GPC-IR to Characterize Macromolecular

Excipients in Pharmaceutical Formulations

Ming Zhou, William Carson,

Sidney Bourne & Tom Kearney

Spectra Analysis, Inc.

August 22, 2010

Contact: ZhouM@Spectra-Analysis.com

Tel. 508-281-62761

ACS 2010 National MeetingDivision of Analytical Chemistry

OUTLINE

GPC-IR Hyphenated Technology: Instrumentation

Excipient Characterization: Copovidone PVP/VAc

Excipient Degradation from HME Process:

HPMCAS, Eudragit L100-55 (PEA/MAA)

Summary: GPC-IR Applications in Pharma Formulations

Q & A

2

Hyphenated Technologies &

Major Applications

Liquid Chromatography

Mass

SpectroscopyInfra Red

Spectroscopy

Separation

Applications Small Molecules, Proteins Polymers

Detection &

Data Analysis

LC-MS LC-IR

Pharma API’s Polymeric Excipients

LC-IR Hyphenation

What is Direct Deposition FTIR?

Continuous Polymer Tracks (GPC-IR)Separated Dots from HPLC-IRSeparated Dot Depositing on Disk

Direct Deposition FTIR

& Data Processing

ZnSe Disk

Features of DiscovIR-LC

High Quality Solid Phase Transmission IR Spectra

Real-Time On-line Detection

Microgram Sensitivity

Compatible with all LC Solvents and Gradients

• e.g. Water, ACN, Methanol, THF, Chloroform, HFIP

Compatible with all GPC/SEC Solvents

Fully Automated Operation: No Fractionation

Multi-Sample Processing: 10 Hr ZnSe Disk Time

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

Compositional Drift Analysis of

Copolymer Poly(A-B) by GPC-IR

Ratio 10/8 12/12 2/4 Total 24/24

A% 56% 50% 33% 50%

High MW Low MW Molar Mass

Ab

so

rpti

on

A/B RatioA

B

Compositional Heterogeneity of

Copolymer Poly(A-B)

High MW Low MW Molar Mass

Ab

so

rpti

on

Ratio 10/8 12/12 2/4 Total 24/24

A% 56% 50% 33% 50%

GPC-IR

IR Bulk 50% (NMR)

GPC

(MS)

GPC-IR Spectrum of Copovidone

Excipient - VP/VAc Copolymer

Peak 1680 cm-1 from VP comonomer

Peak 1740 cm-1 from VAc comonomer

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

% a

ceta

te c

om

onom

er

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

% 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

from Different Manf. Processes

Copovidone A gave clear tablets while Copovidone C led to cloudy ones.

Excipient Characterization

by LC-IR in Pharma Formulations

16

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.

17

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

Excipient HPMCAS Degradation

in Hot Melt Extrusion Process

Unprocessed

Processed at 160C

Processed at 220C

Degradant

Degradant from HPMCAS (220C)

in Hot Melt Extrusion Process

IR Database Search Result: Succinic Acid

HPMCAS Degradation

in Hot Melt Extrusion Process

Functional Group Ratio Changes from High Temp Process (Sample C)

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

Excipient Blends with Plasticizers and Additives

CH3-C=O

HOOC-CH2-CH2-C=O

Eudragit L100-55 Characterization by GPC-IR (Chromatograph + IR Spectra)

Eudragit L100-55 Compositional Drift at

Different Elution Times (Red 8’ & Blue 10’)

COOH

1705

COOEt

1735

CH2 CH3

Areas: L R

Acid / Ester Co-Monomer Ratio ~ Acid / Ester Peak Area Ratio = [(L+R)-2L] / (2L)

IR Spectra of L100-55 Samples atPolymer Peak Center (Elution Time ~9.4’)

24

S0 – Green Ref

S1 – Pink 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

25

COOEt

1735

COOH

1705

S0 – Green Ref

S1 – Pink 130C

S2 – Blue 160C

S3 – Black 190C

NCE?

1805 cm-1

Summary: Eudragit L100-55

Degradation & Stability from HME

26

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

27

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

Polyethylene Oxide: PEO (MW > 20K) or PEG (MW < 20K), PEG/PPG

PLGA Copolymers: Biodegadable

Excipient Combinations with Plasticizers and Additives

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

Excipient Analysis with GPC-IR

in Pharceutical 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

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

31

GPC-IR Operating Conditions

& Sample Preparation

GPC Chromatograph: Agilent® 1200

• GPC Column Temperature: Ambient

• Solvent: THF at 1.0 ml/min

• Column: Jordi Gel DVB Mixed Bed– 250 x 10 mm

• Sample Injections: 100 ml at ~0.5% weight / volume THF

IR Detection

• DiscovIR-LC® solvent-removing direct-deposition solid phase FTIR

• Cyclone Temperature: 150oC

• ZnSe Disk Temperature: -10 ~ -15oC

Sample Preparation:

• 0.050 g excipient solid samples were dissolved in 10 ml THF in ~1

hr and filtered with 0.45 mm PTFE syringe filter before GPC injection

Acid/Ester Ratio Changes with Elution Time (MWD) and Processing Temp.

33

S0 – Green Ref.

S1 – Pink 130C

S2 – Blue 160C

S3 – Black 190C

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-

1060

HPMCAS Grade-to-Grade

Difference (HF/MF/LF) by GPC-IR

Acetyl / C=O (total AS): Peak 1235cm-1 /1740 cm-1 Ratios

HF—0.8

MF—0.5

LF—0.4

IR Band Identifications of HPMCAS

Excipients for Ratio Drift Analysis

CH3

HP

o

HOOC-CH2-CH2-C=O

O

CH3-C=O

CH3-C=O

O

CH3

O

S

A

A

MM M

M

M

M M

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)

C