LC-IR Hyphenated Technology For Excipient Analysis-FDA USP Seminars-1-13-2010

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Presentation slides for FDA / USP seminars given in Jan. 2010 about LC-IR hyphenated technology for excipient characterization, degradation/stabiltiy analysis and deformulation.

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LC-IR Hyphenated Technology For Excipient Analysis-FDA USP Seminars-1-13-2010

  1. 1. LC-IR Hyphenated Technology for Excipient Analysis FDA on Jan. 12, 2010 USP on Jan. 13, 2010 George Giansanti, Tom Kearney Gerrit Blok, Ming Zhou Spectra Analysis, Inc. 1
  2. 2. OUTLINE Introduction: Company & LC-IR Technology DiscovIR-LC System: Instrumentation & Features Applications of LC-IR: Case Studies Q&A 2
  3. 3. The Company 257 Simarano Drive Marlborough, MA 01752 Completed product engineering with patent protected ‘breakthrough’ technology during 2005 & 2006. Initiated sales and began building a ‘top tier’ customer base, 2007 thru 2009. Received R&D Magazine’s ‘Top 100’ product Award, 2008. Received Massachusetts Life Science Center, Certification & Award, 2009. Spectra has great people, ‘breakthrough’ products, huge market and is positioned for explosive growth ! December 2009 3
  4. 4. Meet the Spectra Team George Giansanti William W. Carson, PE Ming Zhou, PhD. Tom Kearney, MBA President & CEO Sr. VP Engineering Applications Engrg. Mgr. Technical Sales Mgr. Cal Poly MIT Univ. Connecticut Univ. Vermont Sidney Bourne, PhD. Andrew Chung David Dunn Stacy Follo Sr. VP & Chief Scientist Product Engineer Sr. Applications Chemist Southeast Sales Rep. Univ. Wisconsin Northeastern Northeastern Northeastern Part time support: Lisa Velardo, CPA – CFO Gerrit Blok Mid-Atlantic Sales Rep. Cheryl McCarthy – Accountant Broek Institute, Amy Guyton – Materials & Logistics Amsterdam James Dwyer, PhD. – Technical Advisor
  5. 5. DiscovIR Users Merck Pharma Johnson & Johnson Pharma Novartis Pharma Shire Pharmaceuticals Pharma Du Pont Polymers Dow Chemical Polymers Lawrence Livermore National Lab Trace Analysis Oak Ridge National Laboratory Environmental Naval Research Laboratory Organics US Army Aberdeen Proving Ground Forensics Pennsylvania State Police Forensics Alabama Department of Forensics Forensics Vermont State Police Forensic lab Forensics
  6. 6. DiscovIR Product Line Separate→Concentrate→Identify DiscovIR-GCTM DiscovIR-LCTM 2008 Award Winner Applications: Applications: General Analytical Capability Excipients Forensic Labs Polymers (Controlled Substance Analysis) Advanced Materials DiscovIR-GCTM (GC-FTIR) DiscovIR-LCTM (LC-FTIR) real-time, vapor to solid phase real-time, solvent removal
  7. 7. DiscovIR Software & Data Processing Dell Desktop Computer Thermo-GRAMS /32 Software Package • Library Search & Creation • Ratio Chromatograms • CFR 21-Part 11 Compliant
  8. 8. Direct Deposition FTIR & Data Processing
  9. 9. How Does It Work?
  10. 10. How is the Solvent Removed? N2 Addition Cyclone From LC Cyclone Evaporator Evaporator Thermal Nebulization Air Cooled Condenser Patent pending: PCT/US2007/025207 Chilled Condenser Particle Stream to DiscovIR Waste Solvent
  11. 11. ZnSe Sample Disk Auto sampler compatible Unattended overnight runs The ZnSe sample disk (yellow) is under vacuum without moisture or CO2 interference Re-usable after solvent cleaning Transmission IR analysis is done on the solid deposit.
  12. 12. DiscovIR Components IR Detector Interferometer PCB Cryogenic LN2 ABB Bomem M C T Sample deposit  ZnSe window Vacuum  chamber Precision Vacuum Back  plate Optical path
  13. 13. Direct Deposition IR in Action 13
  14. 14. What is Direct Deposition FTIR?
  15. 15. GPC-IR Hyphenated Technology 3-dimensional Plot 15
  16. 16. Features of DiscovIR-LC High Quality Solid Phase Transmission IR Spectra Real-Time On-line Detection Microgram Sensitivity Compatible with all LC Solvents and Gradients • e.g. Water, ACN, Methanol, THF, Chloroform, HFIP Compatible with all GPC/SEC Solvents Fully Automated Operation: No Fractionation Multi-Sample Processing: 10 Hr ZnSe Disk Time
  17. 17. Applications Applications of DiscovIR-LC for Excipient Analysis • Excipient Characterization: Copovidone PVP/VAc • Excipient Degradation from HME Process: HPMCAS • Forced Degradation Analysis: PEG • De-Formulation of Polymers and Additives (Macromolecules + Small Molecules) Q&A 17
