New LC-IR Technique to Characterize Polymeric
Excipients for Lot-to-Lot Variations, Degradation
and Stability in Pharmaceutical Formulations
Ming Zhou, PhD
Director of Applications Engineering
Spectra Analysis Instruments, Inc.
Contact: [email protected]
Tel. 508-281-62761
AAPS NERDG 2011 Meeting 4/15/11
OUTLINE
LC-IR Hyphenated Technology
Excipient Characterization: Copovidone PVP/VAc
Excipient Degradation from Thermal Processing:
HPMCAS, Eudragit L100-55 (PEA/MAA)
Summary
2
Hyphenated Technologies &
Major Applications
Liquid Chromatography
Mass
SpectroscopyInfra Red
Spectroscopy
Separation
Applications Small Molecules,Proteins Copolymers / Mixtures
Detection &
Data Analysis
LC-MS LC-IR
Pharma API’s Polymeric Excipients
LC-IR Hyphenated System
Features of LC-IR System
Real-Time On-line Detection
Microgram Sensitivity
All HPLC Solvents, Gradients & Volatile Buffers
• e.g. Water, ACN, Methanol, THF, DMSO …
All GPC/SEC Solvents: e.g. THF, TCB, HFIP, Chloroform, DMF
High Quality Solid Phase Transmission IR Spectra
Fully Automated Operation: No More Manual Fractionation
Multi-Sample Processing: 10 Hr ZnSe Disk Time
GPC-IR to Characterize Compositional
Variations of Copolymer Poly(A-B)
8
high MW low MW
mol
ar m
ass
comonomer A
comonomer B
A/B compositionratio
polymer chains
Ab
so
rba
nce
Bulk 50% (NMR)
GPC-IR Spectrum Snapshot of
Copovidone- VP/VAc Copolymer
Peak 1680 cm-1 from VP comonomer
Peak 1740 cm-1 from VAc comonomer
VP VAc
GPC-IR Chromatogram Overlay with Comonomer IR Peak Ratios
Excipient Compositional Drift
w/ 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
% V
Ac
co
mo
no
mer
comonomer composition
distribution
Excipient Compositional Drift
w/ MWD Vs. Bulk Average
Bulk Average
40% VAc
0
.1
.2
.3
.4
.5
.6
106 104 103 102105Molecular Weight
Copovidone: sample A
sample B
sample C
Copovidone MW Distributions from
Different Suppliers (Manf. Processes)
ma
x. IR
ab
so
rba
nce
Copovidone A gave clear tablets while Copovidone C led to cloudy ones.
0
.1
.2
.3
.4
.5
.6
106 104 103 102105Molecular Weight
Copovidone: sample A
30
35
40
45
50
% V
Ac
Co
mo
no
mer
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
from Different Manf. Processes
Copovidone A gave clear tablets while Copovidone C led to cloudy ones.
Excipient Characterization
by LC-IR in Pharma Formulations
14
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.
15
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 (Screw Speed)
• Torque
• Screw / Die Designs
GPC-IR for HPMCAS Degradation
in Hot Melt Extrusion Process
Unprocessed
Processed at 160C
Processed at 220C
Low MW
Degradant ?
Polymer Change ?
Degradant from HPMCAS (220C)
in Hot Melt Extrusion Process
IR Database Search Result: Succinic Acid
HPMCAS Polymer Degradation
in Hot Melt Extrusion Process
Functional Group Ratio Changes from High Temp Process (220C)
OH
-C=O
GPC-IR Analysis of HPMCAS
Degradation in HME Process
Fig. A Schematic Structure of HPMC-AS
Detected Degradants: Succinic Acid & Derivatives
Detected Functionality Ratio Change: Hydroxyl Vs. Carbonyl
Help Understand Excipient Degradation Mechanism
Study Excipient / API Interactions
Define Safe Process Window: QbD – OK at 160C, Problem at 220C
Excipient Blends with Plasticizers and Additives
CH3-C=O
HOOC-CH2-CH2-C=O
GPC-IR Characterization of Eudragit
L100-55 from Hot Melt Extrusion Process
IR Spectrum at Red Cursor
IR Spectrum at Blue Cursor
GPC Chromatogram by Max IR Band
IR Spectra of L100-55 Samples atPolymer Peak Center (Elution Time ~9.4’)
21
S0 – Green Ref
S1 – Violet 130C
S2 – Blue 160C
S3 – Black 190C
COOEt
1735
COOH
1705
CO-OH
NCE?
