Analytical Techniques to Characterize the Stability
and Degradation of Polymeric Excipients
from Hot Melt Extrusion Processing
Ming Zhou, PhD
Director of Applications Engineering
Spectra Analysis Instruments, Inc.
Contact: [email protected]
Tel. 508-281-62761
AAPS 2011 Meeting 10/26/2011
OUTLINE
Overview: Analytical Techniques to Characterize Polymers
Introduce SEC-IR Hyphenated Technique
SEC-IR to Characterize Excipient Degradation from HME:
SoluPlus, HPMCAS, PEA/MAA
Summary
Note: Size Exclusion Chromatography (SEC) = Gel Permeation Chromatography (GPC)2
Analytical Techniques to
Characterize Homopolymers Poly(A)
High MW Low MW Molar Mass
Ab
so
rpti
on
Polymer MWD Affects Many Application Properties
Analytical Techniques to
Characterize Homopolymers Poly(A)
High MW Low MW Molar Mass
Ab
so
rpti
on
SEC / GPC
(FFF)
Composition AnalysisNMR
IR, ATR-IR, Raman
NIR
MS (MW<10K), difficult to ionize
UV-Vis
Thermal AnalysisDSC or DMA: Tg, Tm
TGA: Weight Loss w/ Temp.
Pyrolysis GC-MS: Volatile Degradant
Analytical Techniques to Characterize
Copolymers Poly(A-B)
5
high MW low MW
mol
ar m
ass
comonomer A
comonomer B
A/B compositionratio
polymer chains
Ab
so
rba
nc
e
Analytical Techniques to Characterize
Copolymers Poly(A-B): Compositions
6
high MW low MW
mol
ar m
ass
comonomer A
comonomer B
A/B compositionratio
polymer chains
Ab
so
rba
nc
e
Bulk Average
Composition
Analysis:NMR
FTIR, Raman
NIR
Analytical Techniques to Characterize
Copolymers Poly(A-B): Compositions
7
high MW low MW
mol
ar m
ass
comonomer A
comonomer B
A/B compositionratio
polymer chains
Ab
so
rba
nc
e
Bulk Average
SEC / GPC
ElutionTime
SEC / GPC
Composition
Analysis:IR
NMR
MS
HPLC
Hyphenated Techniques to
Characterize Copolymers Poly(A-B)
8
high MW low MW
mol
ar m
ass
comonomer A
comonomer B
A/B compositionratio
polymer chains
Ab
so
rba
nc
e
SEC Time
SEC / GPC
Composition
Analysis:IR
NMR
MS
HPLC
Hyphenated (Coupling) TechniquesSEC-IR
LC—NMR: Fractionation (Batching)
LC-MS: for Low MW Portion
2D LC: HPLC x SEC; IPC x SEC
TGA-IR: Volatile Degradant
TGA + GC-MS: Volatile Degradant
SEC-IR to Characterize Compositional
Variations of Copolymers Poly(A-B)
9
high MW low MW
mol
ar m
ass
comonomer A
comonomer B
A/B compositionratio
polymer chains
Ab
so
rba
nc
e
AB
SEC Time
IR Spectra
ZnSe Sample Disk
Rotate at tunable speed
10-0.3 mm/min
The yellow ZnSe disk is under
vacuum without moisture or
CO2 interference
Disk Temp: -140C ~ 100C
Transmission IR analysis is
done on the solid deposit.
Unattended overnight runs
Re-usable after solvent
cleaning
12
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 SEC/GPC Solvents: e.g. THF, DMF, Chloroform, TCB, HFIP
High Quality Solid Phase Transmission IR Spectra
Fully Automated Operation: No More Manual Fractionation
Multi-Sample Processing: 10 Hr ZnSe Disk Time
SEC-IR Direct Deposition
& Data Processing
ZnSe Disk
14
SEC
OUTLINE
Overview: Analytical Techniques to Characterize Polymers
Introduce SEC-IR Hyphenated Technique
SEC-IR to Characterize Excipient Degradation from HME:
SoluPlus, HPMCAS, PEA/MAA
Summary
Note: Size Exclusion Chromatography (SEC) = Gel Permeation Chromatography (GPC)15
Case #1: SoluPlus Copolymer
Stability from HME Processing
16
Sample # Temp.
