hplc2010 pharmaceutical copolymer excipient characterization by gpc-ftir
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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
1
HPLC 2010 Boston: P2062T
LC-IR Hyphenation
Direct Deposition FTIR withDots (HPLC-IR) and Narrow Films (GPC-IR)
Direct Deposition FTIR &
Data Processing (GPC-IR)
GPC-IR Hyphenated Technology: 3D Plot
to Map out Polymer Compositions with Sizes
5
Excipient Characterization by GPC-IR
6
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.
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
GPC-IR Chromatogram Overlay with Comonomer Ratios
Excipient Compositional Drift (IR Peak Ratios)
with MWD Vs. Bulk Average
Abs. Peak Ratio: AVA / AVP = (k1*b*MVA) / (k2*b*MVP) = k (MVA / MVP) ~ Comonomer Ratio
(Molecular Weight Distribution)
Bulk Average
Copovidone
0
.1
.2
.3
.4
.5
.6
106 104 103 102105
ma
x. IR
ab
so
rba
nce
Molecular Weight
Copovidone: sample A
30
35
40
45
50
molecular weight
distribution
% a
ceta
te c
om
onom
er
comonomer composition
distribution
Excipient Compositional Drift (%VAc)
with MWD Vs. Bulk Average
Bulk Average
40% VAc
0
.1
.2
.3
.4
.5
.6
106 104 103 102105 Molecular Weight
Copovidone: sample A
30
35
40
45
50 % a
ceta
te c
om
onom
er
Comonomer Composition
Distribution
sample B
sample C
0
.1
.2
.3
.4
.5
.6
106 104 103 102105
sample B
sample C
Bulk 40% VAc
ma
x. IR
ab
so
rba
nce Molecular Weight
Distribution
Copovidone Compositional Drifts (%VAc)
from Different Manf. Processes
Copovidone A gave clear tablets while Copovidone C led to cloudy ones.
IR Spectrum Difference of Two Grades of HPMC
(Type 2910 & 2208) from GPC-IR
OH
CH2
HP
CH3OCH3
CH2
-C-O-C-
HPMCAS Grade-to-Grade
Difference (LF, MF, HF) by GPC-IR
M
OCH3
2830
C/HP
OH
3470
HP
CH3
1372
A
Acetyl
1235
AS
C=O
1740
HOOC-CH2-CH2-C=O
CH3-C=O
-C-O-C-Backbone
Ether
1060
IR Band Identifications of HPMCAS Excipient
CH3-C=O
HOOC-CH2-CH2-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)
GPC-IR Chromatograph & Spectra of
HPMCAS Sample
GPC-IR Chromatogram Overlay at
Different Wavenumbers of 2 HPMCAS Samples
ES1:
1060 cm-1
2834 cm-1
2838 cm-1
2935 cm-1
SE2:
1060 cm-1
2834 cm-1
2838 cm-1
2935 cm-1
Acetyl/Backbone Ratio Drifts of 2 HPMCAS
Samples with Elution Time (MWD)
ES1SE2
Total C=O AS / Backbone Ratio Drifts of 2 HPMCAS
Samples with Elution Time (MWD)
SE2
ES1
To Find Succinic Acid Level on Backbone
(AS/Backbone)- k (A/Backbone) => S / Backbone
Absorptivity Ratio k
Needs to be Calibrated
from Known Standards
AS / BB Ratios
A / BB Ratios
ES1
SE2
ES1
SE2
HP/Backbone Ratio Drifts of 2 HPMCAS
Samples with Elution Time (MWD)
ES1
SE2
Total OH/Backbone Ratio Drifts of 2 HPMCAS
Samples with Elution Time (MWD)
ES1
SE2
To Find Unsubstituted OH on Backbone
(OH/Backbone)- k (HP/Backbone) => Unsub. OH / Backbone
Absorptivity Ratio k Needs to be Calibrated from
Known Standards
SE2
ES1
ES1
SE2
HP / BB Ratios
OH / BB Ratios
Methoxy / Backbone Ratio Drifts of 2 HPMCAS
Samples with Elution Time (MWD)
SE2
ES1
2935cm-1 CH2 / Backbone Ratio Drifts of
2 HPMCAS Samples with Elution Time (MWD)
ES1
SE2
2935 CH2 / BB & 2935 CH2 / AS Ratio Drifts of 2
HPMCAS Samples with Elution Time (MWD)
SE2
ES1
ES1
SE2
Peak 2935 / AS
Peak 2935 / BB
Small HP/AS Ratio Drifts of 2 HPMCAS Samples
with Elution Time (MWD)
ES1
SE2
Backbone/AS & HP/AS Ratio Drifts of 2 HPMCAS
Samples with Elution Time
SE2
ES1
SE2
ES1
BB / AS
HP / AS
OH/AS Ratio Drifts of 2 HPMCAS Samples with
Elution Time (MWD)
SE2
ES1
Methoxy/AS C=O Ratio Drifts of
2 HPMCAS Samples with Elution Time (MWD)
SE2
ES1
Acetyl/AS C=O Ratio Drifts of
2 HPMCAS Samples with Elution Time (MWD)
SE2
ES1
0.52 ---- MF
0.40 ---- LF
Grade
Levels
Methoxy/2935 CH2 & Methoxy/Backbone Ratio
Drafts of 2 HPMCAS Samples with Elution Time
M / 2935 CH2
M / BB
ES1
SE2
ES1
SE2
Methoxy / Acetyl Ratio Drafts of
2 HPMCAS Samples with Elution Time (MWD)
ES1
SE2
Summary: Compositional Differences
of 2 HPMCAS Samples
32
Sample # Sample
Appearance
Compositional Drifts
w/ MWD
Consistent
Substitution
w/ MWD
ES1 Fine
Powder
Methoxy,
Acetyl / Succinate,
Hydroxyl, CH2
HP
SE2 Fine
Powder
Methoxy,
Acetyl / Succinate,
Hydroxyl, CH2
HP
Difference
Different Drift Patterns
with Methoxy,
Acetyl / Succinate,
Hydroxyl, CH2
Little
Difference
with HP
GPC-IR Chromatogram Overlay
at 1739 cm-1 of 4 HPMCAS-MF Lots
T8 T10 T12 T14 Snapshots
Acetyl/TotalEster Ratio Drifts of 4 MF Lots
Compared to LF & HF HPMCAS
-- LF ---------
-- HF ---------
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
Common Polymeric Excipients
36
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 / PCL / PVAc
Methacrylate Copolymers: Eudragit
Polyethylene Oxide: PEO (MW > 20K) or PEG (MW < 20K)
Excipient Combinations with Plasticizers and Additives
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).
GPC-IR Applications for Excipient Analysis
in Drug Formulations
Excipient
Manufacturing
• Process Control
• Lot-to-lot Variations
• CoA
• Novel Excipient R&D
• Trouble Shooting
Formulation Develop. Drug Manufacturing
• Incoming QC
• Excipient Functionality
• Formulation Development
• QbD
• Process Degradation (Hot Melt Extrusion)
• Define Safe Process Window / QbD
• Process Monitoring
• Trouble Shooting
Formulated Drugs
Shelf Life Stability
• Stressed Degradation
• De-Formulate Excipient Blends
• Trouble-Shoot Problem Drugs in the Market
Users: Excipient Pharma Co. Pharma Co.
Manufacturers HME Service Providers Generic Drug Co.
Excipient QbD Space
GPC-IR-Performance
Slide from USP International Excipient Workshop (July 2009)
GPC
IR
Performance
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
40
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