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Near-ambient pressure instrumentation: New directions for Surface Analysis with
XPS and related core-level spectroscopies
Sven L. M. SchroederRoyal Academy of Engineering Bragg Centenary Chairin Engineering Applications of Synchrotron Radiation
University of LeedsDiamond Light Source
Research Complex at Harwell
Near-ambient pressure (NAP) technology …
No need for samples to be ultra-high vacuum compatible
This opens core level electron spectroscopies to a wide range of new analytical applications….
Specs EnviroESCA - Versatile Operation
Liquids Volatile powders Single crystal facet Woven fabric
Samples are placed on
an analysis table with
XYZ positioning
no mounting on a
manipulator
high flexibility
• Whole devices
• In situ / operando
experiments
• Sample libraries
No requirement for ultra-high vacuum or charge neutralisation
Analyser
entrance coneAnalyser
entrance cone
Analyser entrance
coneAnalyser
entrance cone
Analysis
spot
Analysis
spot
Analysis
spot
Analysis
spot
Feasibility
experiments
Carried out with prototype
EnviroESCA system at
supplier’s site
April/May 2017
1 cm
1 cm 1 cm1 cm
Manufacturing of an Active Pharmaceutical Ingredient
• Formulation: fumarate salt ofAPI
• Normally of white appearance, but some batches yellow
• Specific surface area (gSSA)with low, medium, and highspecific energy inputs (SEI)
• Strong connection between colour and mechanical properties forthe material
• Mechanical milling of material with discoloured surfaces was verydifficult at laboratory scale, and not possible at plant scale
JS Stevens, SJ Byard, E Zlotnikov, SLM Schroeder, J Pharm Sci, 100 (2011) 942-948.
?
Origin of surface colour - conventional techniques provide no answer
• Two functional groups containing nitrogen in the API• One nitrogen group is protonated in the salt (white)• Yellow colour suggestive of free base of the API (no salt)• Validation difficult; conventional techniques tried
X-ray Powder Diffraction (XRPD) - slight evidence of amorphous material(halo)
Differential Scanning Calorimetry (DSC) - No second order events wereobserved to support XRPD result
High Performance Liquid Chromatography (HPLC) – no differences in chemicalpurity
Confocal Raman microscopy – no difference
Attenuated Total Reflection (ATR) IR – no difference
JS Stevens, SJ Byard, E Zlotnikov, SLM Schroeder, J Pharm Sci, 100 (2011) 942-948.
Origin of surface colour……analyse XPS N1s emission
• 58% of nitrogen present as NH+
• 49% of nitrogen present as NH+
Surface region is enriched in free base
JS Stevens, SJ Byard, E Zlotnikov, SLM Schroeder, J Pharm Sci, 100 (2011) 942-948.
As expected for the salt
Salt/Co-crystal Continuum
Acidity Constants of the Donor/Acceptor Groups
X HN+ XH----N
XH N
Co-crystal (DpKa < 0)Salt (DpKa > 3)
proton transferProtonation H-bond
theophylline + 5-sulfosalicylic acid theophylline + oxalic acid
??? 0 < DpKa < 3 ???
Example: Theophylline complexes
+ = 2:1 co-crystal
+ = 1:1 dihydrate salt
DpKa = 0.3
DpKa = 2.3
Theophylline Complexes
J. S. Stevens, S. J. Byard, S. L. M. Schroeder, Cryst. Growth Des. 2010, 10, 1435-1442.J. S. Stevens, S. J. Byard, S. L. M. Schroeder, J. Pharm. Sci., 2010, 11, 4453-4457J. S. Stevens, S. J. Byard, C. A. Muryn, S. L. M. Schroeder, J. Phys. Chem. B, 2010 , 14, 13961-13969
C=N
C=NH+
N1s chemical shift of +2.3 eV on protonation of the base - unequivocal
Isonicotinamide Complexes
J.S. Stevens, S.J. Byard, C.C. Seaton, G. Sadiq, R.J. Davey, S.L.M. Schroeder
Angew. Chem. Int. Ed. 50 (2011), 9916–9918
Physical Chemistry – Chemical Physics, 16 (2014) 1150-1160.
C=N
C=NH+
XPS identifies unequivocally whether protonation has occurred
Shift of +2.0 eV with hydrogen transfer to the base
Salt/Co-Crystal Continuum
Unequivocal N1s binding energy
separation between protonated
(HN+) and unprotonated nitrogen
of the base component
Correct and unequivocal assignment of all complexes – 9 salts, 9 co-crystals
Novel & reliable analytical tool for product development
Universal chemical shift of ~ +2 eV due to protonation
J.S. Stevens, S.J. Byard, C.C. Seaton, G. Sadiq, R.J. Davey, S.L.M. Schroeder
Angew. Chem. Int. Ed. 50 (2011), 9916–9918.
Physical Chemistry – Chemical Physics, 16 (2014) 1150-1160.