(C)
Screw
Speed
(rpm)
Sample
Color
Solution
in DMF
(~2%)
Degradant
Formed
?
Polymer
Changed ?
R
(Ref.)
Not
Processed
White
Powder
Clear
Solution
A 120 125 Off
White
Clear
Solution
? ?
B 120 250 Off
White
Clear
Solution
? ?
C 180 125 Yellowish
White
Clear
Solution
? ?
D 180 250 Yellowish
White
Clear
Solution
? ?
SoluPlus Sample Preparation &
SEC-IR Operating Conditions
Sample Preparation:
• SoluPlus excipient was extruded at different temperatures: 120oC &
180oC and at different extrusion speed 125 rpm & 250 rpm.
• 0.20 g SoluPlus solid samples were dissolved in 10 ml DMF in ~1.5
hr and filtered with 0.45 mm PTFE syringe filter before GPC injection
SEC Chromatography: Agilent® 1200
• SEC Column Temperature: Ambient
• Solvent: DMF at 1.0 ml/min
• Column: Jordi Gel DVB Mixed Bed– 250 x 10 mm
• Sample Injections: 25 ml at ~2% weight / volume DMF
IR Detection
• DiscovIR-LC® solvent-removing direct-deposition solid phase FTIR
• Cyclone Temperature: 225oC
• Condenser Temperature: -5oC
• ZnSe Disk Temperature: 55oC
IR Band Identifications
of SoluPlus Copolymer
Peak 1642 cm-1 from VCap comonomer
Peak 1738 cm-1 from VAc comonomer
NO
O
O
OH
O
O
OH
O
l
m
n
Group VAc VCap Note
C=O 1738 cm-1 1642 cm-1 Peak Ratios for
Compositional
Drifts w/ MWD
Acetyl 1244 cm-1 Internal Ratio
Check vs.
Peak 1738
CH3 1374 cm-1
Acetyl
1244
Methyl
1374
VCap
VAc
PEG
Acetyl Internal Ratio CheckAlmost Flat across MWD for Sample B
1738/1244 Peak Height Ratios
All from VAc Group
Polymer IR Spectrum at Red Marker
Polymer IR Spectrum at Blue Marker
SEC-IR Band Chromatogram & IR
Spectra of SoluPlus Ref. Sample
Polymer IR Spectrum at Red Marker
Polymer IR Spectrum at Blue Marker
Band Chromatogram at 1642 cm-1
1738
VAc
1642
VCap
1738
1642
SoluPlus Ref. Compositional Drifts w/
Elution Time (MWD) by IR Peak Ratios
Comonomer VAc/VCap Ratio ~ Carbonyl Peak 1738/1642 Height Ratio:
Abs(VAc) / Abs(VCap) = (k1*b*MVAc) / (k2*b*MVCap) = k (MVAc / MVCap)
(Molecular Weight Distribution)
IR Spectrum at Red Cursor (Elution Time)
IR Spectrum at Blue Cursor (Peak Chromatogram)
Peak 1738/1642 Height Ratio
Polymer IR Spectrum at Red Marker
Polymer IR Spectrum at Blue Marker
Peak 1738/1642 Height Ratio
1642
1642
VCap
1738
1738
VAc
SoluPlus Stability: VAc/VCap Ratios
Drift Similarly w/ MWD after HME
22
R – Green Unprocessed Reference
A – Black Processed at 120C @ 125rpm
B – Blue Processed at 120C @ 250rpm
C – Brown Processed at 180C @ 125rpm
D – Violet Processed at 180C @ 250rpm
IR Spectra Overlay of All 5 Samples
at ~10’ Elution Time (MWD Center)
SEC-IR Matrix Study Summary: SoluPlus Stability in HME Processing
24
Sample # Temp.
(C)
Screw
Speed
(rpm)
Sample
Color
Solution
in DMF
(~2%)
Degradant
Formed
?
Polymer
Changed ?
R
(Ref.)
Not
Processed
White
Powder
Clear
Solution
Not
Detected
VAc/VCap
Ratio Drift
w/ MWD
A 120 125 Off
White
Clear
Solution
Not
Detected
Same
VAc/VCap
Ratio Drift
B 120 250 Off
White
Clear
Solution
Not
Detected
Same
VAc/VCap
Ratio Drift
C 180 125 Yellowish
White
Clear
Solution
Not
Detected
Same
VAc/VCap
Ratio Drift
D 180 250 Yellowish
White
Clear
Solution
Not
Detected
Same
VAc/VCap
Ratio Drift
Case #2: HPMCAS Stability &
Degradation from HME
25
Sample # Extrusion
Temp.
