HPLC2010 Pharmaceutical Copolymer Excipient Characterization By GPC-FTIR
1. HPLC 2010 Boston: P2062T
Pharmaceutical Copolymer Excipient
Characterization by SEC/GPC-FTIR
William W. Carson; David Dunn; Jim Dwyer;
Ming Zhou; Tom Kearney
Spectra Analysis Instruments, Inc.
June 20, 2010
Contact: CarsonW@Spectra-Analysis.com
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6. Excipient Characterization by GPC-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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7. IR Spectrum of Copovidone Excipient –
VP/VAc Copolymer from GPC-IR
Peak 1680 cm-1 from VP comonomer
Peak 1740 cm-1 from VAc comonomer
8. Excipient Compositional Drift (IR Peak Ratios)
with 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
9. Excipient Compositional Drift (%VAc)
with MWD Vs. Bulk Average
.6
Copovidone: sample A 50
molecular weight
% acetate comonomer
.5
distribution
max. IR absorbance
45
.4
.3 Bulk Average comonomer composition 40
40% VAc distribution
.2
35
.1
0 30
106 105 104 103 102 Molecular Weight
10. Copovidone Compositional Drifts (%VAc)
from Different Manf. Processes
.6
Copovidone: sample A
50
sample B
% acetate comonomer
.5
sample C
45
.4
Molecular Weight
max. IR absorbance
Distribution Comonomer Composition
.3
Distribution
40
Bulk 40% VAc
.2
35
.1
0 30
106 105 104 103 102 Molecular Weight
Copovidone A gave clear tablets while Copovidone C led to cloudy ones.
11. IR Spectrum Difference of Two Grades of HPMC
(Type 2910 & 2208) from GPC-IR
-C-O-C-
OH CH2
HP
OCH3 CH2 CH3
12. HPMCAS Grade-to-Grade
Difference (LF, MF, HF) by GPC-IR
-C-O-C-
Backbone
HOOC-CH2-CH2-C=O Ether
AS A 1060
C=O Acetyl
1740 1235
CH3-C=O
HP
C/HP M
CH3
OH OCH3
1372
3470 2830
13. IR Band Identifications of HPMCAS Excipient
HOOC-CH2-CH2-C=O
CH3-C=O
Groups HP M C A AS Notes
CH3 1372 HP
OCH3 2830 M
OH 3470 (Unsub. OH & HP OH) OH
COCH3 1235 A
Total C=O 1740 AS
CH2 2935 2935 2935 2935 CH2
C-O-C 1060 BackBone
(BB)
17. Total C=O AS / Backbone Ratio Drifts of 2 HPMCAS
Samples with Elution Time (MWD)
ES1
SE2
18. To Find Succinic Acid Level on Backbone
(AS/Backbone)- k (A/Backbone) => S / Backbone
ES1
AS / BB Ratios
SE2
ES1
SE2 A / BB Ratios
Absorptivity Ratio k
Needs to be Calibrated
from Known Standards
21. To Find Unsubstituted OH on Backbone
(OH/Backbone)- k (HP/Backbone) => Unsub. OH / Backbone
Absorptivity Ratio k Needs to be Calibrated from
Known Standards
ES1
HP / BB Ratios
SE2
ES1
OH / BB Ratios
SE2
22. Methoxy / Backbone Ratio Drifts of 2 HPMCAS
Samples with Elution Time (MWD)
ES1
SE2
23. 2935cm-1 CH2 / Backbone Ratio Drifts of
2 HPMCAS Samples with Elution Time (MWD)
SE2
ES1
24. 2935 CH2 / BB & 2935 CH2 / AS Ratio Drifts of 2
HPMCAS Samples with Elution Time (MWD)
SE2
Peak 2935 / AS
ES1
Peak 2935 / BB
SE2
ES1
25. Small HP/AS Ratio Drifts of 2 HPMCAS Samples
with Elution Time (MWD)
SE2
ES1
26. Backbone/AS & HP/AS Ratio Drifts of 2 HPMCAS
Samples with Elution Time
SE2
BB / AS
ES1
SE2
HP / AS
ES1
35. GPC-IR Conclusions
GPC-IR Takes Snapshot IR Pictures of Polymer Excipients
for Compositional Drifts with MW Distributions
Many Ways to Analyze Functional Group Drifts w/ MWD:
Group vs. Backbone, Various Ratios among Groups, etc.
Useful to Characterize Lot-to-Lot, Grade-to-Grade and
Supplier-to-Supplier Variations of Polymeric Excipients
Understand Excipient Manufacturing Variables and QC
GPC-IR is a Powerful Tool to Analyze Compositional
Variations of Copolymers across MWD
37. Excipient Analysis with LC-IR
in Drug Formulations
• Polymeric Excipient Characterization
• Degradation in Process (Hot Melt Extrusion)
• Excipient / API Interactions
• Forced Degradation in Shelf Life Study
December 1, 2008: Vol. 5, No. 6
The cover cartoon illustrates a solid dispersion assembly that is
composed of entangled polymer chains with drug molecules
embedded in the form of single molecule, small clusters, and/or
large aggregates (amorphous).
38. GPC-IR Applications for Excipient Analysis
in Drug Formulations
Excipient Formulation Develop. Formulated Drugs
Manufacturing Drug Manufacturing Shelf Life Stability
• Process Control • Incoming QC • Stressed
• Lot-to-lot • Excipient Degradation
Variations Functionality
• CoA • Formulation • De-Formulate
Development Excipient Blends
• Novel Excipient • QbD
R&D • Trouble-Shoot
• Process Degradation Problem Drugs in
• Trouble Shooting (Hot Melt Extrusion) the Market
• Define Safe Process
Window / QbD
• Process Monitoring
• Trouble Shooting
Users: Excipient Pharma Co. Pharma Co.
Manufacturers HME Service Providers Generic Drug Co.
39. Excipient QbD Space
GPC-IR-Performance
Slide from USP International Excipient Workshop (July 2009)
Performance
GPC
IR
40. GPC-IR & HPLC-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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