaine Hydrochloride
Gozzo, Masciocchi , Griesser, Niederwanger, 2010. Personal Communication
I. Role of Structural Analysis in the Pharmaceutical Industry
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Properties influenced by the solid state structure of
substances and, therefore, influenced by polymorphism:
Solubility
Pharmacokinetics and pharmacodynamics
Thermodynamic properties (e.g. stability of drugs) in-situ non-ambient
time-resolved studies
Spectroscopic properties
Mechanical properties (e.g. hardness, compressibility, tableting, tensile
strength)
I. Role of Structural Analysis in the Pharmaceutical Industry
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Polymorphic studies play a key role throughout the whole life-cycle of products
X-ray Powder Diffraction,
in particular with
synchrotron radiation is a
unique and powerful
technique for such studies
* Example of carbamazepine (see Organic Crystal Engineering, Eds. Tiekink, Vittal & Zaworotko, Wiley 2010)
Compound selection
• Identification and characterization of individual polymorphic
forms and selection of desired form
Technical development
• Development of manufacturing processes to ensure high and
reproducible content of desired polymorphic form
• Polymorphic studies for impurity detection and stability studies
• Crystal engineering (e.g. co-crystallization*)
Commercial production
• Polymorphic characterization to support (1) process validation,
(2) comparability studies following process changes, and (3)
investigations to assess impact of deviation on product quality
Fight against counterfeit drugs
Intellectual Property (IP)
I. Role of Structural Analysis in the Pharmaceutical Industry
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What makes synchrotron-XRPD
such a powerful analytical tool?
II. Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD)
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Our 3 ingredients for state-of-the-art SR-XRPD
A. An efficient synchrotron facility and beamline optics
B. State-of-the-art diffractometers
C. Outstanding detection systems
II. Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD)
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Our 3 ingredients for state-of-the-art SR-XRPD
A. An efficient synchrotron facility and beamline optics
B. State-of-the-art diffractometers
C. Outstanding detection systems
II. Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD)
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Our 3 ingredients for state-of-the-art SR-XRPD
A. An efficient synchrotron facility and beamline optics
B. State-of-the-art diffractometers
C. Outstanding detection systems
Schmitt et al, 2003,
Bergamaschi, Schmitt et al, 2010 Hodeau et al, 1998
Multicrystal Analyser
MYTHEN II
II. Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD)
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A. Synchrotron facility and beamline optics
Properties:
High Spectral Brightness: 1012-1015
photons/sec in small beams (mm2 to mm2)
Tunable and monochromatic photon
energy
Polarization
Time structure
Coherence
Benefits
Efficient data collection, high statistics
Time-resolved in-situ non ambient XRD
Photon-consuming experimental set ups
Penetration of highly absorbing materials
Variable d-spacing resolution
large unit cells (many reflections at very low
angles)
XRD near absorption edges (anomalous
dispersion)
II. Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD)
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Swiss Light Source-Materials Science beamline
Powder Diffraction station
B. State-of-the-art diffractometers
Properties:
Resolution: 1 arcsec
Accuracy: ±2 arcsec
Precision: ±1 arcsec
Large working space and flexibility
Benefits
Great mechanical stability
Highest flexibility to accommodate all
kinds of sample environments
II. Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD)
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Properties:
Angular selection of diffracted beam
Fluorescence suppression
C. Outstanding detection systems
Properties:
Solid state modular microstrip detector
Large dynamic range (24 bits)
Single photon counting read out
Fluorescence suppression
Very fast acquisition times (subsec) Hodeau et al, 1998 Multicrystal Analyser
Schmitt et al, 2003,
Bergamaschi, Schmitt et al, 2010
MYTHEN II
Benefits:
Ultra-high resolution (better than 0.003°)
Angular resolution independent of sample
dimension and position
Independence of transparency effect
High S/N and S/B
Trade-off:
Long measurements (min to hours) radiation damage
Benefits:
120o angular coverage at SLS
High d-spacing resolution
0.004o inherent angular resolution
Capable of simultaneously detecting strong and weak signals
Sub-sec time resolution XRPD for in-situ kinetic studies
Trade-off:
Resolution limited by sample dimension
Sensitive to the uniformity of powder distribution in sample
holder, granularity, statistical orientation
II. Synchrotron Radiation X-Ray Powder Diffraction (SR-XRPD)
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Synchrotron XRPD in the field of pharmaceuticals
Indexation, structural solutions & microstructural analyses
Fast and dose-controlled SR-XRPD
Quantitative Phase Analysis (L.o.D, L.o.Q)
In-situ kinetic studies
Bruni, Gozzo et al, Thermal, spectroscopic, and ab initio structural characterization of carprofen polymorphs, J. Pharm. Sci.2011,
100(6), 2321-2332
Bergamaschi et al, The MYTHEN detector for X-ray powder diffraction experiments at the Swiss Light Source, J. Synchrotron Rad.
