aaps2011 oral--analytical techniques to characterize excipient stability & degradation from hot...

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

http://www.spectra-analysis.com/index.htm

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



Copolymers Poly(A-B): Compositions

6

high MW low MW

mol

ar m

ass

comonomer A

comonomer B


polymer chains

Ab

so

rba

nc

e

Bulk Average

Composition

Analysis:NMR

FTIR, Raman

NIR



Copolymers Poly(A-B): Compositions

7

high MW low MW

mol

ar m

ass

comonomer A

comonomer B


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


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


polymer chains

Ab

so

rba

nc

e

AB

SEC Time

IR Spectra


SEC-IR Hyphenated System

SEC


Schematic View of LC-IR System

SEC

or

HPLC


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



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



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)




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


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


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


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


http://en.wikipedia.org/wiki/File:Generic_Anhydride.png

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


http://en.wikipedia.org/wiki/File:Generic_Anhydride.png

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


White

Clear

Solution

Trace

Anhydrides


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

?


39


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


Study Lot-to-Lot Variations

IR Spectra



43

High MW Low MW SEC

Elution

Time

Ab

so

rban

ce

A/B RatioA

B


Study Supplier-to-Supplier Variations (2nd Source)

IR Spectra



44

High MW Low MW SEC

Elution

Time

Ab

so

rban

ce

A/B RatioA

B


Study Lot-to-Lot or Supplier-to-Supplier Variations

Characterize Polymer Degradation from Processing:

Loss of functional group A (Reduced A/B)

IR Spectra



45

High MW Low MW SEC

Elution

Time

Ab

so

rban

ce

A/B RatioA

B




Loss of functional group A (Reduced A/B)

Cross-linking ( Higher MW)

IR Spectra

Cross Linking



46

High MW Low MW SEC

Elution

Time

Ab

so

rban

ce

A/B RatioA

B




Loss of functional group (Reduced A/B)


Break down ( Lower MW) & Detect low MW degradant

IR Spectra

Break Down



47

High MW Low MW SEC

Elution

Time

Ab

so

rban

ce

A/B RatioA

B




Loss of functional group (Reduced A/B)


Break down ( Lower MW) & Detect low MW degradant

De-Formulate Complex Polymer Mixtures

IR Spectra

Break DownCross Linking



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


aaps2011 oral--analytical techniques to characterize excipient stability & degradation from hot...

Documents

summary secir

lower mw

polymer degradation

mwd sizes lot

degradants low mw

mwd sizes study lot

crosslinking higher

mwd sizes study supplier