  18. 18. IR Spectrum of Copovidone Excipient - VP/VAc Copolymer Peak 1680 cm-1 from VP comonomer Peak 1740 cm-1 from VAc comonomer
  19. 19. 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
  20. 20. 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
  21. 21. 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.
  22. 22. Copovidone Compositional Drifts from Different Manf. Processes .6 Copovidone: sample A 50 sample B % acetate comonomer .5 sample C 45 .4 Molecular Weight Comonomer Composition max. IR absorbance Distribution .3 Distribution 40 Bulk 40% VAc .2 35 .1 0 30 106 105 104 103 102 Molecular Weight
  23. 23. Excipient Characterization by LC-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. 23
  24. 24. Excipient Degradation from HME 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 • Screw Speed (Torque) • Screw Design 24
  25. 25. Excipient HPMCAS Degradation in Hot Melt Extrusion Process
  26. 26. Degradant from HPMCAS in Hot Melt Extrusion Process IR Database Search Result: Succinic Acid
  27. 27. HPMCAS Degradation in Hot Melt Extrusion Process Functional Group Ratio Changes from High Temp Process (Sample C)
  28. 28. Degradation of HPMC-AS in Hot Melt Extrusion Process Detected Degradant: Succinic Acid Detected Functionality Ratio Change: Hydroxyl Vs. Carbonyl Help Understand Excipient Degradation Mechanism Study Excipient / API Interactions Define Process Window: QbD Fig. A Schematic Structure of HPMC Derivatives, Cellulose Ethers & Esters
  29. 29. Forced Degradation Study of Excipient PEG PEG-1000 at 55C Air Bubbling Overnight; Reverse-Phase HPLC: H2O / ACN
  30. 30. IR Spectrum from Main PEG Peak Oxidation bands in bulk material seen at 1720 and 1645
  31. 31. HPLC-IR of Std PEG-1000 AU Scale for all traces 1116 cm-1 band chromatogram 1607 cm-1 band chromatogram 1719 cm-1 band chromatogram Minutes
  32. 32. HPLC-IR for Degraded PEG-1000 Three Chromatographic displays generated from one time ordered set of FTIR Spectra
  33. 33. IR Identification of Degraded Products Na+ or K+ Cation Aldehyde Carboxylate Salt 1719 1607 11.45 minutes 4.93 minutes 1.50 minutes
  34. 34. Proposed Mechanism of PEG Oxidation Supported by HPLC-IR Data
  35. 35. GPC-IR Analysis for Macromolecules and Small Molecules in the Same Run Macromolecules Small Molecules Polymers Additives Excipients Impurities Degradants or API’s (Molecular Weight Distribution) Polymer Additive Analysis Data with GPC-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).
  36. 36. Polymer Additive Analysis with GPC-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.
  37. 37. 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 37
  38. 38. LC-IR Applications in Excipient Supply Chain and Formulations Excipient Formulation Formulated Drugs Manufacturing Develop. & Manf. Shelf Life Stability • Process • Incoming QC • Stressed Control • Excipient Degradation • Lot-to-lot Functionality Variations • Formulation • De-Formulate • CoA Development Excipient • QbD Blends • Novel Excipient R&D • Process (HME) • Trouble-Shoot Degradation Problem Drugs • Define Safe in the Market Process Window • Process Monitoring Users: Excipient Pharma Co. Pharma Co. Manufacturers HME Service Providers Generic Drug Co.
  39. 39. Excipient QbD Space Slide from USP International Excipient Workshop (July 2009)
  40. 40. Excipient QbD Space Slide from USP International Excipient Workshop (July 2009) GPC
  41. 41. Excipient QbD Space GPC-IR-Performance Slide from USP International Excipient Workshop (July 2009) GPC IR
  42. 42. Excipient QbD Space GPC-IR-Performance Slide from USP International Excipient Workshop (July 2009) Performance GPC IR
  43. 43. THANK YOU ! A NEW WORKHORSE TECHNOLOGY – DIRECT DEPOSITION, SOLID PHASE, FULLY AUTOMATED LC-IR Now formulation chemists can characterize excipient macromolecules with more accurate composition information Contact Gerrit Blok Sales Representative Mid-Atlantic (717) 368-0549 blokg@spectra-analysis.com Learn more……….. 43 WWW.SPECTRA-ANALYSIS.COM
  44. 44. LC-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 44

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