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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
LC-IR Hyphenation
Direct Deposition FTIR with
Dots (HPLC-IR) and Narrow Films (GPC-IR)
Direct Deposition FTIR &
Data Processing (GPC-IR)
GPC-IR Hyphenated Technology: 3D Plot
to Map out Polymer Compositions with Sizes




                                             5
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
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
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
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
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.
IR Spectrum Difference of Two Grades of HPMC
       (Type 2910 & 2208) from GPC-IR

                                         -C-O-C-




      OH      CH2
                                   HP
                    OCH3       CH2 CH3
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
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)
GPC-IR Chromatograph & Spectra of
        HPMCAS Sample
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
Acetyl/Backbone Ratio Drifts of 2 HPMCAS
    Samples with Elution Time (MWD)

                           SE2
               ES1
Total C=O AS / Backbone Ratio Drifts of 2 HPMCAS
        Samples with Elution Time (MWD)

                     ES1




                    SE2
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
HP/Backbone Ratio Drifts of 2 HPMCAS
  Samples with Elution Time (MWD)


                  ES1


                        SE2
Total OH/Backbone Ratio Drifts of 2 HPMCAS
      Samples with Elution Time (MWD)



                                  SE2



                                   ES1
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
Methoxy / Backbone Ratio Drifts of 2 HPMCAS
     Samples with Elution Time (MWD)


                           ES1




                           SE2
2935cm-1 CH2 / Backbone Ratio Drifts of
2 HPMCAS Samples with Elution Time (MWD)

                               SE2


                               ES1
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
Small HP/AS Ratio Drifts of 2 HPMCAS Samples
          with Elution Time (MWD)

                           SE2


                                 ES1
Backbone/AS & HP/AS Ratio Drifts of 2 HPMCAS
         Samples with Elution Time

                                 SE2
                                       BB / AS


                        ES1




                          SE2
                                       HP / AS
                           ES1
OH/AS Ratio Drifts of 2 HPMCAS Samples with
            Elution Time (MWD)


                                 SE2


                                 ES1
Methoxy/AS C=O Ratio Drifts of
2 HPMCAS Samples with Elution Time (MWD)



                         ES1




                         SE2
Acetyl/AS C=O Ratio Drifts of
2 HPMCAS Samples with Elution Time (MWD)
                                    0.52 ---- MF
                              SE2

                                    0.40 ---- LF
                        ES1             Grade
                                        Levels
Methoxy/2935 CH2 & Methoxy/Backbone Ratio
Drafts of 2 HPMCAS Samples with Elution Time

                            ES1
                                  M / 2935 CH2

                     SE2




                           ES1

                                  M / BB
                            SE2
Methoxy / Acetyl Ratio Drafts of
2 HPMCAS Samples with Elution Time (MWD)

                          ES1




                    SE2
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
GPC-IR Chromatogram Overlay
at 1739 cm-1 of 4 HPMCAS-MF Lots




        T8   T10   T12   T14   Snapshots
Acetyl/TotalEster Ratio Drifts of 4 MF Lots
              Compared to LF & HF HPMCAS

-- HF ---------




-- LF ---------
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
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
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).
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.
Excipient QbD Space
                GPC-IR-Performance
 Slide from USP International Excipient Workshop (July 2009)




Performance




                                                        GPC



                             IR
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

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HPLC2010 Pharmaceutical Copolymer Excipient Characterization By GPC-FTIR

  • 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
  • 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