Salts
Co-crystals
15N solid state NMR
-140
-120
-100
-80
-60
-40
-20
0
20
40
-5 -3 -1 1 3 5 7 9 11 13 15 17 19
∆pK a
Dd
/ p
pm
Salt (amine)
Co-crystal
Protonated nitrogen identifiable
from the magnitude of change in
chemical shift (Dd)
Smaller shift for protonation of
amine compared to heterocyclic,
aromatic nitrogen
Larger shift for co-crystal with
formation of H-bond and
conformational/crystallographic
packing differences
CASTEP analysis permits
unequivocal assignments
Shifts of 50-100 ppm to low frequency with protonation of heterocyclic, aromatic
nitrogen
J.S. Stevens, S.J. Byard, C.C. Seaton, G. Sadiq, R.J. Davey, S.L.M. Schroeder, Physical
Chemistry – Chemical Physics, 16 (2014) 1150-1160.
Salts
Co-crystals
XPS and ssNMR synergy - accelerated development
example: biomaterials/devices - scaffolds for nerve growth (A)
Poly--caprolactone (PCL)
Identify successful peptide immobilisation
– surface technique
– elemental/chemical group sensitivity
RGD-based peptides elicit positive Schwann
cell response
Promote cell adhesion and proliferation
Strong + Biodegradable
Biocompatible
Low Schwann cell attachment / growth
A. C. del Luca, J. S. Stevens, S. L. M. Schroeder, J.-B.
Guilbaud, A. Saiani, S. Downes, G. Terenghi, J.
Biomed. Mater. Res. A, 2013, 101A, 491
Poly--caprolactone
(C6H10O2)n10 mm
10 mm
40-60 mm thickness
with pits
18 mm2 thin films
Nerve
biomedical materials and devices
RGD Neuropeptide Coatings
• Step I
Activation of polycaprolactone (PCL) film
Attachment of 2-chloroethylamine through
nucleophilic attack at carboxylic acid groups of
PCL, forming an amide bond
• Step II
Peptide immobilization
Attachment of RGDSC pentapeptide through
nucleophilic substitution between thiol (CSH)
of peptide and Cl
ClNH3
+Cl
OO
O
O
O NH
Cl
O NH
Cl
OH OH
O NH
S
Cys
Ser
Asp
Gly
Arg
O NH
S
Cys
Ser
Asp
Gly
Arg
RGDSC
PCL film
PCL film
PCL film
A.C. de Luca, J.S. Stevens, S.L.M. Schroeder, J.B. Guilbaud, A. Saiani, S. Downes & G. Terenghi
Journal of Biomedical Materials Research Part A 101A (2013) 491-501.
J. S. Stevens, A. C. de Luca, S. Downes, G. Terenghi, S. L. M. Schroeder,
Surface and Interface Analysis 46 (2014) 673-678.
PeptidesRGD: Arg-Gly-Asp RGDS: Arg-Gly-Asp-Ser
CC
CCOO/
CCOOH
NC=O
COO
CNH+
CN
NH
NH2
H2N
+
CN
CCOO/
CCOOH
NC=O
COO
CNH+/C
O
CC
NH
NH2
H2N
+
C 1s C 1s
N 1s N 1s
O=CN / O=CN /
CNH+
CNH+
NH
NH2
H2N
+NH
NH2
H2N
+
J. S. Stevens, A. C. de Luca, M. Pelendritis, G. Terenghi, S. Downes, S. L. M. Schroeder
Surface and Interface Analysis 45 (2013), 1238-1246.
Control of Surface Chemistry Using XPS
CCl
2p1/2
CCl
2p3/2
Cl
2p3/2
Cl
2p1/2
N 1s Cl 2p
S 2p
De Luca et al., J. Biomed. Mat. Res. A 101 (2013) 2.
DEB = 1.7 eV
C 1s
C 1s
N 1s
N 1sCombination with StoBe DFT calculations of core level binding energy shifts in monomeric gas phase molecules
JACS 130 (2008) 8150
DEB = 0
Aqueous Imidazolewith Emad Aziz, BerlinLiquids…
• Spectra insensitive to
concentration changes
• Strong self-association of
imidazole in solution?
Concentration
Dependence….
