The document summarizes analytical techniques for characterizing polymeric excipients processed with hot melt extrusion (HME). It discusses using size exclusion chromatography coupled with infrared spectroscopy (SEC-IR) to analyze three case studies: 1) SoluPlus copolymer stability after HME at different temperatures and screw speeds showed compositional drifts but no degradation. 2) HPMCAS processing showed succinic acid formation above 190°C indicating degradation. 3) PEA/MAA crosslinking was observed at 190°C forming anhydrides from carboxylic acids. SEC-IR identified changes and degradation products from HME for each excipient.

1. AAPS 2011 Meeting 10/26/2011
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: ZhouM@Spectra-Analysis.com
Tel. 508-281-6276 1

2. 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

3. Analytical Techniques to
Characterize Homopolymers Poly(A)
Absorption
High MW Low MW Molar Mass
Polymer MWD Affects Many Application Properties

4. Analytical Techniques to
Characterize Homopolymers Poly(A)
SEC / GPC
(FFF)
Absorption
High MW Low MW Molar Mass
Composition Analysis Thermal Analysis
NMR DSC or DMA: Tg, Tm
IR, ATR-IR, Raman TGA: Weight Loss w/ Temp.
NIR Pyrolysis GC-MS: Volatile Degradant
MS (MW<10K), difficult to ionize
UV-Vis

5. Analytical Techniques to Characterize
Copolymers Poly(A-B)
Absorbance
A/B composition
molar mass
ratio
high MW low MW
polymer chains
comonomer A
comonomer B
5

6. Analytical Techniques to Characterize
Copolymers Poly(A-B): Compositions
Composition
Analysis:
NMR
FTIR, Raman
Absorbance
A/B composition
molar mass
ratio NIR
Bulk Average
high MW low MW
polymer chains
comonomer A
comonomer B
6

7. Analytical Techniques to Characterize
Copolymers Poly(A-B): Compositions
Absorbance SEC / GPC
A/B composition
molar mass
ratio
Bulk Average
high MW low MW SEC / GPC
ElutionTime
Composition
Analysis:
IR
polymer chains
NMR comonomer A
MS
HPLC comonomer B
7

8. Hyphenated Techniques to
Characterize Copolymers Poly(A-B)
Absorbance SEC / GPC
A/B composition
molar mass
ratio
high MW low MW SEC Time
Hyphenated (Coupling) Techniques
Composition SEC-IR
Analysis: LC—NMR: Fractionation (Batching)
IR
polymer chains
LC-MS: for Low MW Portion
NMR 2D LC: HPLC x SEC; IPC x SEC
comonomer A
MS
HPLC TGA-IR: Volatilecomonomer B
Degradant
TGA + GC-MS: Volatile Degradant 8

9. SEC-IR to Characterize Compositional
Variations of Copolymers Poly(A-B)
IR Spectra
A
B
Absorbance
A/B composition
molar mass
ratio
high MW low MW SEC Time
polymer chains
comonomer A
comonomer B
9

10. SEC-IR Hyphenated System
SEC

11. Schematic View of LC-IR System
SEC
or
HPLC

12. 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

13. 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

14. SEC-IR Direct Deposition
& Data Processing
SEC
ZnSe Disk
14

15. 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

16. Case #1: SoluPlus Copolymer
Stability from HME Processing
Sample # Temp. Screw Sample Solution Degradant Polymer
(C) Speed Color in DMF Formed Changed ?
(rpm) (~2%) ?
R Not White Clear
(Ref.) Processed Powder Solution
A 120 125 Off Clear ? ?
White Solution
B 120 250 Off Clear ? ?
White Solution
C 180 125 Yellowish Clear ? ?
White Solution
D 180 250 Yellowish Clear ? ?
White Solution 16

17. 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

18. IR Band Identifications
of SoluPlus Copolymer
HO
Group VAc VCap Note
PEG VCap
O
O
N C=O 1738 cm-1 1642 cm-1 Peak Ratios for
Compositional
l
O m
Drifts w/ MWD
n
O Acetyl 1244 cm-1 Internal Ratio
O Check vs.
O Peak 1738
VAc
CH3 1374 cm-1
HO
Peak 1642 cm-1 from VCap comonomer Methyl Acetyl
1374 1244
Peak 1738 cm-1 from VAc comonomer

19. Acetyl Internal Ratio Check
Almost 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

20. SEC-IR Band Chromatogram & IR
Spectra of SoluPlus Ref. Sample
Band Chromatogram at 1642 cm-1
1642
Polymer IR Spectrum at Red Marker
1738
1642
Polymer IR Spectrum at Blue Marker 1738 VCap
VAc

