Embed Size (px)
Citation preview
1
Understanding Melt Extrusion
Processes by Simulation
Presented by Adam Dreiblatt
Director, Process Technology
Evonik Industries
4th International Symposium on
Pharmaceutical Melt Extrusion
All rights reserved, 2011, Century Extrusion
Why simulation ?
Limited availability and cost of API‟s
Evaluate alternate machine configurations, processes
Virtual DOE
Obtain information not otherwise available
Thermal history
Melt residence time
Troubleshoot and optimize
Accurately predict scale-up behavior
Correlates w/degradation
2
3
Extruders cannot differentiate between pharma polymers
and “traditional” thermoplastics
The extruder can only detect viscosity, degree-of-fill,
pressure, etc…
Hot melt extruder geometry is identical to “traditional”
polymer machinery – from the perspective of the melt in
the screw channel (intermeshing, co-rotating Erdmenger
self-wiping profile).
Simulation Strategy
4
Hot melt extrusion applications can use existing
modeling and simulation tools available for “traditional”
polymer processing.
Interpretation of results is critical to the successful use
of these tools…
Simulation Strategy
3
What do we know about HME?
“BLACK BOX”
Composition
(Polymer + API + Excipients)
Product Properties
(e.g. Crystallinity, Dissolution, Stability)
We know much about the raw materials (e.g. chemistry)
We know much about the extruded product (e.g. functionality)
We do not know much about what happens in between…
What is inside the “Black Box”?
Composition
(Polymer + API + Excipients)
Product Properties
(e.g. Crystallinity, Dissolution, Stability)
Extruder type: Intermeshing, co-rotating, twin-screw
Diameter (mm), Length (L/D) = Free volume
Torque (Nm), Speed (rpm) = Available power
Screw design = Mixing, Specific Mechanical Energy
Die geometry = Size, shaping
“BLACK BOX”
4
What do we know about the extruder?
Barrel / die temperature setpoints (°C)
Vacuum (mbar) Feed rate (g/min)
Screw
speed
(rpm)
Composition
(Polymer + API + Excipients)
Product Properties
(e.g. Crystallinity, Dissolution, Stability)
We know what we want to occur inside the extruder (melt, mix, etc.)
We are not so sure where, when and how it occurs…if it does…
What do we know about HME process?
Motor
Load
(kW)
Temperature, Pressure
Barrel / die temperature (actual) (°C)
We can measure average residence time, residence time distribution
We can measure specific energy input (mechanical, thermal)
Composition
(Polymer + API + Excipients)
Product Properties
(e.g. Crystallinity, Dissolution, Stability)
5
System Analytical Model for Twin Screw Extrusion*
Machine Parameters Free Volume
Screw Configuration
Die Geometry
Process Parameters Screw Speed
Feed Rate
Barrel Temperature
Specific Energy Mechanical
Thermal
Melt Temperature
Residence Time
RTD
Physical Properties Morphology
Crystalinity
Rheology Mol. weight
Mw Distribution
Other Dissolution
Color
Product Quality
Attributes
Key System
Parameters
Extrusion
Parameters
Molecular
Structure
Shear Rate
Shear Stress
*Ref: Berhard Van Lengerich, PhD Thesis, Tech. Univ. Berlin
What don‟t we know about HME process?
Where is the
polymer
melting?
Where (when)
is the API
melting or
dissolving?
How long is
the API at high
temperature
(degradation)?
There is no method or instrumentation to obtain this data directly…
1D simulation can provide such insight to the HME process !
6
12
Simulation Step 1 - Define Geometry
Extruder type (manufacturer, model)
Free volume
Available power, maximum speed
Geometric parameters
Feeding and venting positions
Screw configuration
Die geometry
7
Assemble “virtual” extruder
14
Polymers
Solid state thermal and physical properties
Melt thermal and rheological properties
Rheological model
Solid additives
Solid state thermal and physical properties
Non-melting “inert” filler as API placebo
Rheological model
Liquid additives
Plasticizing effect
Simulation Step 2 - Define Raw Materials
8
Example Eudragit L100-55* Rheology
*20% TEC Plasticizer
16
Screw speed
Feed position
Feed temperature
Feed rate
Temperature profile
Simulation Step 3 - Define HME Process
9
Enter processing conditions
18
Degree-of-fill
Melting
Pressure
Temperature
Specific energy
Residence time
Viscosity
Mixing
Simulation Step 4 – Analyze Results
10
Specific mechanical energy is
0.151 kWh/kg
Average residence time is 45
seconds
Discharge melt temperature is
178-179°C
(note barrel temperature
setpoints are 150°C )
The tail of the RTD can lead to
degradation, discoloration, etc.
11
Mechanical Energy vs Screw Speed
Nearly 50% of
mechanical
energy is applied
to solid polymer
Degree-of Mixing vs Screw Speed
Quantitative
measure of
“mixing” to
compare screw
designs and
operating
conditions
12
Polymer Melting
Critical to know WHERE
polymer (API) is melting !
Where Is Polymer Melting ?
13
Polymer Melting vs Screw Speed
Melting of polymer occurs faster at higher screw speed
Exact position where polymer is
100% molten at 300 rpm
Melt temperature is 135°C when
polymer is 100% molten
14
Residence time for molten polymer
(in contact with API) is 22 seconds
Polymer Melting vs Feed Rate
Melting of polymer occurs faster at lower feed rate
Polymer begins melting very early at
very low feed rate
15
Residence Time vs Feed Rate
Mean residence time is a strong (non-linear) function of feed rate
Exact position where polymer starts
melting at low feed rate
Melting vs Barrel Temperature
Barrel heating has very little effect
on melting in twin-screw extruders
16
Product Temperature vs Barrel Temperature
Barrel temperature has small influence
on actual product temperature
Mechanical Energy vs Barrel Temperature
Lower barrel temperature and
resulting higher melt viscosity results
in higher mechanical energy input
17
Heat Transfer vs Barrel Temperature
Energy balance on HME process
reveals how much energy must be
removed through barrel cooling
system to result in lower discharge
temperature
Melt Viscosity vs Barrel Temperature
Increase in melt viscosity as a result of
barrel temperature settings below
actual melt temperature
18
Example API dissolving at 185°C –
exact location where this occurs at
2.5 kg/hr and 300 rpm
Example API dissolving at 185°C –
residence time from this point to
discharge is 6.13 seconds
19
Example API dissolving at 185°C –
because the dissolution occurs late
in the screw design, there is very
little mixing after this position
Example API dissolving at 185°C –
exact location where this occurs at
2.5 kg/hr and 450 rpm
20
Example API dissolving at 185°C –
residence time from this point to
discharge is 13.87 seconds
Example API dissolving at 185°C –
because the dissolution occurs
earlier in the screw design, there is
sufficient mixing after this position
21
41
1D process simulation for HME applications is
commercially available and provides a cost-effective
tool to probe inside the extruder
Obtain data not otherwise available
Scale-up, process optimization
Eliminates „black box‟ concept
Quality by Design product/process development
Computer simulation can be used to model both solid
solution, solid dispersion and controlled release oral
solid dosage forms
Summary
42
Raw materials characterization for polymer/API remains a
challenge for any simulation/modeling technique
Multiple rheological models needed to simulate the
plasticizing effect of API‟s after polymer is molten
Requires polymer testing capabilities and expertise
Validation of simulation results requires resources and
commitment…
Summary - continued
22
43
Questions ?
44
Thank You !
