Short Topic Presentation at AAPS NERDG on 4/23/2010. GPC-IR to Characterize Macromolecular Excipeints in Pharmaceutical Formulations

1. AAPS NERDG 2010 Annual Meeting
Short Topic Presentation #5
GPC-IR to Characterize Macromolecular
Excipients in Pharmaceutical Formulations
Ming Zhou, David Dunn, William Carson,
Sidney Bourne & Tom Kearney
Spectra Analysis, Inc.
April 23, 2010
Contact: ZhouM@Spectra-Analysis.com
Tel. 508-281-6276
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2. OUTLINE
GPC-IR Hyphenated Technology: Instrumentation
Excipient Characterization: Copovidone PVP/VAc
Excipient Degradation from HME Process: HPMCAS
Summary: GPC-IR Applications in Pharma Formulations
Q&A
2

3. LC-IR Hyphenation

4. Direct Deposition FTIR

5. Direct Deposition FTIR
& Data Processing
ZnSe Disk

6. GPC-IR Technology: 3D View to
Map out Polymer Compositions
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7. IR Spectrum of Copovidone
Excipient - VP/VAc Copolymer
Peak 1680 cm-1 from VP comonomer
Peak 1740 cm-1 from VAc comonomer

8. 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

9. Excipient Compositional Drift
w/ MWD Vs. Bulk Average
.6
Copovidone: sample A 50
molecular weight
.5
% acetate comonomer
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 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.

11. Copovidone Compositional Drifts
from Different Manf. Processes
.6
Copovidone: sample A
50
sample B
.5
% acetate comonomer
sample C
45
.4
Molecular Weight
max. IR absorbance
Distribution Comonomer Composition
.3
Distribution
40
Bulk 40% VAc
.2
35
.1
0 30
Molecular Weight
106 105 104 103 102
Copovidone A gave clear tablets while Copovidone C led to cloudy ones.

12. 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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13. Excipient Degradation from
Hot Melt Extrusion 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
• Torque
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14. GPC-IR to Analyze HPMCAS
Degradation in HME Process
Samples: A- Not Processed; B- Processed at Low Temp.;
C- Processed at High Temp. (Degradant peak around 14.5 min.)

15. Degradant Identification from
HPMCAS in HME Process (C)
IR Database Search Result: Succinic Acid

16. Polymer Compositional Change
from HPMCAS Degradation in HME
-C=O
OH
Functional Group Ratio Changes from High Temp Process (Sample C)

17. GPC-IR Analysis of HPMCAS
Degradation in HME Process
Detected Degradant: Succinic Acid
Detected Functionality Ratio Change: Hydroxyl Vs. Carbonyl
Help Understand Excipient Degradation Mechanism
Study Excipient / API Interactions
Define Safe Process Window: QbD
HOOC-CH2-CH2-C=O
CH3-C=O
Fig. A Schematic Structure of HPMC-AS

18. HPMCAS Grade-to-Grade
Difference (LF/MF/HF) by GPC-IR
-C-O-C-
HOOC-CH2-CH2-C=O
AS A
C=O Acetyl
CH3-C=O
M HP
C OCH3 CH3
OH

19. HPMCAS Grade-to-Grade
Difference (LF/MF/HF) by GPC-IR
-C-O-C-
C=O Acetyl
HP
CH3

20. Common Polymeric Excipients
Neutral Cellulose Derivatives
• HydroxyPropyl Methoxy Cellulose (Hypromellose): HPMC
• HydroxyPropyl Cellulose: HPC
• Cellulose Acetate Butyrate: CAB
Acidic Cellulose Derivatives
• HPMC Acetate Succinate: HPMC-AS
• HPMC Phthalate: HPMC-P
• Cellulose Acetate Phthalate: C-A-P
Copovidone: PolyVinyl Pyrrolidone / Vinyl Acetate – PVP/VAc
SoluPlus Terpolymer: PEG / PVAc / PVCap
Methacrylic or Methacrylate Copolymers: Eudragit
Polyethylene Oxide: PEO (MW > 20K) or PEG (MW < 20K), PEG/PPG
Excipient Combinations with Plasticizers and Additives
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21. Excipient Analysis with GPC-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).

22. 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 Functionality Degradation
Variations • Formulation
• CoA Development • De-Formulate
• QbD Excipient Blends
• Novel Excipient
R&D • Process Degradation
(Hot Melt Extrusion)
• Define Safe Process
Window / QbD
• Process Monitoring
• Trouble Shooting • Trouble Shooting • Trouble-Shoot
Problem Drugs in
the Market
Users: Excipient Pharma Co. Pharma Co.
Manufacturers HME Service Providers Generic Drug Co.

23. Excipient Degradation Analysis
in HME Process by GPC-IR
Detect Degradation Intermediates with MW Distributions
Detect Functionality Changes
Probe Polymer Degradation Mechanism
Solve Degradation Problems
Understand Excipient / API Interactions
Define Safe Process Window: QbD
HME Process Monitoring: PAT
Various Macromolecular Excipients
Excipient Blends with Plasticizers and Additives
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24. Excipient QbD Space
GPC-IR-Performance
Slide from USP International Excipient Workshop (July 2009)
Performance
GPC
IR

25. 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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