M Thomason, GA Hembury, B Sattelle, JS Stevens, E. F. Aziz & S. L. M. Schroeder
Faraday Discussions 179 (2015) 269-289
XPS of Para-aminobenzoic acid (PABA)
a-polymorph
Strong H-bonded COOH dimers and intermolecular NHO bonds
p-p stacking between offset aromatic rings
XPS identifies different chemical moieties
C 1s
J. S. Stevens, C. R. Seabourne, C. Jaye, D. A. Fischer, A. J. Scott
S. L. M. Schroeder, J. Phys. Chem B 118 (2014) 12121-12129.
b-polymorph
Orbitals: GAUSSIAN09 B3LPY/6-31G* DFT
a-PABA
p* resonances sensitive to
chemical environment and
unoccupied MOs
C K-edge
NEXAFS
C K-edge
Electronic and
chemical environment
J. S. Stevens, C. R. Seabourne, C. Jaye, D. A. Fischer, A. J. Scott, S. L. M.
Schroeder, J. Phys. Chem B 118 (2014) 12121-12129.
a-PABA
b-PABA
a-PABA
b-PABACN
XPS XANES
a-PABA
b-PABA
a-PABA
b-PABA
Variation in local environment –
electronic structure and bonding
NEXAFS Spectroscopy
Highest sensitivity for N spectra as only single
nitrogen atom and directly involved in H-
bonding
Polymorphism: a- and b-PABA C
O
N
a-PABA
b-PABA
AMBNAC07 / 08
a-PABA
Only single type of nitrogen, so
more sensitive probe of
electronic structure
Two oxygen environments
Electronic and
chemical environment
O K-edge N K-edge
NEXAFS
J. S. Stevens, C. R. Seabourne, C. Jaye, D. A. Fischer, A. J. Scott, S. L. M. Schroeder, J. Phys. Chem B 118 (2014) 12121-12129.
Solutions: pH dependence
Direct observation of alterations
for in situ solution species
b-
N K-edge
p* sensitive to protonation state
and solvation through unoccupied
MOs
Beam
Microjet
J. S. Stevens, A. Gainar, C. Jaye, E. Suljoti, J. Xiao, R. Golnak, E. F. Aziz & S. L. M. Schroeder
Chem. Eur. J. 21 (2015) 7256-7263
b-
N K-edgeProtonation state and bond length
Ionisation potential (IP) is a direct reflection of
the chemical state and electron density
a
b
Anionic
Cationic
s*CN energy relative to IP is dependent on C
N bond length (term value d = s*CN – IP)
J. S. Stevens, A. Gainar, C. Jaye, E. Suljoti, J. Xiao, R. Golnak, E. F. Aziz & S. L. M. Schroeder
Chem. Eur. J. 21 (2015) 7256-7263
pH dependence
RIXS at nitrogen edge excitation
energies for in situ solution species
Occupied states: RIXS – resonant
inelastic X-ray scattering
Essentially, high resolution X-ray emission
spectroscopy
Similarities in shape for pH 11 and methanol, with shift to lower energy for anionic form
Highest energy peaks (2p p→1s) absent for pH 1 cationic form as use of nitrogen lone pair in extra NH bond instead of delocalised into p MOs
N RIXS
RIXS of pH dependence: interpretation
Widening energy gap between
nitrogen-contributing orbitals for
anionic species
Larger nitrogen HOMO-LUMO gap
for anionic than non-ionic form
J. S. Stevens, A. Gainar, C. Jaye, E. Suljoti, J. Xiao, R. Golnak, E. F. Aziz & S. L. M. Schroeder
Chem. Eur. J. 21 (2015) 7256-7263
Amorphous Components
Surface Amorphous Phases - ‘Dynamic Vapour NEXAFS’Before Humidity Cycle
After Humidity Cycle
• C K-edge – High Surface
Sensitivity
• Micronised API looks like
amorphous API
100% Relative
Humidity Cycle
• Micronised API looks like
Crystalline API
• Recrystallisation of surface
amorphous component has
taken place
A. M. Booth, S. Braun, T. Lonsborough, J. Purton, S. Patel, S. L. M. Schroeder, Am. Inst. Phys. Proc, 882 (2007) 325-327.
Coatings
Presence of an XPS signal from an active pharmaceutical ingredient (API) under a PEG-coat
• Either a very thin coating was applied• Or the coating is present in patches on the surface• Or a physical mixture of the components• Or a more complicated heterogeneous product has been prepared
Patchy polymer coating
Closed-layer PEG coating with thickness below the sampling depth of XPS (1-2 nm)
?
NEXAFS of the Coated API: C K-edge
Coated samples look like the API – where is the PEG ?
C K-edge after Humidity Cycle
• Coated samples look like PEG
• Signal from API suppressed after high humidity
• PEG wets surface if given sufficient mobility through presence of water
DLCDiamond-Leeds
Collaboration
VERSOX - Versatile Soft X-ray
Spectroscopy Beamline
+ complementary Diamond
beamlines
funded by
CMAC @ RCaHContinuous
Manufacturing and
Crystallisation
Research Group
funded by
RAEng Bragg Centenary ChairEngineering Applications of Synchrotron Radiation
Funded by
(Bragg Centre)
VXSFVersatile X-ray
Spectroscopy Facility
XPS / EnviroESCA / XES /
HAXPES
Service and build user
community– industry &
academia
funded by
Facility
Location
Funders
Integrated NAP X-ray Core Level Spectroscopy Infrastructure