AAPS NERDG 2010 Annual Meeting
                     Short Topic Presentation #5


 GPC-IR to Characterize Macromolecular
E...
OUTLINE


GPC-IR Hyphenated Technology: Instrumentation

Excipient Characterization: Copovidone PVP/VAc

Excipient Degrada...
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 ...
Excipient Compositional Drift
                                   w/ MWD Vs. Bulk Average
          GPC-IR Chromatogram Ove...
Excipient Compositional Drift
                                                  w/ MWD Vs. Bulk Average
                  ...
Copovidone MW Distributions from
                                                   Different Suppliers (Manf. Processes)
...
Copovidone Compositional Drifts
                                                   from Different Manf. Processes
        ...
Excipient Characterization
                                           by GPC-IR

Copolymer Compositional Analysis with MW ...
Excipient Degradation from
                          Hot Melt Extrusion Process

Hot Melt Extrusion Process: To Make Solid...
GPC-IR to Analyze HPMCAS
                        Degradation in HME Process




Samples: A- Not Processed;     B- Processe...
Degradant Identification from
               HPMCAS in HME Process (C)




IR Database Search Result: Succinic Acid
Polymer Compositional Change
                      from HPMCAS Degradation in HME


                                      ...
GPC-IR Analysis of HPMCAS
                   Degradation in HME Process
Detected Degradant: Succinic Acid
Detected Functio...
HPMCAS Grade-to-Grade
      Difference (LF/MF/HF) by GPC-IR

                                       -C-O-C-

     HOOC-CH2...
HPMCAS Grade-to-Grade
      Difference (LF/MF/HF) by GPC-IR


                          -C-O-C-



C=O              Acetyl...
Common Polymeric Excipients

Neutral Cellulose Derivatives
 • HydroxyPropyl Methoxy Cellulose (Hypromellose): HPMC
 • Hydr...
Excipient Analysis with GPC-IR
                               in Drug Formulations


                         • Polymeric ...
GPC-IR Applications for Excipient
                               Analysis in Drug Formulations

  Excipient               ...
Excipient Degradation Analysis
                        in HME Process by GPC-IR


Detect Degradation Intermediates with MW...
Excipient QbD Space
                             GPC-IR-Performance
 Slide from USP International Excipient Workshop (July...
GPC-IR & HPLC-IR Applications

Excipient Characterization, Functionality & Degradation Analysis

Copolymer Compositional A...
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GPC-IR To Characterize Macromolecular Excipients In Pharmaceutical Formulations-AAPS-NERDG- 4 23 2010

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Short Topic Presentation at AAPS NERDG on 4/23/2010.
GPC-IR to Characterize Macromolecular Excipeints in Pharmaceutical Formulations

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Transcript of "GPC-IR To Characterize Macromolecular Excipients In Pharmaceutical Formulations-AAPS-NERDG- 4 23 2010"

  1. 1. AAPS NERDG 2010 Annual Meeting Short Topic Presentation #5 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. 508-281-6276 1
  2. 2. 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
  3. 3. LC-IR Hyphenation
  4. 4. Direct Deposition FTIR
  5. 5. Direct Deposition FTIR & Data Processing ZnSe Disk
  6. 6. GPC-IR Technology: 3D View to Map out Polymer Compositions 6
  7. 7. IR Spectrum of Copovidone Excipient - VP/VAc Copolymer Peak 1680 cm-1 from VP comonomer Peak 1740 cm-1 from VAc comonomer
  8. 8. Excipient Compositional Drift w/ MWD Vs. Bulk Average GPC-IR Chromatogram Overlay with Comonomer Ratios Copovidone Bulk Average (Molecular Weight Distribution) Abs. Peak Ratio: AVA / AVP = (k1*b*MVA) / (k2*b*MVP) = k (MVA / MVP) ~ Comonomer Ratio
  9. 9. Excipient Compositional Drift w/ MWD Vs. Bulk Average .6 Copovidone: sample A 50 molecular weight .5 % acetate comonomer distribution max. IR absorbance 45 .4 .3 Bulk Average comonomer composition 40 40% VAc distribution .2 35 .1 0 30 106 105 104 103 102 Molecular Weight
  10. 10. Copovidone MW Distributions from Different Suppliers (Manf. Processes) .6 Copovidone: sample A sample B .5 sample C max. IR absorbance .4 .3 .2 .1 0 Molecular Weight 106 105 104 103 102 Copovidone A gave clear tablets while Copovidone C led to cloudy ones.
  11. 11. Copovidone Compositional Drifts from Different Manf. Processes .6 Copovidone: sample A 50 sample B .5 % acetate comonomer sample C 45 .4 Molecular Weight max. IR absorbance Distribution Comonomer Composition .3 Distribution 40 Bulk 40% VAc .2 35 .1 0 30 Molecular Weight 106 105 104 103 102 Copovidone A gave clear tablets while Copovidone C led to cloudy ones.
  12. 12. Excipient Characterization by GPC-IR 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. 12
  13. 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 13
  14. 14. 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.)
  15. 15. Degradant Identification from HPMCAS in HME Process (C) IR Database Search Result: Succinic Acid
  16. 16. Polymer Compositional Change from HPMCAS Degradation in HME -C=O OH Functional Group Ratio Changes from High Temp Process (Sample C)
  17. 17. GPC-IR Analysis of HPMCAS Degradation in HME Process Detected Degradant: Succinic Acid Detected Functionality Ratio Change: Hydroxyl Vs. Carbonyl Help Understand Excipient Degradation Mechanism Study Excipient / API Interactions Define Safe Process Window: QbD HOOC-CH2-CH2-C=O CH3-C=O Fig. A Schematic Structure of HPMC-AS
  18. 18. HPMCAS Grade-to-Grade Difference (LF/MF/HF) by GPC-IR -C-O-C- HOOC-CH2-CH2-C=O AS A C=O Acetyl CH3-C=O M HP C OCH3 CH3 OH
  19. 19. HPMCAS Grade-to-Grade Difference (LF/MF/HF) by GPC-IR -C-O-C- C=O Acetyl HP CH3
  20. 20. Common Polymeric Excipients 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 20
  21. 21. Excipient Analysis with GPC-IR in 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. 6 The 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).
  22. 22. GPC-IR Applications for Excipient Analysis in Drug Formulations Excipient Formulation Develop. Formulated Drugs Manufacturing Drug Manufacturing Shelf Life Stability • Process Control • Incoming QC • Stressed • Lot-to-lot • Excipient Functionality Degradation Variations • Formulation • CoA Development • De-Formulate • QbD Excipient Blends • Novel Excipient 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.
  23. 23. Excipient Degradation Analysis in HME Process by GPC-IR 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 23
  24. 24. Excipient QbD Space GPC-IR-Performance Slide from USP International Excipient Workshop (July 2009) Performance GPC IR
  25. 25. 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 25
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