(2010). 17, 653–668
Gozzo et al, Instrumental profile of MYTHEN detector in Debye-Scherrer geometry, Z. Kristallogr. 225 (2010) 616–624
Brunelli et al, Solving Larger Molecular Crystal Structures from Powder Diffraction Data by Exploiting Anisotropic Thermal
Expansion, (2003). Angew. Chem. 115, 2075–2078.
Graesslin et al, Advances in exploiting preferred orientation in the structure analysis of polycrystalline materials, J. Appl. Cryst.
(2013). 46, 173–180
Karavassili et al, Structural studies of human insulin cocrystallized with phenol or resorcinol via powder diffraction, Acta
Crystallogr D Biol Crystallogr. 2012 Dec;68(Pt 12):1632-41
III. Synchrotron XRPD in the field of pharmaceuticals
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Minimization of radiation damage control with fast and
dose-controlled SR-XRPD
Radiation Damage is the alteration of the structural and chemical properties of the material under
investigation induced by its exposure to electromagnetic radiation. It is dose and energy dependent
In XRD patterns we observe shift (usually anisotropic) and broadening of reflections and their
progressive disappearance it usually undermines the success of structural solution
The effect is very serious at 3rd generation synchrotron facilities and affects the
study of organic compounds, in particular pharmaceuticals
III. Synchrotron XRPD : Dose-controlled SR-XRPD
Our high-resolution, fast and dose controlled SR-XRPD
measurements have opened a new gate to the systematic
structural analyses of organic compounds!
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Gozzo F. , 2008
See: Bergamaschi et al, J. Synchrotron
Rad. (2010). 17, 653–668
1 mm capillary,
Mythen data at 50% reduced intensity
No radiation damage up to 3min
Large counting statistics
in subsec acquisition times
In-situ kinetic studies of organic
compounds!
III. Synchrotron XRPD : Dose-controlled SR-XRPD
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Why is Quantitative Phase Analysis relevant to the
pharmaceutical industry?
Polymorphic purity: detect and quantify unwanted polymorphic forms in both
drug substance and drug product
Level of Detection (LoD)
Level of Quantitation (LoQ)
Assess the polymorphic composition in drug substance and product
In formulated materials, the API/excipients relative proportion is paramount
and needs to be kept under control
Degree of Crystallinity in amorphous/crystalline mixtures
III. Synchrotron XRPD applications: Quantitative Phase Analysis
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Quantification of organic compound mixtures can be achieved via different
methods (e.g. spectroscopic, thermal and diffraction methods)
Diffraction methods are direct methods diffraction information is directly
produced by the crystal structure of the component phases in the mixture
Quantitative phase analysis with conventional lab-XRPD is widely used and an
established practice in the pharmaceutical industry LoD and LoQ down to
very few % wt is achieved with reasonable acquisition time and powder
volumes
III. Synchrotron XRPD: Quantitative Phase Analysis
Can SR-XRPD achieve considerably lower LoD and LoQ without
increasing costs and complexity?
With our fast and dose controlled SR-XRPD we were able to directly
detect and quantify traces of API as low as 0.05% wt in mixtures
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2q (degree)
Dif
frac
ted i
nte
nsi
ty (
a.u
.)
11.811.611.411.21110.810.610.410.2109.89.6
50'000
49'500
49'000
48'500
48'000
47'500
47'000
46'500
46'000
45'500
45'000
44'500
44'000
43'500
Minority phase: Indomethacin
Majority phase (intensity up to 1.5 M counts): Haloperidol
0.05 %
0.1 %
1.0 %
5 %
QPA of a binary API physical mixtures with fast SR-XRPD
Indo % wt
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API mixtures are often characterized by an inhomogeneous distribution of the
phase components
SR-XRPD in Debye-Scherrer geometry (transmission in glass capillaries) probes
relatively small powder volumes
SR-XRPD patterns were recorded at several locations on the glass
capillary and the effect on the accuracy of our QPA was studied
III. Synchrotron XRPD: Quantitative Phase Analysis
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Whole-patterns QPA Methods
Rietveld Method
Rietveld, JAC (1969). 2, 65
Hill & Howard, JAC (1987). 20, 467-474
• all phases should be crystalline and a valid structure model available for all phases in the mixture
• amorphous or unknown phases quantified as a group by generating absolute phase abundances for
the analyzed phases (e.g. internal standard)
Rietveld-like Methods (PONKCS and Quanto+) NO structural model required!
