Overview

1. Supercritical Fluid Assisted Processing of Medical PolymersProfessor Peter HornsbyPolymers ClusterSchool of Mechanical and Aerospace Engineering

2. Overview • Introduction and uses of scCO2 • ScCO2 plasticisation of polymers • Application to polymer processing • Development of scCO2 assisted extrusion technology • Use in the preparation of drug delivery dosage forms.

3. Supercritical CO2-phase diagram • Properties lie between those of liquids and gases: • -High solubility (liquid-like) • -High diffusivity (gas-like) • -Low viscosity (in between gas and liquid) SOLID SUPERCRITICAL STATE Critical • point 74 Pressure (bar) LIQUID Triple • point GAS 8 GAS 303 (-60ºC) (31.1ºC) Temperature (K)

4. Applications for supercritcal CO2 Decaffeination of coffee Porous polymer tissue scaffolds Pharmaceutical preparation

5. Microcellular Foams *Baldwin et al., 1995

6. Polymer Processing Aids • Definition: “Additives that facilitate the processing of polymers” • Advantages: • Reduction of melt fracture • Reduction of die build-up • Reduction of melt pressure and temperature • Increase of output • Reduction of energy consumption • Examples: • Fluoropolymer • Siloxane • Low molecular weight Acrylics • Remain in the polymer after extrusion modifying physical properties (may not be suitable for medical applications) • Supercritical CO2 can be used as a transient plasticiser

7. Viscosity Reduction using CO2 High pressure rheology of PS melts plasticized with CO2. J.R. Royer et al, J.Polym.Sci., Part B, Phys., Vol 38, 3168-3180, 2000.

8. CO2 Plasticizing Mechanism Diffusion of CO2 molecules into the polymer matrix and interaction with basic sites present Swelling of the polymer matrix giving an increase in free volume (controlled by pressure) Causes an increase in mobility of the polymer molecules, with CO2 acting as ‘molecular lubricant’ The glass transition temperature (Tg) of the polymer is reduced resulting in a decrease in melt viscosity Enhanced interdiffusion in miscible polymer systems O.S. Fleming, K.L.A. Chan, and S.G. Kazarian, Polymer, 47, 4649-4658 (2006) A.R. Berens, G.S. Huvard, R.W. Korsmeyer, and F.W. Kunig, J. Appl. Pol. Sci., 46, 231-242 (1992)

9. Enhanced Flow in Injection Moulding Polypropylene homopolymer

10. Supercritical Fluid assisted Extrusion Objectives: • To investigate the plasticizing effect of scCO2 during extrusion of polymers, with a capability to produce foam-free extrudate • To establish rates of gas diffusion from polymer in off-line studies using a pressure vessel • To estabilish study the effect of scCO2 treatment on the structure and properties of the polymer

11. Regulated higher pressure Lower pressure regulated by extruder High pressure Constant flow Back Pressure Regulator One-way Injection valve CO2 cylinder Low Pressure Delivery P2 Dual Syringe Pump CO2 Injection System

12. Polymer Extrusion • 25 mm single screw exruder • 25:1 L/D • 5 kg/hr output • CO2 injected at18D • Gas delivery system: • Teledyne Isco dual syringe pump • Back pressure regulator • Injection (poppet) valve

13. Polymer Extrusion • Lower processing temperatures • Easier processing of highly • viscous polymers • Reduced die pressures • Increased throughput • Reduced energy usage

14. *Changes are compared with unmodified polymer at 0% CO2 Benefits during unplasticised PVC extrusion

15. Extended Die Design To extruder Main die body Extended Cooling Die Clamp ring adaptor with variable entry angle Provides simultaneous control of rate of pressure drop and cooling rate through die Int. Patent Application PCT/GB2009/050249 (Hornsby, Billham, Kusmanto)

16. Extrudate Cross-section(Extruded PVC K-65) 2 mm Virgin PVC –no CO2 Extruded using 0.6% CO2

17. Thermal and Mechanical Data -after CO2 removal (at 23°C) (unplasticised PVC extrudate)

18. Pressure Chamber Design

19. CO2 Diffusion at 23 C Unplasticised PVC K-65 after CO2 saturated at 100 bar, 40oC Sample thickness: 2mm

20. Effect of CO2 Diffusion on Flexural Modulus (at 30 °C) PVC K-65 -CO2 saturated at 100 bar, 40oC, 24 hours DMTA: variable frequencies, test temperature 30oC Sample thickness: 2mm

21. Biomaterial Extrusion StudiesDrug delivery dosage form Eudragit E100 R = CH3or C4H9 Triethyl Citrate (TEC) Bovine Serum Albumin Model Protein Goes from a normal to denatured state above 60°C Used as a plasticiser in pharmaceutical formulations Copolymer of acrylic and methacrylic acid esters

22. Effect of scCO2 Addition and Temperature on Melt Pressure of Eudragit formulations Melt pressure at die Melt pressure opposite CO2 injection point 85 oC + CO2 +BSA 85 oC + CO2 95 oC + CO2 100 oC + CO2 110 oC No CO2 105 oC No CO2 105 oC + CO2 80 oC No CO2 BSA – 1 wt% bovine serum albumin 0.2 wt% CO2 addition Eudragit E100 + 10wt% TEC

23. Bovine Serum Albimin Release from Eudragit in Simulated Intestinal Fluid* Determined by Size Exclusion HPLC * KH2PO4 + NaOH solution (pH 6.8)

24. Summary • CO2 assisted polymer extrusion system has been developed to show CO2 plasticisation effect, with a capability to produce foam-free extrudate. • CO2 can be used as a transient plasticising aid during polymer extrusion without influencing the properties of final products. • Benefits of CO2 assisted extrusion: • Reduce pressure, viscosity • Reduce motor current, power • Increase output rate • Lower processing temperature, thus avoid degradation • Easier processing of highly viscous polymer • With thermally sensitive polymers and additives CO2 assisted melt processing can reduce thermal degradation effects.

25. Acknowledgements Queen’sUniversity Belfast Febe Kusmanto Mark Billham Peter Marshall Gavin Andrews Project funding: EU Sixth Framework Programme ‘FLOWFREE’ (COLL-516255- 2) PROJECT PART-FINANCED BY THE EUROPEAN UNION

26. Real Time Graphfor CO2 additions No CO2 Stop CO2 Start CO2 Pressure 1.3 ml/min CO2 0.7 ml/min CO2 1 ml/min CO2 Time Pressure measured at P3