The document describes Spectra Analysis's DiscovIR-LC technology for online liquid chromatography-infrared spectroscopy (LC-IR). The technology removes solvent from the LC eluent in real-time, depositing the dried sample on a zinc selenide disk for FTIR analysis. This allows for characterization of excipient polymers and assessment of degradation across molecular weight distributions. Case studies demonstrate analysis of copolymer composition drift, excipient variability from different manufacturers, and degradation products from hot melt extrusion processes. The LC-IR can also be used for de-formulation, process analysis, and general analytical applications.
LC-IR Hyphenated Technology For Excipient Analysis-FDA USP Seminars-1-13-2010
1. LC-IR Hyphenated Technology for
Excipient Analysis
FDA on Jan. 12, 2010
USP on Jan. 13, 2010
George Giansanti, Tom Kearney
Gerrit Blok, Ming Zhou
Spectra Analysis, Inc.
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2. OUTLINE
Introduction: Company & LC-IR Technology
DiscovIR-LC System: Instrumentation & Features
Applications of LC-IR: Case Studies
Q&A
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3. The Company
257 Simarano Drive
Marlborough, MA 01752
Completed product engineering
with patent protected ‘breakthrough’
technology during 2005 & 2006.
Initiated sales and began building a ‘top tier’ customer base, 2007 thru 2009.
Received R&D Magazine’s ‘Top 100’ product Award, 2008.
Received Massachusetts Life Science Center, Certification & Award, 2009.
Spectra has great people, ‘breakthrough’ products, huge market and is positioned for
explosive growth !
December 2009 3
4. Meet the Spectra Team
George Giansanti William W. Carson, PE Ming Zhou, PhD. Tom Kearney, MBA
President & CEO Sr. VP Engineering Applications Engrg. Mgr. Technical Sales Mgr.
Cal Poly MIT Univ. Connecticut Univ. Vermont
Sidney Bourne, PhD. Andrew Chung David Dunn Stacy Follo
Sr. VP & Chief Scientist Product Engineer Sr. Applications Chemist Southeast Sales Rep.
Univ. Wisconsin Northeastern Northeastern Northeastern
Part time support:
Lisa Velardo, CPA – CFO
Gerrit Blok
Mid-Atlantic Sales Rep.
Cheryl McCarthy – Accountant
Broek Institute,
Amy Guyton – Materials & Logistics
Amsterdam
James Dwyer, PhD. – Technical Advisor
5. DiscovIR Users
Merck Pharma
Johnson & Johnson Pharma
Novartis Pharma
Shire Pharmaceuticals Pharma
Du Pont Polymers
Dow Chemical Polymers
Lawrence Livermore National Lab Trace Analysis
Oak Ridge National Laboratory Environmental
Naval Research Laboratory Organics
US Army Aberdeen Proving Ground Forensics
Pennsylvania State Police Forensics
Alabama Department of Forensics Forensics
Vermont State Police Forensic lab Forensics
6. DiscovIR Product Line
Separate→Concentrate→Identify
DiscovIR-GCTM DiscovIR-LCTM
2008 Award Winner
Applications: Applications:
General Analytical
Capability Excipients
Forensic Labs Polymers
(Controlled
Substance Analysis) Advanced
Materials
DiscovIR-GCTM (GC-FTIR) DiscovIR-LCTM (LC-FTIR)
real-time, vapor to solid phase real-time, solvent removal
10. How is the Solvent Removed?
N2 Addition
Cyclone
From LC Cyclone Evaporator
Evaporator
Thermal Nebulization
Air Cooled
Condenser
Patent pending:
PCT/US2007/025207
Chilled
Condenser
Particle Stream to DiscovIR
Waste Solvent
11. ZnSe Sample Disk
Auto sampler compatible
Unattended overnight runs
The ZnSe sample disk (yellow)
is under vacuum without
moisture or CO2 interference
Re-usable after solvent
cleaning
Transmission IR analysis is
done on the solid deposit.
12. DiscovIR Components
IR Detector
Interferometer PCB
Cryogenic LN2
ABB Bomem
M
C
T
Sample deposit
ZnSe window
Vacuum
chamber
Precision Vacuum Back
plate Optical path
16. Features of DiscovIR-LC
High Quality Solid Phase Transmission IR Spectra
Real-Time On-line Detection
Microgram Sensitivity
Compatible with all LC Solvents and Gradients
• e.g. Water, ACN, Methanol, THF, Chloroform, HFIP
Compatible with all GPC/SEC Solvents
Fully Automated Operation: No Fractionation
Multi-Sample Processing: 10 Hr ZnSe Disk Time
17. Applications
Applications of DiscovIR-LC for Excipient Analysis
• Excipient Characterization: Copovidone PVP/VAc
• Excipient Degradation from HME Process: HPMCAS
• Forced Degradation Analysis: PEG
• De-Formulation of Polymers and Additives
(Macromolecules + Small Molecules)
Q&A
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18. IR Spectrum of Copovidone
Excipient - VP/VAc Copolymer
Peak 1680 cm-1 from VP comonomer
Peak 1740 cm-1 from VAc comonomer
19. Excipient Compositional Drift
w/ MWD Vs. Bulk Average
GPC-IR Chromatogram Overlay with Comonomer Ratios
Copovidone
Bulk Average
(Molecular Weight Distribution)
Abs. Peak Ratio: AVA / AVP = (k1*b*MVA) / (k2*b*MVP) = k (MVA / MVP) ~ Comonomer Ratio
20. Excipient Compositional Drift
w/ MWD Vs. Bulk Average
.6
Copovidone: sample A 50
molecular weight
.5
% acetate comonomer
distribution
max. IR absorbance
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.4
.3 Bulk Average comonomer composition 40
40% VAc distribution
.2
35
.1
0 30
106 105 104 103 102 Molecular Weight
21. Copovidone MW Distributions from
Different Suppliers (Manf. Processes)
.6
Copovidone: sample A
sample B
.5
sample C
max. IR absorbance
.4
.3
.2
.1
0
Molecular Weight
106 105 104 103 102
Copovidone A gave clear tablets while Copovidone C led to cloudy ones.
