Extrusion of Reactive Systems
and
Pharmaceutical Formulations
Costas Gogos, Huiju Lu, Ming W. Young
Polymer Processing Institute (PPI)
Newark, NJ
USA
Slides 6-14 are extracted and modified from a recent presentation at the
2011 ALEC Pharmaceutical Extrusion Seminar by Dr. Costas Gogos
Outline
Two case studies of Reactive Processing One recent study related to Pharmaceutical application
One commercial success related to Industrial application
What do they have in common?
How do we support the Pharmaceutical
industry as the polymer processing people?
What’s on the horizon?
CASE STUDY 1
Hot Melt Extrusion (HME)
Model Compound Study
Hot Melt Extrusion (HME)
Embed drugs in a polymeric carrier via the
melt extrusion process
Attribute HME current revival to US FDA’s call for a continuous mfg process
Poor solubility of many currently developed API’s
A number of major challenges Thermal sensitivity
Scalability
HME (continued)
Advantages Disadvantages
Enhanced Bioavailability Need to Melt
Neat Process Limited Number of Excipients
Safety & Cost Savings New Equipment & mfg Scheme
Various Dosage Forms
Widely Attainable Geometry
no.Setting Temperature
(ºc)rpm Sampling Time
1 100 20
55 100 145 285
420
2 100 100
3 110 20
4 110 100
5 140 20
CH2C C
CH3
C
O
O
H2C C
CH3
C
OC2H4N(CH3)2
O
*
C4H9
CH3
C
O
CH3
*
O
N
CO Cl
CH3
H2C COOH
OH3C
Eudragit E PO (E PO)
Tg= 48 ºC
Indomethacin (INN)
Tm= 162 ºC
Batch Mixing StudyEudragit E PO : Indomethacin = 70 : 30
Tg+ 50~100 ºC < THME < Tm drug
Suspended drug particles
(high viscosity)
Tg+ 50~100 ºC < THME < Tm drug
Drug/polymer solution
(lowest viscosity)
Premixed drug and
polymer particlesSuspended drug particles
(high viscosity)
Suspended drug particles
dissolving at high rates
(low viscosity)
Polymer
melts
Boundary
layer
formats
Diffusion Diffusion
Distributive
mixing
Distributive
mixing
100 s 145 s 285 s 420 s
Dissolution Evolution During Mixing
100 ºC 20 rpm
100 µm
110 ºC 100 rpm
55 s 100 s 145 s 285 s 420 s
100 µm
DSC Thermograms
Heat of Dissolution
100 ºC 20 rpm
128.12°C
97.13°C
11.99J/g
125.22°C
94.42°C
8.473J/g
127.23°C
92.42°C
3.387J/g
131.07°C
91.24°C
4.861J/g
420s
285s
145s
100s
physical mixture
159.85°C
155.75°C
17.90J/g
-2
-1
0
1
2
He
at F
low
(W
/g)
20
40
60
80
100
120
140
160
Temperature (°C)
Exo Up
Universal V4.5A TA Instruments
159.85°C
155.75°C
17.90J/g
physical mixture
55s
100s
145s
285s
420s
135.27°C
96.86°C
5.960J/g
153.87°C
153.12°C
1.310J/g
132.43°C
105.09°C
1.270J/g
-1.0
-0.5
0.0
0.5
1.0
1.5
He
at F
low
(W
/g)
20
40
60
80
100
120
140
160
Temperature (°C)
Exo Up
Universal V4.5A TA Instruments
110 ºC 100 rpm
Dissolution Profiles
in pH=1.2 Buffer Solution
0
20
40
60
80
100
0 30 60 90 120 150
Time (min)
% indom
eth
acin
rele
ased
100C 20 rpm
110C 100rpm
indomethacin
physical mixture
The Evolution of Specific Enthalpy
0.0
20.0
40.0
60.0
0 100 200 300 400Mixer residence time (seconds)
Sp
ecific
en
tha
lpy (
J/g
)
110ºC-20rpm 110ºC-100rpm 140ºC-20rpm
100ºC-20rpm 100ºC-100rpm
12
Two mixing zones (M2)
One moderate mixing zone (M1)
8 13 19 24 28Sampling lobe number
12 paddles (9 forward 30º plus 3
reversed 30 º) 10 paddles (forward 30º)
10 paddles (7 forward 30º plus 3
reversed 30 º)
One aggressive mixing zone (M1S)
No mixing zone (M0)
10 paddles (5 forward 60º plus 5
reversed 30 º)
Effect of Screw Configuration on Dissolution
Polarized optical microscope
images
8 13 19 24 28Lobe no.