21. 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)
Peak 1738/1642 Height Ratio
Peak 1738/1642 Height Ratio
1642
IR Polymer IR Spectrum at Red Marker
Spectrum at Red Cursor (Elution Time)
1738
1642
IR Spectrum atIR Spectrum at Blue Marker
Polymer Blue Cursor (Peak Chromatogram) 1738 VCap
VAc
(Molecular Weight Distribution)

22. SoluPlus Stability: VAc/VCap Ratios
Drift Similarly w/ MWD after HME
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
22

23. IR Spectra Overlay of All 5 Samples
at ~10’ Elution Time (MWD Center)

24. SEC-IR Matrix Study Summary:
SoluPlus Stability in HME Processing
Sample # Temp. Screw Sample Solution Degradant Polymer
(C) Speed Color in DMF Formed Changed ?
(rpm) (~2%) ?
R Not White Clear Not VAc/VCap
(Ref.) Processed Powder Solution Detected Ratio Drift
w/ MWD
A 120 125 Off Clear Not Same
White Solution Detected VAc/VCap
Ratio Drift
B 120 250 Off Clear Not Same
White Solution Detected VAc/VCap
Ratio Drift
C 180 125 Yellowish Clear Not Same
White Solution Detected VAc/VCap
Ratio Drift
D 180 250 Yellowish Clear Not Same
White Solution Detected VAc/VCap
24
Ratio Drift

25. Case #2: HPMCAS Stability &
Degradation from HME
Sample # Extrusion Sample Sample Degradant Polymer
Temp. Color in THF Formed ? Change?
(~0.5%)
Ref. Not White Clear None None
Processed Powder Solution
A 180 C Yellowish Clear
Powder Solution
B 200 C Yellowish Some ? ?
Powder Residue
C 220 C Brownish Some ? ?
Powder Residue
25

26. SEC-IR Band Chromatogram & IR
Spectra of HPMCAS Sample (220oC)
Band Chromatogram at 1720 cm-1
Low MW Degradant
at 14.6’
Polymer
Polymer IR Spectrum at Red Marker
Polymer IR Spectrum at Blue Marker

27. IR Database Search to Identify
Degradant at 14.6’: Succinic Acid

28. SEC-IR Band Chromatogram to
Identify Degradant & Additive
Band Chromatogram at 1670 cm-1 Sample C
for HPMCAS & Additive & Degradant (HME @220oC)
Polymer
Degradant IR Spectrum at 14.6 Min. (Red Marker)
Succinic Acid
Additive IR Spectrum at 14.1 Min. (Blue Marker)
Baseline Not Corrected

29. IR Spectra Overlay of HPMCAS,
Additive & Degradant from Sample C
1670cm-1
Baselines Not Corrected
Succinic Acid at 14.65 Min
Additive at 14.1 Min
HPMCAS at 11.2 Min
Additive-Specific Peak

30. SEC-IR Band Chromatogram of
Additive only for HPMCAS Ref. Sample
Band Chromatogram at 3360 cm-1 No Degradant
for Additive Only at 14.1 Min. (Succinic Acid)
Additive IR Spectrum at 14.6 Min. (Red Marker)
No Succinic Acid
Additive IR Spectrum at 14.1 Min. (Blue Marker)

31. Degradant Level Comparison of
HPMCAS Samples after HME
Band Chromatograms at 1670 cm-1
Sample C: Violet (220C)
Sample B: Brown (200C)
Sample A: Aqua (180C)
Sample R: Blue (Ref.)
Degradant
at 14.6 Min.
Normalized to Additive Level
Additive
at 14.1 Min.

32. Degradant Level Increases with
Higher HME Processing Temp.
Succinic Acid Formation with Hot Melt ExtrusionTemperature
5
Succinic Acid Normalized Peak Height
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
0 50 100 150 200 250
Process Temperarure (C) ~190oC
Samples: Ref. A B C

33. HPMCAS Matrix Study Summary:
Degradation & Stability from HME
Sample # Extrusion Sample Sample Degradant Polymer
Temp. Color in THF Formed Change
(~0.5%)
Ref. Not White Clear None None
Processed Powder Solution
A 180 C Yellowish Clear Little None
Powder Solution Succinic
Acid
B 200 C Yellowish Some Succinic
Powder Residue Acid
C 220 C Brownish Some Succinic Higher
Powder Residue Accid OH/C=O
Ratio
33

34. Case #3: PEA/MAA Samples
from Hot Melt Extrusion Process
Sample # Extrusion Screw Sample Sample Degradant Polymer
Temp. Speed Color in THF Formed Changed
(~0.5%) ? ?
S0 Not White Clear
Processed Solution
S1 130 C 250 rpm Off Clear
White Solution
S2 160 C 250 rpm Off Clear
White Solution
S3 190 C 250 rpm Brownish Some ? ?
Residue
Note: Samples S1-S3 contain 20% plasticizer TEC to assist extrusion process. 34