22. Copovidone Compositional Drifts
from Different Manf. Processes
.6
Copovidone: sample A
50
sample B
% acetate comonomer
.5
sample C
45
.4
Molecular Weight
Comonomer Composition
max. IR absorbance
Distribution
.3
Distribution
40
Bulk 40% VAc
.2
35
.1
0 30
106 105 104 103 102
Molecular Weight
23. Excipient Characterization
by LC-IR
Copolymer Compositional Analysis with MW Distributions
• Comonomer Ratio Drift (Functional Groups) vs. Bulk Average
• Excipient Lot-to-Lot Variations: QbD Studies
Excipient Performance & Functional Group Correlations
• Hydrophobic/Hydrophilic Ratio Drift vs. Phase Separations
• Effects on Excipient Dissolution Behavior
Reference
(1) Chemical Heterogeneity on Dissolution of HPMC,
EU J. of Pharma Sci., P392 (2009), A. Viriden et al.
(2) Comp Drift Effect on Dissolution of PMMA/MAA,
Materials Letters, P1144 (2009), E. Manias et al.
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24. Excipient Degradation from HME
Process
Hot Melt Extrusion Process: To Make Solid Dispersions
for Low Solubility Drugs to Improve Bioavailability
Degradation Issues
• Excipient & API Degradation at High Temp. (100-200C)
• Discoloration / Residues
• Degradant / API Interactions
Process Variables
• Temperature
• Time
• Screw Speed (Torque)
• Screw Design
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26. Degradant from HPMCAS
in Hot Melt Extrusion Process
IR Database Search Result: Succinic Acid
27. HPMCAS Degradation
in Hot Melt Extrusion Process
Functional Group Ratio Changes from High Temp Process (Sample C)
28. Degradation of HPMC-AS in
Hot Melt Extrusion Process
Detected Degradant: Succinic Acid
Detected Functionality Ratio Change: Hydroxyl Vs. Carbonyl
Help Understand Excipient Degradation Mechanism
Study Excipient / API Interactions
Define Process Window: QbD
Fig. A Schematic Structure of HPMC Derivatives, Cellulose Ethers & Esters
29. Forced Degradation Study of
Excipient PEG
PEG-1000 at 55C Air Bubbling Overnight; Reverse-Phase HPLC: H2O / ACN
30. IR Spectrum from
Main PEG Peak
Oxidation bands in bulk material seen at
1720 and 1645
31. HPLC-IR of Std PEG-1000
AU Scale for all traces
1116 cm-1 band chromatogram
1607 cm-1 band chromatogram
1719 cm-1 band chromatogram
Minutes
32. HPLC-IR for
Degraded PEG-1000
Three Chromatographic displays
generated from one time ordered set of
FTIR Spectra
33. IR Identification of
Degraded Products
Na+ or K+ Cation
Aldehyde Carboxylate Salt
1719 1607
11.45 minutes
4.93 minutes
1.50 minutes
35. GPC-IR Analysis for Macromolecules and
Small Molecules in the Same Run
Macromolecules Small Molecules
Polymers Additives
Excipients Impurities
Degradants
or API’s
(Molecular Weight Distribution)
Polymer Additive Analysis Data with GPC-IR for ABS Plastic w/o Extraction Step:
IR chromatogram and ratio plot for ABS sample. Ratio (green) of characteristic IR
absorbance bands for nitrile (2240 cm-1) and styrene (1495 cm-1).
36. Polymer Additive Analysis with
GPC-IR for ABS Plastic w/o Extraction Step
IR spectra at different elution times across the low MW peak of the SEC analysis of ABS. Spectra
indicate presence of multiple components.
41. Excipient QbD Space
GPC-IR-Performance
Slide from USP International Excipient Workshop (July 2009)
GPC
IR
42. Excipient QbD Space
GPC-IR-Performance
Slide from USP International Excipient Workshop (July 2009)
Performance
GPC
IR
43. THANK YOU !
A NEW WORKHORSE TECHNOLOGY – DIRECT
DEPOSITION, SOLID PHASE, FULLY AUTOMATED
LC-IR
Now formulation chemists can
characterize excipient
macromolecules with
more accurate
composition
information
Contact
Gerrit Blok
Sales Representative
Mid-Atlantic
(717) 368-0549
blokg@spectra-analysis.com
Learn more………..
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WWW.SPECTRA-ANALYSIS.COM
44. LC-IR Applications
Excipient Characterization, Functionality & Degradation Analysis
Copolymer Compositional Analysis across MW Distribution
Polyolefin Copolymer Branching Analysis by High Temp GPC-IR
Polymer Blend Ratio Analysis across MW Distribution
Polymer Additive & Impurity Analysis
De-Formulation for Polymers and Additives: Competitive Analysis
Process Control & Optimization
Excipients, Plastics, Rubbers, Films, Fibers, Foams & Composites
Reactive Polymer Analysis for Coating, Adhesive, Sealant & Elastomer
Isomer Analysis for Chemicals, Forensics & Pharmaceuticals
General Analytical Capability: Trouble Shooting
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