50 µm
50 µm
One aggressive mixing zone (M1S)
No mixing zone (M0)
Morphology Evolution (140°C, 50rpm, 0.2 kg/hr)
14
Shift of the INN Benzoyl C=O IR Absorption
1683
1686
1689
1692
0 5 10 15 20 25 30
Screw lobe number
Waven
um
ber
one mixing zone one strong mixing zone
two mixing zone no mixing-one camel
Benzoyl v C=O
1692 cm-1 for γ- INN
1683 cm-1 for amorphous INN(Taylor and Zografi, 1997)
1st kneading zone
140 ºC
50rpm
0.2 kg/hr
Cl
NH3C
OCH3
HO
O
O
Case Study 2
Thermally Curable Acrylic Powder Clear
Coat for Automotive Applications
Mission Statement
Increase production output
Eliminate batch-to-batch variations
Reduce the use of solvent and other VOC’s
Integrate the Base resin mfg and
compounding operation in one production site
Minimize the drift dispersion in key properties
Cost/Performance ratio!
Di-acid Addition:
50 gm/min
Catalyst
2.7 g/minDevolatilization
Back Vent(optional)
Feed
Tank 97.32% conversion
Residuals:
Acrylates/Styrene
2.60/0.08
~11.7 Kg/hr Solids
W&P ZSK30 Co-Rotating Twin Screw
Extruder, L/D=40
Flaking &
Grinding
Powder99.65% solids
Total Throughput ~ 14.8Kg/hr.
Monomer
Disposal
Continuous Bulk Manufacturing Process
Thermally Curable Acrylic Powder
Acryaltes/Styrene
90/10
Di-t-Amyl Peroxide
6 wt.% per total monomer mix
25°C
CSTR
Avg temp: 115°C, 450 rpm
Temp:<140°C
Pressure:<4.2 mmHg
Total Residual monomer
removal rate (Back vent +
Devo): ~6 g/min
Constituents &
Processing Criteria
Base resin -- Low molecular weight copolymer from
various Acrylates and Styrene, Tg ~ 55°C
Co-reactive agent – a long chain Aliphatic Di-acid,
Tm ~ 130°C
Catalyst – t-Amine
Weathering package & other additives
Creating a uniform Reactive System with minimum
advancement of the X-linking reaction
Acrylic Powder
Basic Chemistry
Catalyst
Compounding I
Compounding II
Compounding III
MorphologyExtruder Type & Screw Configuration
TC-3-535-50-WPTT-2-450-50-TSME TT-2-535-50-WPTT-1-450-50-LZ
- Coating Performance +
Outcome
More than 50 folds increase in productivity
Much narrower in mw and cc distribution
Eliminate issues related to batch to batch
consistency
Solvent-less process with significant energy cost
savings
Establishment of a $46M production plant in US
What’s in common?
The need of creating a Stable Solid Solution of heat
sensitive system via Reactive Extrusion
Batch to a Continuous process
Basic analytic setup but solid interpretation skills
Close connection to the Customer Base
Manufacturability
StabilityAvailability
Polymer Processing Techniques
for Pharmaceutical Applications
Foaming Enhance solubility
Produce heat sensitive fine powders
Lower processing temperature
Extract volatiles
Injection Molding Produce tablets via direct compacting
Various advanced IM techniques
Co-Extrusion
Thermoforming………………
Acknowledgements
We want to thank our colleagues at the HEM Processing, Scale-up, and Pharmaceutical Product Characterization Lab of the Polymer Processing Institute (PPI), and the Chemical, Biological and Pharmaceutical Department of NJIT, Newark, NJ.
PPI NJIT
Dr. Linjie Zhu Prof. Costas G. Gogos
Dr. Herman Suwardie Prof. Marino Xanthos
Dr. Niloufar Faridi Dr. Huiju Liu
Dr. Fei Shen Ms. Min Yang
Dr. David B. Todd Ms. Graciela Terife
URI – Prof. Peng Wang
Financial support: NSF CMMI-0927142
