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

• 1. LC-IR Hyphenated Technology forExcipient AnalysisFDA on Jan. 12, 2010 USP on Jan. 13, 2010 George Giansanti, Tom KearneyGerrit Blok, Ming ZhouSpectra Analysis, Inc. 1

2. OUTLINEIntroduction: Company & LC-IR TechnologyDiscovIR-LC System: Instrumentation & FeaturesApplications of LC-IR: Case StudiesQ&A2 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 Magazines 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. Meet the Spectra TeamGeorge GiansantiWilliam W. Carson, PEMing Zhou, PhD. Tom Kearney, MBA President & CEO Sr. VP Engineering Applications Engrg. Mgr. Technical Sales Mgr. Cal PolyMIT Univ. ConnecticutUniv. Vermont Sidney Bourne, PhD.Andrew Chung David Dunn Stacy Follo Sr. VP & Chief ScientistProduct Engineer Sr. Applications ChemistSoutheast Sales Rep. Univ. Wisconsin Northeastern NortheasternNortheastern Part time support:Lisa Velardo, CPA CFOGerrit Blok Mid-Atlantic Sales Rep.Cheryl McCarthy Accountant Broek Institute,Amy Guyton Materials & LogisticsAmsterdamJames Dwyer, PhD. Technical Advisor 5. DiscovIR UsersMerck Pharma Johnson & Johnson Pharma NovartisPharma Shire Pharmaceuticals Pharma Du Pont Polymers Dow ChemicalPolymers 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. DiscovIR Product Line SeparateConcentrateIdentifyDiscovIR-GCTMDiscovIR-LCTM 2008 Award Winner Applications: Applications: General Analytical CapabilityExcipients 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. DiscovIR Software & Data ProcessingDell Desktop ComputerThermo-GRAMS /32Software Package Library Search & Creation Ratio Chromatograms CFR 21-Part 11 Compliant 8. Direct Deposition FTIR & Data Processing 9. How Does It Work? 10. How is the Solvent Removed?N2 AdditionCyclone From LC CycloneEvaporatorEvaporator Thermal Nebulization Air CooledCondenser Patent pending:PCT/US2007/025207ChilledCondenserParticle Stream to DiscovIRWaste Solvent 11. ZnSe Sample DiskAuto sampler compatibleUnattended overnight runsThe ZnSe sample disk (yellow) is under vacuum without moisture or CO2 interferenceRe-usable after solvent cleaningTransmission IR analysis is done on the solid deposit. 12. DiscovIR Components IRDetectorInterferometer PCBCryogenicLN2ABBBomemMCT Sampledeposit ZnSewindowVacuumchamberPrecisionVacuumBack plate Opticalpath 13. Direct Deposition IR in Action 13 14. What is Direct Deposition FTIR? 15. GPC-IR Hyphenated Technology 3-dimensional Plot15 16. Features of DiscovIR-LC High Quality Solid Phase Transmission IR SpectraReal-Time On-line DetectionMicrogram SensitivityCompatible with all LC Solvents and Gradients e.g. Water, ACN, Methanol, THF, Chloroform, HFIPCompatible with all GPC/SEC SolventsFully Automated Operation: No FractionationMulti-Sample Processing: 10 Hr ZnSe Disk Time 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&A17 18. IR Spectrum of Copovidone Excipient - VP/VAc Copolymer Peak 1680 cm-1 from VP comonomerPeak 1740 cm-1 from VAc comonomer 19. Excipient Compositional Driftw/ MWD Vs. Bulk Average GPC-IR Chromatogram Overlay with Comonomer RatiosCopovidoneBulk Average (Molecular Weight Distribution) Abs. Peak Ratio: AVA / AVP = (k1*b*MVA) / (k2*b*MVP) = k (MVA / MVP) ~ Comonomer Ratio 20. Excipient Compositional Driftw/ MWD Vs. Bulk Average.6Copovidone: sample A50 molecular weight.5% acetate comonomer distribution max. IR absorbance45.4.3 Bulk Average comonomer composition 40 40% VAcdistribution.235 .1 030106 105 104 103 102 Molecular Weight 21. Copovidone MW Distributions fromDifferent Suppliers (Manf. Processes).6Copovidone: sample A sample B.5 sample C max. IR absorbance.4.3.2.1 0Molecular Weight106 105104 103 102 Copovidone A gave clear tablets while Copovidone C led to cloudy ones. 22. Copovidone Compositional Drifts from Different Manf. Processes.6Copovidone: 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 30106 105 104103 102Molecular Weight 23. Excipient Characterizationby LC-IRCopolymer Compositional Analysis with MW Distributions Comonomer Ratio Drift (Functional