LC-IR Hyphenated Technology for

Polymer / Excipient Analysis

Ming Zhou, William Carson, Sidney Bourne,

David Dunn and Tom Kearney

Spectra Analysis, Inc.

Contact: ZhouM@Spectra-Analysis.com

Nov. 16, 20091

OUTLINELC-IR Hyphenated Technology

DiscovIR-LC System & Instrumentation

Features & Applications of DiscovIR-LC

Copolymer Compositional Analysis across MW Distributions:

e.g. Styrene/Butadiene, Excipient PVP/VAc Characterization

Excipient Degradation Analysis: HPMCAS, PEG

Polyolefin Branching Analysis by High Temp GPC-IR: Copolymers

Polymer Blend Ratio Analysis across MWD: EVA/PMMA

Polymer Additive Analysis: De-Formulation of Motor Oil Lubricants

Summary2

Hyphenated Technologies

Gas Phase & Liquid PhaseChromatography

MassSpectroscopy

Infra RedSpectroscopy

Separation

Identification

DiscovIR-GC

DiscovIR-LC

Detection

Data Acquisition & Analysis

GC-MS GC-IRLC-MS LC-IR

4

The DiscovIR-LCTM is a fully automated direct deposition LC-IR analyzer used by chemists to identify unknown components in complex mixtures.

LC-IR Hyphenated System

How Does It Work?

How is the Solvent Removed?

CycloneEvaporator

Thermal NebulizationFrom LC

Nitrogen Addition

ChilledCondenser

Waste Solvent

Particle Stream to DiscovIR

Air CooledCondenser

CycloneEvaporator

Patent pending: PCT/US2007/025207

What is Direct Deposition FTIR?

Direct Deposition FTIR and Data Processing

LC-IR Hyphenated Technology for Polymer Analysis

9

Features of DiscovIR-LC

Online Fully Integrated SystemFully Automated Operation: No FractionationMulti-Sample Processing: 8-40 Hr ZnSe Disk TimeMicrogram Sensitivity at Sample Injection PointReal-Time Chromatography & Spectral DataSolid Phase Transmission IR Spectra: High Quality w/ Purified AnalytesDatabase Search Capability & In-House Library CreationData Analysis: GRAMS for Chemometrics, 3D LC-IR, Functional Group Chromatograms & Comparisons at any Wavenumbers or across PeaksAll LC Solvents: Water, ACN, Methanol, THF, Chloroform, HFIPGPC/SEC: TCB @ High Temperature (150C)HPLC: Isocratic or Gradient; Normal & Reverse- PhaseCompatible with LC-MS Set-Up in Parallel

LC-IR Applications

Excipient Characterization, Functionality & Degradation Analysis

Copolymer Composition 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

Reactive Polymer Analysis for Coating, Adhesive, Sealant & Elastomer

Plastics, Rubbers, Films, Fibers, Foams, Composites & Biopolymers

Isomer Analysis for Chemicals, Forensics & Pharmaceuticals

General Analytical Capability: Trouble Shooting

11

IR Spectrum of Styrene/Butadiene Copolymer

The three bands filled in red arise from the styrene comonomer (1605, 1495, and 698 cm-1)

The green filled band (968 cm-1) is generated by the butadiene comonomer.

There is no significant overlap of any of these bands by the other comonomer species.

Cove this

Styrene/Butadiene CopolymerChemical Composition Across Molecular Weight Distribution

Styrene in eluted polymer - ratio of (styrene) 1495cm-1 / (butadiene) 968 cm-1

Bulk Average – 10% Styrene

Excipient Characterization IR Spectrum of Copovidone VP/VAc Copolymer

Peak 1680 cm-1 from VP comonomer

Peak 1740 cm-1 from VAc comonomer

GPC-IR Chromatogram Overlay with Comonomer Ratios

Excipient Copovidone Compositional Drift with MW Distributions Vs. Bulk Average

Abs. Peak Ratio: AVA / AVP = (k1*b*MVA) / (k2*b*MVP) = k (MVA / MVP) ~ Comonomer Ratio

(Molecular Weight Distribution)

Bulk Average

Excipient Functionality Characterization by LC-IR

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Copolymer Compositional Analysis with MW Distributions• Comonomer Ratio Drift (Functional Groups) vs. Bulk Average• Hydrophilic/Hydrophobic Ratio Drift vs. Phase Separations • Morphology Effects on Excipient (/Drug) Dissolution Rate• Excipient Lot-to Lot Variations• Quality by Design (QbD) Studies• Excipient Performance & Functional Group Correlations

Various Excipient Copolymers & Terpolymers• Copovidone: PolyVinyl Pyrrolidone / Vinyl Acetate – PVP/VAc

• Methacrylate Copolymers: Eudragit

• SoluPlus Terpolymer: PEG / PCL / PVAc

Cellulose Derivatives (Lot-to-Lot Variations)• Hypromellose: HPMC, HPMC-AS, HPMC-P• HydroxyPropyl Cellulose: HPC, HEC• Cellulose Esters: CAB, C-A-P

Degradation Study of Excipient HPMCAS in Hot Melt Extrusion Process by GPC-IR

HME Processing Temperatures: (Lowest) A < B < C (Highest)

Excipient HPMCAS Degradantin Hot Melt Extrusion Process

IR Database Search Result: Succinic Acid (Degradant)

Degradation Study of HPMC-AS Excipient in Hot Melt Extrusion Process by GPC-IR

Fig. A Schematic Structure of HPMC Derivatives, Cellulose Ethers & Esters

Detected Degradant: Succinic AcidDetected Functionality Ratio Change: Hydroxyl Vs. CarbonylHelp Understand Excipient Degradation MechanismStudy Excipient / API Interactions

Excipient HPMCAS Degradationin Hot Melt Extrusion Process

Functional Group Ratio Changes from High Temp Process (C)

Excipient Characterization with LC-IRin Drug Formulations

• Polymeric Excipient Characterization

• Degradation in Process (Hot Melt Extrusion)

• Excipient / API Interactions

• Forced Degradation in Shelf Life Study

December 1, 2008: Vol. 5, No. 6The cover cartoon illustrates a solid dispersion assembly that is composed of entangled polymer chains with drug molecules embedded in the form of single molecule, small clusters, and/or large aggregates (amorphous).

