Evonik Industries 4 th International Symposium on Pharmaceutical Melt Extrusion Understanding Melt Extrusion Processes by Simulation Presented by Adam Dreiblatt Director, Process Technology 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 Correlates w/degradation Melt residence time Troubleshoot and optimize Accurately predict scale-up behavior 1
Simulation Strategy 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). 3 Simulation Strategy 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 4 2
What do we know about HME? Composition (Polymer + API + Excipients) Product Properties (e.g. Crystallinity, Dissolution, Stability) BLACK BOX 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) BLACK BOX 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 3
What do we know about the extruder? Composition (Polymer + API + Excipients) Feed rate (g/min) Product Properties (e.g. Crystallinity, Dissolution, Stability) Vacuum (mbar) Screw speed (rpm) Barrel / die temperature setpoints ( C) 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? Composition (Polymer + API + Excipients) Product Properties (e.g. Crystallinity, Dissolution, Stability) Temperature, Pressure Motor Load (kw) Barrel / die temperature (actual) ( C) We can measure average residence time, residence time distribution We can measure specific energy input (mechanical, thermal) 4
System Analytical Model for Twin Screw Extrusion* Shear Rate Shear Stress Molecular Structure Extrusion Parameters Key System Parameters Product Quality Attributes 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 *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! 5
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 12 6
Assemble virtual extruder Simulation Step 2 - Define Raw Materials 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 14 7
Example Eudragit L100-55* Rheology *20% TEC Plasticizer Simulation Step 3 - Define HME Process Screw speed Feed position Feed temperature Feed rate Temperature profile 16 8
Enter processing conditions Simulation Step 4 Analyze Results Degree-of-fill Melting Pressure Temperature Specific energy Residence time Viscosity Mixing 18 9
Discharge melt temperature is 178-179 C (note barrel temperature setpoints are 150 C ) Average residence time is 45 seconds Specific mechanical energy is 0.151 kwh/kg The tail of the RTD can lead to degradation, discoloration, etc. 10
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 11
Polymer Melting Critical to know WHERE polymer (API) is melting! Where Is Polymer Melting? 12
Polymer Melting vs Screw Speed Exact position where polymer is 100% molten at 300 rpm Melting of polymer occurs faster at higher screw speed Melt temperature is 135 C when polymer is 100% molten 13
Residence time for molten polymer (in contact with API) is 22 seconds Polymer Melting vs Feed Rate Polymer begins melting very early at very low feed rate Melting of polymer occurs faster at lower feed rate 14
Residence Time vs Feed Rate Exact position where polymer starts melting at low feed rate Mean residence time is a strong (non-linear) function of feed rate Melting vs Barrel Temperature Barrel heating has very little effect on melting in twin-screw extruders 15
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 16
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 17
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 18
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 19
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 20
Summary 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 41 Summary - continued 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 42 21
Questions? 43 Thank You! 44 22