Sample
Color
Sample
in THF
(~0.5%)
Degradant
Formed ?
Polymer
Change?
Ref. Not
Processed
White
Powder
Clear
Solution
None None
A 180 C Yellowish
Powder
Clear
Solution
B 200 C Yellowish
Powder
Some
Residue
? ?
C 220 C Brownish
Powder
Some
Residue
? ?
SEC-IR Band Chromatogram & IR
Spectra of HPMCAS Sample (220oC)
Band Chromatogram at 1720 cm-1
Polymer IR Spectrum at Red Marker
Polymer IR Spectrum at Blue Marker
Low MW Degradant
at 14.6’Polymer
IR Database Search to Identify
Degradant at 14.6’: Succinic Acid
SEC-IR Band Chromatogram to
Identify Degradant & Additive
Band Chromatogram at 1670 cm-1
for HPMCAS & Additive & Degradant
Degradant IR Spectrum at 14.6 Min. (Red Marker)
Succinic Acid
Additive IR Spectrum at 14.1 Min. (Blue Marker)
Baseline Not Corrected
Polymer
Sample C
(HME @220oC)
IR Spectra Overlay of HPMCAS,
Additive & Degradant from Sample C
Baselines Not Corrected
Succinic Acid at 14.65 Min
Additive at 14.1 Min
HPMCAS at 11.2 Min
Additive-Specific Peak
1670cm-1
SEC-IR Band Chromatogram of
Additive only for HPMCAS Ref. Sample
Band Chromatogram at 3360 cm-1
for Additive Only at 14.1 Min.
Additive IR Spectrum at 14.6 Min. (Red Marker)
No Succinic Acid
Additive IR Spectrum at 14.1 Min. (Blue Marker)
No Degradant
(Succinic Acid)
Degradant Level Comparison of
HPMCAS Samples after HME
Normalized to Additive Level
Additive
at 14.1 Min.
Degradant
at 14.6 Min.
Sample C: Violet (220C)
Sample B: Brown (200C)
Sample A: Aqua (180C)
Sample R: Blue (Ref.)
Band Chromatograms at 1670 cm-1
Degradant Level Increases with
Higher HME Processing Temp.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 50 100 150 200 250
Su
ccin
ic A
cid
No
rmalized
Peak H
eig
ht
Process Temperarure (C)
Succinic Acid Formation with Hot Melt ExtrusionTemperature
Ref. A B CSamples:
~190oC
HPMCAS Matrix Study Summary:
Degradation & Stability from HME
33
Sample # Extrusion
Temp.
Sample
Color
Sample
in THF
(~0.5%)
Degradant
Formed
Polymer
Change
Ref. Not
Processed
White
Powder
Clear
Solution
None None
A 180 C Yellowish
Powder
Clear
Solution
Little
Succinic
Acid
None
B 200 C Yellowish
Powder
Some
Residue
Succinic
Acid
C 220 C Brownish
Powder
Some
Residue
Succinic
Accid
Higher
OH/C=O
Ratio
Case #3: PEA/MAA Samples
from Hot Melt Extrusion Process
34
Sample # Extrusion
Temp.
Screw
Speed
Sample
Color
Sample
in THF
(~0.5%)
Degradant
Formed
?
Polymer
Changed
?
S0 Not
Processed
White Clear
Solution
S1 130 C 250 rpm Off
White
Clear
Solution
S2 160 C 250 rpm Off
White
Clear
Solution
S3 190 C 250 rpm Brownish Some
Residue
? ?
Note: Samples S1-S3 contain 20% plasticizer TEC to assist extrusion process.
IR Spectra of PEA/MAA Samples at Polymer MWD Center (ET ~9.4’)
35
S0 – Green Ref
S1 – Violet 130C
S2 – Blue 160C
S3 – Black 190C
COOEt
1735
COOH
1705
CO-OH
NCE?
1805 cm-1
PEA/MAA Crosslinked to Anhydride
from COOH at Higher HME Temp
36
COOEt
1735
COOH
1705
S0 – Green Ref
S1 – Violet 130C
S2 – Blue 160C
S3 – Black 190C
NCE?