Degradation Study by HPLC-IR for Degraded PEG-1000 Excipient

Three Chromatographic displays generated from one time ordered set of FTIR Spectra

Identification of Homologous Series from Degraded PEG by Reverse Phase HPLC-IR

11.45 minutes

4.93 minutes

1.50 minutes

Na+ or K+ Cation Carboxylate Salt

1607

Aldehyde1719

Proposed Mechanism of PEG Air OxidationSupported by LC-IR Data

High Temp GPC-IR for Polyolefin Branching Analysis Polyethylene Sample with & without TCB Solvent

DiscovIR-LC Removes TCB Completely and Gives Clean IR Spectrum (Blue).

Polyolefin Branching Analysis by GPC-IR

Copolymer Compositional Drift ~ CH3 Branching ~ Peak Ratio A1378/A1468

GPC-IR Chromatogram of PE/PP Copolymer Overlaid with Peak Ratio Abs1378/Abs1468

(Molecular Weight Distribution)

Area Ratio = Area (2940-3100cm-1) / Area (2940-2800cm-1)

Polyolefin Branching Analysis by ChemometricsGPC-IR Chromatograms Overlaid with Area Ratios

(Molecular Weight Distribution)

Area Ratio = Area (Peak 1375 cm-1) / Area (Peak 1465 cm-1)

Branching Levels (Area Ratios) with a GPC-IR Chromatogram

(Molecular Weight Distribution)

GPC-IR Branching Analysis of Dow ENGAGE® Polyolefins

Polymer Blend Ratio Analysis by GPC-IRfor EVA / PBMA Mixture

IR spectral bands of EVA & PBMA are closely overlapped. The 1152 and 2852 cm-1 bands selected for minimal convolution.

Polymer Blend EVA/PBMA Ratios with MWD Determined by Spectral Peak Ratios

(Molecular Weight Distribution)

Calibration Curve: Y = 1.6162 X-0.2149 by Flow Injection Method w/o LC SeparationY is Mass Ratio, X is Peak Ratio Abs(2852)/Abs(1152)

y = 1.6162x - 0.2149

0

0.5

1

1.5

2

2.5

3

3.5

4

0 0.5 1 1.5 2 2.5

absEVA(2852)/absPBMA(1152)

mEV

A/m

PBM

A

Polymer Additive Analysis withGPC-IR for ABS Plastic w/o Extraction Step

IR chromatogram and ratio plot for ABS sample. Ratio (green) of characteristic IR absorbance bands for nitrile (2240 cm-1) and styrene (1495 cm-1).

Polymer Additive Analysis withGPC-IR for ABS Plastic w/o Extraction Step

IR spectra at different elution times across the low MW peak of the SEC analysis of ABS. Spectra indicate presence of multiple components.

Polymer Additive AnalysisPolyDiMethyl Siloxane in THF/H2O

PDMS is Difficult to be Detected by UV or RI.IR is an Universal Detector for Organics

De-Formulation of Motor Oil LubricantGPC-IR 3D View for Additive Analysis

SAE 15W-40 Heavy Duty Oil in THF

Low MW Mineral Oil Diverted after 12.2 min

Wavenumber, cm-1

Elution Time

(Min. & MW)

De-Formulation of Motor Oil Additives with GPC-IR (Database Searchable)

De-Formulate Polymeric Additives in Motor Oil Lubricant

Additive #1 @ Retention Time 9.2 Min•Styrene-Acrylate Copolymer (IR Database Search)•Narrow MW Distribution ~ Average 600K •Viscosity Index Improver•No Comonomer Compositional Drift Stable [700cm-1/1735cm-1] Band Ratio

Additive #2 @ Retention Time 10-12 Min•Polyisobutenyl Succinimide (PIBS) (IR Database Search)•Broad MW Range: 8-30K•A Dispersant•Small Comonomer Compositional Drift [dimethyl (1367cm-1)/imide (1700cm-1)] Ratio Change <10%

Polymer Degradation Study – Oil Change Schedule

SUMMARYDiscovIR-LC is a Powerful Tool for Polymer, Excipient & Materials Analysis

Excipient Characterization, Functionality & Degradation Analysis

Copolymer Compositional Drift Analysis across MW Distributions

Polyolefin Copolymer Branching Analysis by High Temp GPC-IR

Polymer Blend Ratio Analysis across MWD

Polymer Additive & Impurity Analysis

De-Formulation for Polymers, Excipients and Additives

Process Control & Optimization

Reactive Polymer Analysis for Coating, Adhesive, Sealant & Elastomer

Plastics, Rubbers, Films, Fibers, Foams, Composites & Biopolymers

Isomer Analysis for Chemicals, Forensics & Pharmaceuticals

General Analytical Capability: Trouble Shooting 36