GPC-IR to Characterize Macromolecular

Excipients in Pharmaceutical Formulations

Ming Zhou, David Dunn, William Carson,

Sidney Bourne & Tom Kearney

Spectra Analysis, Inc.

April 23, 2010

Contact: ZhouM@Spectra-Analysis.com

Tel. 508-281-62761

AAPS NERDG 2010 Annual Meeting Short Topic Presentation #5

OUTLINE

GPC-IR Hyphenated Technology: Instrumentation

Excipient Characterization: Copovidone PVP/VAc

Excipient Degradation from HME Process: HPMCAS

Summary: GPC-IR Applications in Pharma Formulations

Q & A

2

LC-IR Hyphenation

Direct Deposition FTIR

Direct Deposition FTIR & Data Processing

ZnSe Disk

GPC-IR Technology: 3D View to Map out Polymer Compositions

6

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 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

max

. IR

abs

orba

nce

Molecular Weight

Copovidone: sample A

30

35

40

45

50molecular weightdistribution

% acetate com

onomer

comonomer compositiondistribution

Excipient Compositional Drift w/ MWD Vs. Bulk Average

Bulk Average40% VAc

0

.1

.2

.3

.4

.5

.6

106 104 103 102105 Molecular Weight

Copovidone: sample Asample Bsample C

Copovidone MW Distributions from Different Suppliers (Manf. Processes)

max

. IR

abso

rban

ce

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

% acetate com

onomer

Comonomer CompositionDistribution

sample Bsample C

0

.1

.2

.3

.4

.5

.6

106 104 103 102105

sample Bsample C

Bulk 40% VAc

max

. IR

abso

rban

ce Molecular WeightDistribution

Copovidone Compositional Driftsfrom Different Manf. Processes

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

Excipient Characterization by GPC-IR

12

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.

13

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• Torque

GPC-IR to Analyze HPMCAS Degradation in HME Process

Samples: A- Not Processed; B- Processed at Low Temp.;C- Processed at High Temp. (Degradant peak around 14.5 min.)

Degradant Identification from HPMCAS in HME Process (C)

IR Database Search Result: Succinic Acid

Polymer Compositional Change from HPMCAS Degradation in HME

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 Degradant: Succinic AcidDetected Functionality Ratio Change: Hydroxyl Vs. CarbonylHelp Understand Excipient Degradation MechanismStudy Excipient / API InteractionsDefine Safe Process Window: QbD

CH3-C=O

HOOC-CH2-CH2-C=O

HPMCAS Grade-to-GradeDifference (LF/MF/HF) by GPC-IR

MOCH3C

OH

HPCH3

AAcetyl

ASC=O

HOOC-CH2-CH2-C=O

CH3-C=O

-C-O-C-

HPMCAS Grade-to-GradeDifference (LF/MF/HF) by GPC-IR

HPCH3

AcetylC=O

-C-O-C-

Common Polymeric Excipients

20

Neutral Cellulose Derivatives• HydroxyPropyl Methoxy Cellulose (Hypromellose): HPMC• HydroxyPropyl Cellulose: HPC• Cellulose Acetate Butyrate: CAB

Acidic Cellulose Derivatives• HPMC Acetate Succinate: HPMC-AS• HPMC Phthalate: HPMC-P• Cellulose Acetate Phthalate: C-A-P

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

Excipient Combinations with Plasticizers and Additives

Excipient Analysis with GPC-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).

GPC-IR Applications for Excipient Analysis in Drug Formulations

ExcipientManufacturing

• 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 DrugsShelf 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 Degradation Analysisin HME Process by GPC-IR

23

Detect Degradation Intermediates with MW Distributions

Detect Functionality Changes

Probe Polymer Degradation Mechanism

Solve Degradation Problems

Understand Excipient / API Interactions

Define Safe Process Window: QbD

HME Process Monitoring: PAT

Various Macromolecular Excipients

Excipient Blends with Plasticizers and Additives

Excipient QbD SpaceGPC-IR-Performance

Slide from USP International Excipient Workshop (July 2009)

GPC

IR

Performance

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 Shooting25