1805 cm-1
Excipient L100-55 Crosslinked from
COOH to Anhydride at Higher Temp
22
COOEt
1735
COOH
1705
S0 – Green Ref
S1 – Violet 130C
S2 – Blue 160C
S3 – Black 190C
NCE?
1805 cm-1
QbD Study: Eudragit L100-55
Degradation & Stability from HME
23
Sample # Extrusion
Temp.
Screw
Speed
Sample
Color
Sample
in THF
(~0.5%)
Degradant
Formed
Polymer
Change
S0 Not
Processed
White Clear
Solution
Ref. Ref.
S1 130 C 250 rpm Off
White
Clear
Solution
Trace
Anhydrides
S2 160 C 250 rpm Off
White
Clear
Solution
Anhydrides Acid/Ester
Ratio
Decreased
S3 190 C 250 rpm Brownish Some
Residue
Anhydrides Acid/Ester
Ratio
Decreased
Common Polymeric Excipients
24
Cellulose Derivatives
• HydroxyPropyl Methoxy Cellulose (Hypromellose): HPMC
• HPMC Acetate Succinate: HPMC-AS
• HPMC Phthalate: HPMC-P
• HydroxyPropyl Cellulose: HPC
Copovidone: PolyVinyl Pyrrolidone / Vinyl Acetate – PVP/VAc
SoluPlus Terpolymer: PEG / PVAc / PVCap
Methacrylic or Methacrylate Copolymers: Eudragit Polymers
Polyethylene Oxide: PEO (MW > 20K) or PEG (MW < 20K), PEG/PPG
PLGA Copolymers: Biodegadable
Excipient Combinations with Plasticizers and Additives
LC-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-Variations
• 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.
Summary: GPC-IR Characterization
of Excipient Copolymers Poly(A-B)
High MW Low MW GPC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out copolymer compositions across MWD (sizes)
IR Spectra
Summary: GPC-IR Characterization
of Excipient Copolymers Poly(A-B)
High MW Low MW GPC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out copolymer compositions across MWD (sizes)
Lot-to-lot or supplier-to-supplier variations
IR Spectra
Summary: GPC-IR Characterization
of Excipient Copolymers Poly(A-B)
High MW Low MW GPC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out copolymer compositions across MWD (sizes)
Lot-to-lot or supplier-to-supplier variations
Degradation from processing:
Loss of functional group
Cross-linking
Break down, Low MW degradant
IR Spectra
0
.1
.2
.3
.4
.5
.6
107 105 104 103106Molecular Weight
Break down
30
35
40
45
50
A %
0
.1
.2
.3
.4
.5
.6
Cross-linked
Starting Excipient
ma
x. IR
ab
so
rba
nce
Low MW
Degradant
Compositional / MWD Changes from
Excipient Processing Degradation
Cross Linking Break down
Summary: GPC-IR Characterization
of Excipient Copolymers Poly(A-B)
High MW Low MW GPC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out copolymer compositions across MWD (sizes)
Lot-to-lot or supplier-to-supplier variations
Degradation from processing:
Loss of functional group
Cross-linking
Break down, Low MW degradant
Validate Excipient Stability: To define safe processing window (QbD)
IR Spectra
Summary: LC-IR Analysis of
Excipients in Drug Formulations
Polymeric Excipient Characterization
Compositional Variations with MWD: Functional Group Ratios
Lot-to-Lot, Supplier-to-Supplier Variations
Degradation Analysis in Thermal Process (HME)
Detect Degradants (Low MW)
Polymer Structural Changes:
• Cross-Linking (New Chemical Entity)
• Functional Group Changes
Stability Study under Forced Conditions
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