1805 cm-1
PEA/MAA Matrix Study Summary:
Degradation & Stability from HME
37
Sample # Extrusion
Temp.
Screw
Speed
Sample
Color
Sample
in THF
(~0.5%)
Degradant
Formed
Polymer
Change
S0 Not
Processed
White Clear
Solution
None None
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
for Hot Melt Extrusion by SEC-IR
38
COCH3
HOOC-CH2-CH2-C=O
NO
O
O
OH
O
O
OH
O
l
m
n
H - (OCH2CH2 )n - OH
HPMCAS ~ 190C
PEA/MAA ~ 160C
Copovidone > 200C
SoluPlus > 200C
PEG
Excipient Combinations with Plasticizers and Additives
?
Summary
SEC-IR Maps out Polymer Compositions across MWD (Sizes) for
Copolymers and Formulated Polymer Mixtures
SEC-IR Useful to Characterize Excipient Stability/Degradation
from HME Processing: SoluPlus, HPMCAS, PEA/MAA
Detected Degradants (Low MW)
Analyzed Polymer Compositional / Structural Changes:
• Cross-Linking (New Chemical Entity) & Functional Group Changes
Define Safe Processing Windows / QbD to Validate Excipient Stability40
41
High MW Low MW SEC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out Copolymer Compositions (A/B Ratio) across MWD (Sizes)
IR Spectra
Summary: SEC-IR ApplicationsProfile Polymer Compositions = f (Sizes)
42
High MW Low MW SEC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out Copolymer Compositions (A/B Ratio) across MWD (Sizes)
Study Lot-to-Lot Variations
IR Spectra
Summary: SEC-IR ApplicationsProfile Polymer Compositions = f (Sizes)
43
High MW Low MW SEC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out Copolymer Compositions (A/B Ratio) across MWD (Sizes)
Study Supplier-to-Supplier Variations (2nd Source)
IR Spectra
Summary: SEC-IR ApplicationsProfile Polymer Compositions = f (Sizes)
44
High MW Low MW SEC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out Copolymer Compositions (A/B Ratio) across MWD (Sizes)
Study Lot-to-Lot or Supplier-to-Supplier Variations
Characterize Polymer Degradation from Processing:
Loss of functional group A (Reduced A/B)
IR Spectra
Summary: SEC-IR ApplicationsProfile Polymer Compositions = f (Sizes)
45
High MW Low MW SEC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out Copolymer Compositions (A/B Ratio) across MWD (Sizes)
Study Lot-to-Lot or Supplier-to-Supplier Variations
Characterize Polymer Degradation from Processing:
Loss of functional group A (Reduced A/B)
Cross-linking ( Higher MW)
IR Spectra
Cross Linking
Summary: SEC-IR ApplicationsProfile Polymer Compositions = f (Sizes)
46
High MW Low MW SEC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out Copolymer Compositions (A/B Ratio) across MWD (Sizes)
Study Lot-to-Lot or Supplier-to-Supplier Variations
Characterize Polymer Degradation from Processing:
Loss of functional group (Reduced A/B)
Cross-linking ( Higher MW)
Break down ( Lower MW) & Detect low MW degradant
IR Spectra
Break Down
Summary: SEC-IR ApplicationsProfile Polymer Compositions = f (Sizes)
47
High MW Low MW SEC
Elution
Time
Ab
so
rban
ce
A/B RatioA
B
Map out Copolymer Compositions (A/B Ratio) across MWD (Sizes)
Study Lot-to-Lot or Supplier-to-Supplier Variations
Characterize Polymer Degradation from Processing:
Loss of functional group (Reduced A/B)
Cross-linking ( Higher MW)
Break down ( Lower MW) & Detect low MW degradant
De-Formulate Complex Polymer Mixtures
IR Spectra
Break DownCross Linking
Summary: SEC-IR ApplicationsProfile Polymer Compositions = f (Sizes)
Summary: SEC-IR Characterization
of Excipient Copolymers Poly(A-B)
High MW Low MW SEC
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
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.
50
LC-IR Hyphenated System
HPLC
or GPC
Hyphen
Desolvation
Deposition
Microscopic FTIR
System Control
Data Processing