Supercritical Fluid Assisted Processing

of Medical Polymers

Professor Peter Hornsby

Polymers Cluster

School of Mechanical and Aerospace Engineering

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.

Supercritical CO2-phase diagram

•

SOLID

GAS

LIQUID

SUPERCRITICAL STATE

Triplepoint

Criticalpoint

•

Pre

ssu

re (

bar

)

Temperature (K)

303

74

(31.1ºC)(-60ºC)

8

Properties lie between those of liquids and gases:-High solubility (liquid-like)-High diffusivity (gas-like)-Low viscosity (in between gas and liquid)

GAS

Applications for supercritcal CO2

Decaffeination of coffee

Pharmaceutical preparation

Porous polymer tissue scaffolds

Microcellular Foams

*Baldwin et al., 1995

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

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.

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)

Enhanced Flow in Injection Moulding

0

50

100

150

200

250

300

0 -20 -30 -40

Temperature Reduction / C

Flo

w len

gth

: T

hic

kn

ess

With CO2

Initialconditions,withoutCO2

Polypropylene homopolymer

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

CO2 Injection System

CO

2 cylinder

Low Pressure Delivery

Dual Syringe Pump

High pressure Constant flow

Regulated higher pressure

BackPressureRegulator

Lower pressureregulated byextruder

One-way Injection valve

P2

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

Polymer Extrusion

Polymer CO2 Level

(wt%)

ViscosityReduction

(%)

Polystyrene 0.4 7.0

Poly methylmethacrylate

2.9 18.2

Polycarbonate 3.6 55.4

Polyethylene 2.4 15.3

Polypropylene 3.4 17.5

•Lower processing temperatures

•Easier processing of highly viscous polymers

•Reduced die pressures

•Increased throughput

•Reduced energy usage

Benefits during unplasticised PVC extrusion

*Changes are compared with unmodified polymer at 0% CO2

0

10

20

300.68wt% CO2 0.65wt% CO2

0.6wt% CO2 0.58wt% CO2

0.68wt% CO2 27.1 21.4

0.65wt% CO2 23.1 18.6 18.9

0.6wt% CO2 17.9 17.1 17.6

0.58wt% CO2 15.4 15.2 12.2

Pressure reduction (%)

Motor currentreduction (%)

Output rateincrease (%)

Extended Die Design

Main die body

Clamp ring adaptorwith variable entry angle

To extruder

Extended Cooling Die

Int. Patent Application PCT/GB2009/050249 (Hornsby, Billham, Kusmanto)

Provides simultaneous control of rate of pressure drop and cooling rate through die

Extrudate Cross-section(Extruded PVC K-65)

Virgin PVC –no CO2

Extruded using 0.6% CO2

2 mm

Thermal and Mechanical Data -after CO2 removal (at 23°C)

(unplasticised PVC extrudate)

CO2 added

(%)

Density (g/cm3)

Tg (oC) Tensile Modulus

(MPa)

Yield Stress (MPa)

Yield Strain (%)

0 1.421 84.8 1697 ± 90 48.6 ± 2.4 8.4 ± 0.5

0.5 1.424 84.9 1486 ± 81 45.2 ± 1.1 7.5 ± 0.2

0.55 1.420 84.4 1446 ± 209 44.5 ± 2.6 7.5 ± 0.4

0.58 1.422 84.8 1515 ± 95 43.7 ± 2.0 7.1 ± 0.5

0.6 1.418 83.6 1621 ± 212 42.6 ± 0.9 7.3 ± 1.5

0.65 1.413 85.0 1464 ± 171 47.4 ± 1.5 7.4 ± 0.2

Pressure Chamber Design

CO2 Diffusion at 23 C

0.000

1.000

2.000

3.000

4.000

5.000

6.000

0 5 10 15 20 25 30

Time (days)

CO

2 l

ev

el

in p

oly

me

r (%

) 24hr sat 1hr sat

Unplasticised PVC K-65 after CO2 saturated at 100 bar, 40oC

Sample thickness: 2mm

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

9

9.05

9.1

9.15

9.2

9.25

0 5 10 15 20 25 30

Log

Ben

ding

Mod

ulus

E'

Time (day)

30Hz Sat 3Hz Sat 0.3 Hz Sat

30Hz Virgin 3Hz Virgin 0.3Hz Virgin

Biomaterial Extrusion Studies Drug delivery dosage form

Eudragit E100

R = CH3 or C4H9

Triethyl Citrate (TEC)

Copolymer of acrylic and methacrylic acid esters

Bovine Serum Albumin

Model Protein

Goes from a normal to denatured state above 60°C

Used as a plasticiser in pharmaceutical formulations

Effect of scCO2 Addition and Temperature on Melt Pressure of Eudragit formulations

Melt Pressure in Zones 5 and 7

0

50

100

150

200

250

300

0 1000 2000 3000 4000 5000Time

Pre

ss

ure

(B

ar)

Zone 7

Zone 5

110 oC

No CO2

105 oC

No CO2

105 oC

+ CO2

100 oC

+ CO2

95 oC

+ CO2

85 oC

+ CO2

80 oC

No CO2

85 oC

+ CO2

+BSA

Melt pressure at dieMelt pressure opposite CO2 injection point

BSA – 1 wt% bovine serum albumin0.2 wt% CO2 addition Eudragit E100 + 10wt% TEC

Bovine Serum Albimin Release from Eudragit in Simulated Intestinal Fluid* Determined by Size

Exclusion HPLC

* KH2PO4 + NaOH solution (pH 6.8)

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.

Acknowledgements

Febe Kusmanto

Mark Billham

Peter Marshall

Gavin Andrews

Project funding:

EU Sixth Framework Programme ‘FLOWFREE’

(COLL-516255- 2)

PROJECT PART-FINANCEDBY THE EUROPEAN UNION

Queen’s University Belfast

Real Time Graph for CO2 additions

1 ml/min CO2

0.7 ml/min CO2

1.3 ml/min CO2

No CO2 Stop CO2

Time

Pre

ssur

e

Start CO2

Pressure measured at P3