advances in synchrotron xrpd for the enhanced characterization of pharmaceuticals · 2018-11-14 ·...

Copyrights Excelsus Consortium www.excels.us [email protected]

PPXRD-12

20-24 May, 2013

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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PPXRD-12

20-24 May, 2013

Beijing, China

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


PPXRD-12

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Beijing, China

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


PPXRD-12

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Beijing, China

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)



PPXRD-12

20-24 May, 2013

Beijing, China

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)



PPXRD-12

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Beijing, China

What makes synchrotron-XRPD

such a powerful analytical tool?



PPXRD-12

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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



PPXRD-12

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Our 3 ingredients for state-of-the-art SR-XRPD

A. An efficient synchrotron facility and beamline optics



Schmitt et al, 2003,

Bergamaschi, Schmitt et al, 2010 Hodeau et al, 1998

Multicrystal Analyser

MYTHEN II



PPXRD-12

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Beijing, China

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)



PPXRD-12

20-24 May, 2013

Beijing, China

Swiss Light Source-Materials Science beamline

Powder Diffraction station


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



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20-24 May, 2013

Beijing, China

Properties:

Angular selection of diffracted beam

Fluorescence suppression


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



PPXRD-12

20-24 May, 2013

Beijing, China

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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20-24 May, 2013

Beijing, China

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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Beijing, China

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


PPXRD-12

20-24 May, 2013

Beijing, China

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


PPXRD-12

20-24 May, 2013

Beijing, China

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


PPXRD-12

20-24 May, 2013

Beijing, China III. Synchrotron XRPD: Quantitative Phase Analysis

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


PPXRD-12

20-24 May, 2013

Beijing, China

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



PPXRD-12

20-24 May, 2013

Beijing, China

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)



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



PPXRD-12

20-24 May, 2013

Beijing, China

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%)


powder volumes




PPXRD-12

20-24 May, 2013

Beijing, China


Mea

sure

d (

wt%

)

Weighed (wt%)

0

1

2

3

4

5

6

0 1 2 3 4 5 6


powder volumes

individual powder

volumes


The average of %wt values at individual capillary powder volumes was consistent

with %wt values from merged diffraction patterns


PPXRD-12

20-24 May, 2013

Beijing, China

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


PPXRD-12

20-24 May, 2013

Beijing, China

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





PPXRD-12

20-24 May, 2013

Beijing, China

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)





PPXRD-12

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Beijing, China

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


PPXRD-12

20-24 May, 2013

Beijing, China

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

www.excels.us [email protected]


PPXRD-12

20-24 May, 2013

Beijing, China

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

advances in synchrotron xrpd for the enhanced characterization of pharmaceuticals · 2018-11-14 ·...

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