Scarlett & Madsen, Powder Diffr. 21(4), 2006, 278-284
Giannini, Guagliardi & Mililli, JAC (2002). 35, 481-490
real structure factors substituted with empirical values derived from whole patterns refinement on
pure phases
Requirements: pure phases available (PONKCS & Quanto+), spiked pure phases (PONKCS)
Benefits: Rietveld-like QPA with only partial structural knowledge (PONKCS & Quanto+),
with NO structural knowledge (PONKCS), application to amorphous materials
(PONKCS)
III. Synchrotron XRPD: Quantitative Phase Analysis
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Whole-pattern QPA refinements on very diluted API mixtures
Mea
sure
d (
wt%
)
Weighed (wt%)
0
1
2
3
4
5
6
0 1 2 3 4 5 6
Rietveld PONKCS Quanto+ Average over multiple
powder volumes
III. Synchrotron XRPD: Quantitative Phase Analysis
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The average of %wt values at individual capillary powder volumes was consistent
with %wt values from merged diffraction patterns
Mea
sure
d (
wt%
)
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Weighed (wt%)
Rietveld PONKCS Quanto+ Average over multiple
powder volumes
Whole-pattern QPA refinements on very diluted API mixtures
III. Synchrotron XRPD: Quantitative Phase Analysis
Copyrights Excelsus Consortium www.excels.us fabia.gozzo@excels.us
PPXRD-12
20-24 May, 2013
Beijing, China
Whole-pattern QPA refinements on very diluted API mixtures
Mea
sure
d (
wt%
)
Weighed (wt%)
0
1
2
3
4
5
6
0 1 2 3 4 5 6
Rietveld PONKCS Quanto+ Average over multiple
powder volumes
individual powder
volumes
III. Synchrotron XRPD: Quantitative Phase Analysis
The average of %wt values at individual capillary powder volumes was consistent
with %wt values from merged diffraction patterns
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5% Indomethacin + 95% Haloperidol
0.250.240.230.220.210.20.190.180.170.160.15
24'000
22'000
20'000
18'000
16'000
14'000
0.250.240.230.220.210.20.190.180.170.160.15
0.250.240.230.220.210.20.190.180.170.160.15
84'000
82'000
80'000
78'000
76'000
74'000
72'000
70'000
68'000
66'000
64'000
62'000
60'000
58'000
56'000
54'000
52'000
50'000
48'000
46'000
44'000
42'000
Minority
phase
0.16 0.17 0.18 0.19 0.20 0.21
1/d (Å-1)
Dif
fract
ed i
nte
nsi
ty (
a.u
.)
Fast- SR-XRPD
HR- SR-XRPD
Lab-XRPD
2 min
100 min
17 min
0.22 0.23 0.24 0.25
III. Synchrotron XRPD: fast SR-XRPD vs HR-SR-XRPD and Lab-XRPD
HR-XRPD: A.Fitch, ID31, ESRF
Lab-XRPD: I. Madsen, CSIRO, Australia
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0.250.240.230.220.210.20.190.180.170.160.15
30'000
28'000
26'000
24'000
22'000
20'000
18'000
16'000
0.16 0.17 0.18 0.19 0.20 0.21 0.22 0.23 0.24 0.25
1/d (Å-1)
0.250.240.230.220.210.20.190.180.170.160.15
0.250.240.230.220.210.20.190.180.170.160.15
56'000
54'000
52'000
50'000
48'000
46'000
44'000
42'000
40'000
Dif
fract
ed i
nte
nsi
ty (
a.u
)
1% Indomethacin + 99% Haloperidol
Fast- SR-XRPD
HR- SR-XRPD
Lab-XRPD
Minority
phase 4.5 min
60 min
17 min
III. Synchrotron XRPD: fast SR-XRPD vs HR-SR-XRPD and Lab-XRPD
HR-XRPD: A.Fitch, ID31, ESRF
Lab-XRPD: I. Madsen, CSIRO, Australia
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0.250.240.230.220.210.20.190.180.170.160.15
0.250.240.230.220.210.20.190.180.170.160.15
84'000
82'000
80'000
78'000
76'000
74'000
72'000
70'000
68'000
66'000
64'000
62'000
60'000
58'000
56'000
54'000
52'000
50'000
48'000
46'000
44'000
42'000
0.16 0.17 0.22 0.23 0.24 0.250.240.230.220.210.20.190.180.170.160.15
28'000
26'000
24'000
22'000
20'000
18'000
16'000
14'000
0.250.240.230.220.210.20.190.180.170.160.15
0.250.240.230.220.210.20.190.180.170.160.15
50'000
48'000
46'000
44'000
42'000
0.25
Dif
fract
ed i
nte
nsi
ty (
a.u
.)