Groups) vs. Bulk Average Excipient Lot-to-Lot Variations: QbD StudiesExcipient Performance & Functional Group Correlations Hydrophobic/Hydrophilic Ratio Drift vs. Phase Separations Effects on Excipient Dissolution BehaviorReference(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. Excipient Degradation from HME ProcessHot Melt Extrusion Process: To Make Solid Dispersions for Low Solubility Drugs to Improve BioavailabilityDegradation Issues Excipient & API Degradation at High Temp. (100-200C) Discoloration / Residues Degradant / API InteractionsProcess Variables Temperature Time Screw Speed (Torque) Screw Design 24 25. Excipient HPMCAS Degradationin Hot Melt Extrusion Process 26. Degradant from HPMCAS in Hot Melt Extrusion Process IR Database Search Result: Succinic Acid 27. HPMCAS Degradationin Hot Melt Extrusion Process Functional Group Ratio Changes from High Temp Process (Sample C) 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. Forced Degradation Study ofExcipient PEG PEG-1000 at 55C Air Bubbling Overnight; Reverse-Phase HPLC: H2O / ACN 30. IR Spectrum from Main PEG PeakOxidation bands in bulk material seen at1720 and 1645 31. HPLC-IR of Std PEG-1000AU Scale for all traces 1116 cm-1 band chromatogram 1607 cm-1 band chromatogram 1719 cm-1 band chromatogram Minutes 32. HPLC-IR forDegraded PEG-1000 Three Chromatographic displays generated from one time ordered set of FTIR Spectra 33. IR Identification ofDegraded Products Na+ or K+ Cation AldehydeCarboxylate Salt 1719 160711.45 minutes 4.93 minutes1.50 minutes 34. Proposed Mechanism of PEG OxidationSupported by HPLC-IR Data 35. GPC-IR Analysis for Macromolecules andSmall Molecules in the Same RunMacromoleculesSmall MoleculesPolymersAdditivesExcipientsImpuritiesDegradantsor APIs(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. Polymer Additive Analysis withGPC-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. Common Polymeric ExcipientsNeutral 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/VAcSoluPlus Terpolymer: PEG / PCL / PVAcMethacrylate Copolymers: EudragitPolyethylene Oxide: PEO (MW > 20K) or PEG (MW < 20K)Excipient Combinations with Plasticizers and Additives 37 38. LC-IR Applications in Excipient Supply Chain and FormulationsExcipientFormulation Formulated Drugs ManufacturingDevelop. & Manf.Shelf Life Stability Process Incoming QC StressedControl ExcipientDegradation Lot-to-lotFunctionalityVariations Formulation De-Formulate CoA DevelopmentExcipient QbDBlends NovelExcipient R&D Process (HME) Trouble-ShootDegradationProblem Drugs Define Safein the MarketProcess Window ProcessMonitoring Users:Excipient Pharma Co. Pharma Co.Manufacturers HME Service Providers Generic Drug Co. 39. Excipient QbD SpaceSlide from USP International Excipient Workshop (July 2009) 40. Excipient QbD SpaceSlide from USP International Excipient Workshop (July 2009)GPC 41. Excipient QbD Space GPC-IR-Performance Slide from USP International Excipient Workshop (July 2009)GPCIR 42. Excipient QbD SpaceGPC-IR-PerformanceSlide from USP International Excipient Workshop (July 2009) Performance GPC IR 43. THANK YOU !A NEW WORKHORSE TECHNOLOGY DIRECT DEPOSITION, SOLID PHASE, FULLY AUTOMATEDLC-IR Now formulation chemists can characterize excipient macromolecules with more accurate composition informationContact Gerrit Blok Sales RepresentativeMid-Atlantic(717) 368-0549 [email protected] Learn more..43 WWW.SPECTRA-ANALYSIS.COM 44. LC-IR Applications Excipient Characterization, Functionality & Degradation AnalysisCopolymer Compositional Analysis across MW DistributionPolyolefin Copolymer Branching Analysis by High Temp GPC-IRPolymer Blend Ratio Analysis across MW DistributionPolymer Additive & Impurity AnalysisDe-Formulation for Polymers and Additives: Competitive AnalysisProcess Control & OptimizationExcipients, Plastics, Rubbers, Films, Fibers, Foams & CompositesReactive Polymer Analysis for Coating, Adhesive, Sealant & ElastomerIsomer Analysis for Chemicals, Forensics & PharmaceuticalsGeneral Analytical Capability: Trouble Shooting44