ACS2010 GPC-IR To Characterize Macromolecular Excipients In Pharmaceutical Formulations-8-22-2010

ACS 2010 National Meeting Division of Analytical Chemistry GPC-IR to Characterize Macromolecular Excipients in Pharmaceutical Formulations Ming Zhou, William Carson, Sidney Bourne & Tom Kearney Spectra Analysis, Inc. August 22, 2010 Contact: ZhouM@Spectra-Analysis.com Tel. 508-281-6276 1

OUTLINE  GPC-IR Hyphenated Technology: Instrumentation  Excipient Characterization: Copovidone PVP/VAc  Excipient Degradation from HME Process: HPMCAS, Eudragit L100-55 (PEA/MAA)  Summary: GPC-IR Applications in Pharma Formulations Q&A 2

Hyphenated Technologies & Major Applications LC-MS LC-IR Separation Liquid Chromatography Detection & Mass Infra Red Data Analysis Spectroscopy Spectroscopy Applications Small Molecules, Proteins Polymers Pharma API’s Polymeric Excipients

LC-IR Hyphenation

What is Direct Deposition FTIR? Separated Dot Depositing on Disk Separated Dots from HPLC-IR Continuous Polymer Tracks (GPC-IR)

Direct Deposition FTIR & Data Processing ZnSe Disk

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

Compositional Drift Analysis of Copolymer Poly(A-B) by GPC-IR A A/B Ratio B Absorption High MW Low MW Molar Mass Ratio 10/8 12/12 2/4 Total 24/24 A% 56% 50% 33% 50%

Compositional Heterogeneity of Copolymer Poly(A-B) GPC-IR GPC Absorption IR Bulk 50% (NMR) (MS) High MW Low MW Molar Mass Ratio 10/8 12/12 2/4 Total 24/24 A% 56% 50% 33% 50%

GPC-IR Spectrum of Copovidone Excipient - VP/VAc Copolymer Peak 1680 cm-1 from VP comonomer Peak 1740 cm-1 from VAc comonomer

Excipient Compositional Drift w/ MWD Vs. Bulk Average GPC-IR Chromatogram Overlay with Comonomer IR Peak 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 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

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.

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.

Excipient Characterization by LC-IR in Pharma Formulations  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. 16

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 (Screw Speed) • Torque • Screw / Die Designs 17

Excipient HPMCAS Degradation in Hot Melt Extrusion Process Unprocessed Processed at 160C Degradant Processed at 220C

Degradant from HPMCAS (220C) in Hot Melt Extrusion Process IR Database Search Result: Succinic Acid

HPMCAS Degradation in Hot Melt Extrusion Process -C=O OH Functional Group Ratio Changes from High Temp Process (Sample C)

GPC-IR Analysis of HPMCAS Degradation in HME Process  Detected Degradants: Succinic Acid & Derivatives  Detected Functionality Ratio Change: Hydroxyl Vs. Carbonyl  Help Understand Excipient Degradation Mechanism  Study Excipient / API Interactions  Define Safe Process Window: QbD  Excipient Blends with Plasticizers and Additives HOOC-CH2-CH2-C=O CH3-C=O Fig. A Schematic Structure of HPMC-AS

Eudragit L100-55 Characterization by GPC-IR (Chromatograph + IR Spectra)

Eudragit L100-55 Compositional Drift at Different Elution Times (Red 8’ & Blue 10’) COOEt 1735 COOH 1705 CH2 CH3 Areas: L R Acid / Ester Co-Monomer Ratio ~ Acid / Ester Peak Area Ratio = [(L+R)-2L] / (2L)

IR Spectra of L100-55 Samples at Polymer Peak Center (Elution Time ~9.4’) S0 – Green Ref COOEt S1 – Pink 130C 1735 S2 – Blue 160C S3 – Black 190C COOH 1705 NCE? 1805 cm-1 CO-OH 24

Excipient L100-55 Crosslinked from COOH to Anhydride at Higher Temp COOEt 1735 S0 – Green Ref S1 – Pink 130C S2 – Blue 160C COOH S3 – Black 190C 1705 NCE? 1805 cm-1 25

Summary: Eudragit L100-55 Degradation & Stability from HME Sample # Extrusion Screw Sample Sample Degradant Polymer Temp. Speed Color in THF Formed Change (~0.5%) S0 Not White Clear None None Processed Solution S1 130 C 250 rpm Off Clear Trace White Solution Anhydrides S2 160 C 250 rpm Off Clear Anhydrides Acid/Ester White Solution Ratio Decreased S3 190 C 250 rpm Brownish Some Anhydrides Acid/Ester Residue Ratio Decreased 26

Common Polymeric Excipients Cellulose Derivatives • HydroxyPropyl Methoxy Cellulose (Hypromellose): HPMC • HPMC Acetate Succinate: HPMC-AS • HPMC Phthalate: HPMC-P • HydroxyPropyl Cellulose: HPC  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  PLGA Copolymers: Biodegadable  Excipient Combinations with Plasticizers and Additives 27

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.

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

Excipient Analysis with GPC-IR in Pharceutical Formulations  Polymeric Excipient Characterization  Compositional Variations with MWD: Functional Group Ratios  Lot-to-Lot, Supplier-to-Supplier Variations  Degradation Analysis in Thermal Process (HME)  Detect Degradants (Low MW)  Polymer Structural Changes: • Cross-Linking (New Chemical Entity) • Functional Group Changes

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 31

GPC-IR Operating Conditions & Sample Preparation  GPC Chromatograph: Agilent® 1200 • GPC Column Temperature: Ambient • Solvent: THF at 1.0 ml/min • Column: Jordi Gel DVB Mixed Bed– 250 x 10 mm • Sample Injections: 100 ml at ~0.5% weight / volume THF  IR Detection • DiscovIR-LC® solvent-removing direct-deposition solid phase FTIR • Cyclone Temperature: 150oC • ZnSe Disk Temperature: -10 ~ -15oC  Sample Preparation: • 0.050 g excipient solid samples were dissolved in 10 ml THF in ~1 hr and filtered with 0.45 mm PTFE syringe filter before GPC injection

Acid/Ester Ratio Changes with Elution Time (MWD) and Processing Temp. S0 – Green Ref. S1 – Pink 130C S2 – Blue 160C S3 – Black 190C 33

HPMCAS Grade-to-Grade Difference (LF/MF/HF) by GPC-IR -C-O-C- 1060 HOOC-CH2-CH2-C=O AS A C=O Acetyl 1740 1235 CH3-C=O HP C/HP M CH3 OH OCH3 1372 3470 2830

HPMCAS Grade-to-Grade Difference (HF/MF/LF) by GPC-IR Acetyl / C=O (total AS): Peak 1235cm-1 /1740 cm-1 Ratios HF—0.8 MF—0.5 LF—0.4

IR Band Identifications of HPMCAS Excipients for Ratio Drift Analysis S A HP HOOC-CH2-CH2-C=O CH3-C=O C O M M M M o O O M CH3 M CH3 M CH3-C=O A 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)

ACS2010 GPC-IR To Characterize Macromolecular Excipients In Pharmaceutical Formulations-8-22-2010

by mzhou45

Accessibility

Upload Details

Usage Rights

1 Embed 1

Statistics