80 min
17 min
Fast- SR-XRPD
20 min
HR- SR-XRPD
Lab-XRPD
0.05% Indomethacin + 99.95% Haloperidol
Minority
phase
0.18 0.19 0.20 0.21
1/d (Å-1)
III. Synchrotron XRPD: fast SR-XRPD vs HR-SR-XRPD and Lab-XRPD
HR-XRPD: A.Fitch, ID31, ESRF
Lab-XRPD: I. Madsen, CSIRO, Australia
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In-situ dynamic study of the LaNi5 hydrogen absorption process
• In-situ hydrogen absorption at 15 bar • In-situ desorption by connecting the cell to a vacuum pump • Continuous measurements using the μstrip detector while the reaction takes place • Acquisition times between 5 and 20 sec per pattern, depending on the reaction kinetic.
Courtesy of Prof. Cerny, Uni. Geneva - Joubert et al. Acta Materialia, 54 (2006), 713-719
13 14 15 16 17 18 19
2q (°)
0 5 10 15 20 25 30 35 400
20
40
60
80
100
t (s)
0 5 10 15 20 25 30 35 400
1
2
3
4
5
6
t (s)
t = 0 s
0 5 10 15 20 25 30 35 400
1
2
3
4
5
6
t (s)
13 14 15 16 17 18 19
2q (°)
0 5 10 15 20 25 30 35 400
20
40
60
80
100
t (s)
t = 5 s t = 10 s
13 14 15 16 17 18 19
2q (°)
0 5 10 15 20 25 30 35 400
20
40
60
80
100
t (s)
0 5 10 15 20 25 30 35 400
1
2
3
4
5
6
t (s)
t = 15 s
13 14 15 16 17 18 19
2q (°)
0 5 10 15 20 25 30 35 400
20
40
60
80
100
t (s)
0 5 10 15 20 25 30 35 400
1
2
3
4
5
6
t (s)
t = 20 s
13 14 15 16 17 18 19
2q (°)
0 5 10 15 20 25 30 35 400
20
40
60
80
100
t (s)
0 5 10 15 20 25 30 35 400
1
2
3
4
5
6
t (s)
t = 25 s
13 14 15 16 17 18 19
2q (°)
0 5 10 15 20 25 30 35 400
20
40
60
80
100
t (s)
0 5 10 15 20 25 30 35 400
1
2
3
4
5
6
t (s)
t = 30 s
0 5 10 15 20 25 30 35 400
1
2
3
4
5
6
t (s)
13 14 15 16 17 18 19
2q (°)
0 5 10 15 20 25 30 35 400
20
40
60
80
100
t (s)
t = 35 s
0 5 10 15 20 25 30 35 400
1
2
3
4
5
6
t (s)
13 14 15 16 17 18 19
2q (°)
0 5 10 15 20 25 30 35 400
20
40
60
80
100
t (s)
t = 40 s
0 5 10 15 20 25 30 35 400
1
2
3
4
5
6
t (s)
13 14 15 16 17 18 19
2q (°)
0 5 10 15 20 25 30 35 400
20
40
60
80
100
t (s)
hydrogen uptake diffraction pattern phase content %
New beamline optics+ Mythen II 10 faster
III. Synchrotron XRPD: an example of in-situ kinetic study
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Polymorphic forms may have a significant impact on the quality or performance
of pharmaceutical and chemical products
For pharmaceuticals, a careful characterization of the polymorphism of substances
and drug product should therefore play a key role throughout the whole life-cycle
of products
Polymorphic studies have also started to play a key role during patent litigations
and in the fight against counterfeit drugs
Synchrotron-Radiation Powder Diffraction has become a unique and very
powerful tool for polymorphic studies, such as kinetic analyses, the identification
of closely related polymorphic forms and high-sensitivity quantitative phase
analyses
This use is in line with the regulatory expectations (ICH guidelines and FDA
guidance) that newly available analytical technologies are used for continuous
improvements in process understanding and product characterization
IV. Conclusions
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Acknowledgments
SLS direction (C. Quitmann, F. van der Veen) and SLS TT AG (Ph. Dietrich, S. Mueller)
MS beamline (Ph. Willmott, A. Cervellino, N. Casati, M. Lange, D. Meister and B.
Schmitt, A. Bergamaschi)
Arturo Araque, Excelsus Scientific Engineering, USA
Industrial customers: Bernd Hinrichsen (BASF), Thomas Laube (Cilag AG)
G. Bruni, API mixtures for the QPA project, Uni. Pavia, Italy
Ian Madsen & Nikki Scarlett for the lab-XRPD data and support for the QPA analyses,
CSIRO, Australia
C. Giannini & B. Aresta for the QPA analyses with QUANTO+, CNR-IC-Italy
A. Fitch, ID31 beamline at ESRF, Grenoble, Fr
A. Kern, M. Saviano, P. Stephens, A. Cossy, D. Sheptyakov and many others