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HPLC2010 Pharmaceutical Copolymer Excipient Characterization By GPC-FTIR

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HPLC2010 Boston Presentation

HPLC2010 Boston Presentation


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  • 1. HPLC 2010 Boston: P2062T Pharmaceutical Copolymer Excipient Characterization by SEC/GPC-FTIR William W. Carson; David Dunn; Jim Dwyer; Ming Zhou; Tom Kearney Spectra Analysis Instruments, Inc. June 20, 2010 Contact: CarsonW@Spectra-Analysis.com 1
  • 2. LC-IR Hyphenation
  • 3. Direct Deposition FTIR with Dots (HPLC-IR) and Narrow Films (GPC-IR)
  • 4. Direct Deposition FTIR & Data Processing (GPC-IR)
  • 5. GPC-IR Hyphenated Technology: 3D Plot to Map out Polymer Compositions with Sizes 5
  • 6. 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. 6
  • 7. IR Spectrum of Copovidone Excipient – VP/VAc Copolymer from GPC-IR Peak 1680 cm-1 from VP comonomer Peak 1740 cm-1 from VAc comonomer
  • 8. Excipient Compositional Drift (IR Peak Ratios) with 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. Excipient Compositional Drift (%VAc) with MWD Vs. Bulk Average .6 Copovidone: sample A 50 molecular weight % acetate comonomer .5 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. Copovidone Compositional Drifts (%VAc) from Different Manf. Processes .6 Copovidone: sample A 50 sample B % acetate comonomer .5 sample C 45 .4 Molecular Weight max. IR absorbance Distribution Comonomer Composition .3 Distribution 40 Bulk 40% VAc .2 35 .1 0 30 106 105 104 103 102 Molecular Weight Copovidone A gave clear tablets while Copovidone C led to cloudy ones.
  • 11. IR Spectrum Difference of Two Grades of HPMC (Type 2910 & 2208) from GPC-IR -C-O-C- OH CH2 HP OCH3 CH2 CH3
  • 12. HPMCAS Grade-to-Grade Difference (LF, MF, HF) by GPC-IR -C-O-C- Backbone HOOC-CH2-CH2-C=O Ether AS A 1060 C=O Acetyl 1740 1235 CH3-C=O HP C/HP M CH3 OH OCH3 1372 3470 2830
  • 13. IR Band Identifications of HPMCAS Excipient HOOC-CH2-CH2-C=O CH3-C=O 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)
  • 14. GPC-IR Chromatograph & Spectra of HPMCAS Sample
  • 15. GPC-IR Chromatogram Overlay at Different Wavenumbers of 2 HPMCAS Samples ES1: 1060 cm-1 2834 cm-1 2838 cm-1 2935 cm-1 SE2: 1060 cm-1 2834 cm-1 2838 cm-1 2935 cm-1
  • 16. Acetyl/Backbone Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) SE2 ES1
  • 17. Total C=O AS / Backbone Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) ES1 SE2
  • 18. To Find Succinic Acid Level on Backbone (AS/Backbone)- k (A/Backbone) => S / Backbone ES1 AS / BB Ratios SE2 ES1 SE2 A / BB Ratios Absorptivity Ratio k Needs to be Calibrated from Known Standards
  • 19. HP/Backbone Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) ES1 SE2
  • 20. Total OH/Backbone Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) SE2 ES1
  • 21. To Find Unsubstituted OH on Backbone (OH/Backbone)- k (HP/Backbone) => Unsub. OH / Backbone Absorptivity Ratio k Needs to be Calibrated from Known Standards ES1 HP / BB Ratios SE2 ES1 OH / BB Ratios SE2
  • 22. Methoxy / Backbone Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) ES1 SE2
  • 23. 2935cm-1 CH2 / Backbone Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) SE2 ES1
  • 24. 2935 CH2 / BB & 2935 CH2 / AS Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) SE2 Peak 2935 / AS ES1 Peak 2935 / BB SE2 ES1
  • 25. Small HP/AS Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) SE2 ES1
  • 26. Backbone/AS & HP/AS Ratio Drifts of 2 HPMCAS Samples with Elution Time SE2 BB / AS ES1 SE2 HP / AS ES1
  • 27. OH/AS Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) SE2 ES1
  • 28. Methoxy/AS C=O Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) ES1 SE2
  • 29. Acetyl/AS C=O Ratio Drifts of 2 HPMCAS Samples with Elution Time (MWD) 0.52 ---- MF SE2 0.40 ---- LF ES1 Grade Levels
  • 30. Methoxy/2935 CH2 & Methoxy/Backbone Ratio Drafts of 2 HPMCAS Samples with Elution Time ES1 M / 2935 CH2 SE2 ES1 M / BB SE2
  • 31. Methoxy / Acetyl Ratio Drafts of 2 HPMCAS Samples with Elution Time (MWD) ES1 SE2
  • 32. Summary: Compositional Differences of 2 HPMCAS Samples Sample # Sample Compositional Drifts Consistent Appearance w/ MWD Substitution w/ MWD Methoxy, ES1 Fine Acetyl / Succinate, HP Powder Hydroxyl, CH2 Methoxy, SE2 Fine Acetyl / Succinate, HP Powder Hydroxyl, CH2 Different Drift Patterns Little Difference with Methoxy, Difference Acetyl / Succinate, with HP Hydroxyl, CH2 32
  • 33. GPC-IR Chromatogram Overlay at 1739 cm-1 of 4 HPMCAS-MF Lots T8 T10 T12 T14 Snapshots
  • 34. Acetyl/TotalEster Ratio Drifts of 4 MF Lots Compared to LF & HF HPMCAS -- HF --------- -- LF ---------
  • 35. GPC-IR Conclusions  GPC-IR Takes Snapshot IR Pictures of Polymer Excipients for Compositional Drifts with MW Distributions  Many Ways to Analyze Functional Group Drifts w/ MWD: Group vs. Backbone, Various Ratios among Groups, etc.  Useful to Characterize Lot-to-Lot, Grade-to-Grade and Supplier-to-Supplier Variations of Polymeric Excipients  Understand Excipient Manufacturing Variables and QC  GPC-IR is a Powerful Tool to Analyze Compositional Variations of Copolymers across MWD
  • 36. 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 / PCL / PVAc  Methacrylate Copolymers: Eudragit  Polyethylene Oxide: PEO (MW > 20K) or PEG (MW < 20K)  Excipient Combinations with Plasticizers and Additives 36
  • 37. Excipient Analysis with LC-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).
  • 38. 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 Degradation Variations Functionality • CoA • Formulation • De-Formulate Development Excipient Blends • Novel Excipient • QbD R&D • Trouble-Shoot • Process Degradation Problem Drugs in • Trouble Shooting (Hot Melt Extrusion) the Market • Define Safe Process Window / QbD • Process Monitoring • Trouble Shooting Users: Excipient Pharma Co. Pharma Co. Manufacturers HME Service Providers Generic Drug Co.
  • 39. Excipient QbD Space GPC-IR-Performance Slide from USP International Excipient Workshop (July 2009) Performance GPC IR
  • 40. 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 40