35. IR Spectra of PEA/MAA Samples
at Polymer MWD Center (ET ~9.4’)
S0 – Green Ref COOEt
S1 – Violet 130C 1735
S2 – Blue 160C
S3 – Black 190C
COOH
1705
NCE?
1805 cm-1
CO-OH
35

36. PEA/MAA Crosslinked to Anhydride
from COOH at Higher HME Temp
COOEt
1735 S0 – Green Ref
S1 – Violet 130C
S2 – Blue 160C
COOH S3 – Black 190C
1705
NCE?
1805 cm-1
36

37. PEA/MAA Matrix Study Summary:
Degradation & Stability from HME
Sample # Extrusion Screw Sample Sample Degradant Polymer
Temp. Speed Color in THF Formed Change
(~0.5%)
S0 Not White Clear None None
Processed Solution
S1 130 C 250 rpm Off Clear Trace
White Solution Anhydrides
S2 160 C 250 rpm Off Clear Anhydrides Acid/Ester
White Solution Ratio
Decreased
S3 190 C 250 rpm Brownish Some Anhydrides Acid/Ester
Residue Ratio
Decreased
37

38. Common Polymeric Excipients
for Hot Melt Extrusion by SEC-IR
?
HOOC-CH2-CH2-C=O
HPMCAS ~ 190C COCH3
PEA/MAA ~ 160C
HO
O
O
N
l
O m
n
Copovidone > 200C O
O
O
H - (OCH2CH2 )n - OH SoluPlus > 200C
PEG HO
 Excipient Combinations with Plasticizers and Additives
38

39. 39

40. 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 Stability
40

41. Summary: SEC-IR Applications
Profile Polymer Compositions = f (Sizes)
IR Spectra B A
A/B Ratio
Absorbance
High MW Low MW SEC
Elution
Time
 Map out Copolymer Compositions (A/B Ratio) across MWD (Sizes)
41

42. Summary: SEC-IR Applications
Profile Polymer Compositions = f (Sizes)
IR Spectra B A
A/B Ratio
Absorbance
High MW Low MW SEC
Elution
Time
 Map out Copolymer Compositions (A/B Ratio) across MWD (Sizes)
 Study Lot-to-Lot Variations
42

43. Summary: SEC-IR Applications
Profile Polymer Compositions = f (Sizes)
IR Spectra B A
A/B Ratio
Absorbance
High MW Low MW SEC
Elution
Time
 Map out Copolymer Compositions (A/B Ratio) across MWD (Sizes)
 Study Supplier-to-Supplier Variations (2nd Source)
43

44. Summary: SEC-IR Applications
Profile Polymer Compositions = f (Sizes)
IR Spectra B A
A/B Ratio
Absorbance
High MW Low MW SEC
Elution
Time
 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)
44

45. Summary: SEC-IR Applications
Profile Polymer Compositions = f (Sizes)
Cross Linking
IR Spectra B A
A/B Ratio
Absorbance
High MW Low MW SEC
Elution
Time
 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)
45
 Cross-linking ( Higher MW)

46. Summary: SEC-IR Applications
Profile Polymer Compositions = f (Sizes)
Break Down
IR Spectra B A
A/B Ratio
Absorbance
High MW Low MW SEC
Elution
Time
 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)
46
 Cross-linking ( Higher MW)
 Break down ( Lower MW) & Detect low MW degradant

47. Summary: SEC-IR Applications
Profile Polymer Compositions = f (Sizes)
Cross Linking Break Down
IR Spectra B A
A/B Ratio
Absorbance
High MW Low MW SEC
Elution
Time
 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)
47
 Cross-linking ( Higher MW)
 Break down ( Lower MW) & Detect low MW degradant
 De-Formulate Complex Polymer Mixtures

48. Summary: SEC-IR Characterization
of Excipient Copolymers Poly(A-B)
IR Spectra B A
A/B Ratio
Absorbance
High MW Low MW SEC
Elution
Time
 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)

49. LC-IR Applications for Excipient
Analysis in Drug Formulations
Excipient Formulation Develop. Formulated Drugs
Manufacturing Drug Manufacturing Shelf Life Stability
• Process Control • Incoming QC-Variations • Stressed
• Lot-to-lot Variations • Excipient Functionality Degradation
• CoA • Formulation Development
• QbD • De-Formulate
• Novel Excipient Excipient Blends
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.

50. LC-IR Hyphenated System
System Control Deposition Hyphen HPLC
50
Data Processing Microscopic FTIR Desolvation or GPC