APV 2 nd Experts Workshop

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1 APV 2 nd Experts Workshop Hot melt extrusion and its use in the manufacturing of pharmaceutical dosage forms December 1-2, 2009 Modeling of the extrusion process and prediction of scale-up and transfer behaviour Adam Dreiblatt Extrusioneering International, Inc.

2 Presentation outline Modeling strategy Simulation of hot melt extrusion process 1D simulation case study Transfer technology (i.e. scale-up ) Summary Extrusioneering International, Inc. 2

3 Why modeling? Limited availability and cost of API s Evaluate alternate machine configurations Evaluate process variables (virtual DOE) Obtain data not otherwise available Troubleshoot problems Scale-up Extrusioneering International, Inc. 3

4 Simulation strategy Several options available 3D modeling Response surface methodology 1D modeling Extrusioneering International, Inc. 4

5 3D modeling 3D finite element modeling 2D flow analysis network Rigorous treatment Accurate, detailed Limited to unit ops Resource intensive Image courtesy Century Extrusion, with permission Extrusioneering International, Inc. 5

6 Response surface methodology Rigorous treatment Accurate Limited extrapolation Resource intensive Image courtesy Bernhard Van Lengerich, with permission Extrusioneering International, Inc. 6

7 1D simulation Approximations Versatile Cost effective Integrated cross-section Image courtesy Mahesh Gupta (Peldom), with permission Extrusioneering International, Inc. 7

8 Modeling basis Extruders cannot differentiate between pharma polymers and traditional thermoplastics API s that do not melt are no different than filled thermoplastic compounds. Pharma solid dispersion is no different than polymer alloy. The extruder can only detect viscosity, degree-of-fill, pressure, etc Extrusioneering International, Inc. 8 Presented by: Adam Dreiblatt

9 Modeling basis 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). 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 Extrusioneering International, Inc. 9

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11 Modeling challenge Why Not Simulate Twin Screw Extrusion? Complex geometry + Complex rheology Precludes comprehensive treatment of complete process Extrusioneering International, Inc. 11

12 1D simulation example T F = Feed temperature of melt T B = Inner barrel surface temperature Density, Specific Heat = constant, independent of melt temp. Melt viscosity = strong function of temperature and shear rate Extrusioneering International, Inc. 12

13 Mass, momentum balance B dp q= AN +, 0< z< L η dz q = Volumetric melt flow (assumed uniform melt density) N = Screw rotation speed A, B = Characteristic for each screw component, function of (z) Melt viscosity = strong function of temperature and shear rate Extrusioneering International, Inc. 13

14 Energy balance Energy Balance dt dz = φη, 0< z< 2 q C N DU T TB ( ) L φ = Screw fill level U = Heat transfer coefficient between melt and barrel T B = Inner barrel surface temperature C, D = Known functions of geometry and physical properties Extrusioneering International, Inc. 14

15 Calculate axial temp, press Calculate p(z) and T(z), 0 < z < L Extruder geometry Material properties Operating conditions Defined Values Assumes p, T are function of z only T = cross-section average temperature Extrusioneering International, Inc. 15

16 Solving balance equations Boundary condition 1 p = p DIE at z = L Boundary condition 2 T = T F at z = 0 Problems: A,B = Complex function of (z), different for each screw component P(z) = Function of viscosity (strong function of temperature) T(z) = Function of screw fill level (φ = 1 if p > 0, φ < 1 if p = 0) Extrusioneering International, Inc. 16

17 Alternative solution Divide each screw component into computational elements More subdivisions assigned to active screw types N = total number of computational elements Extrusioneering International, Inc. 17

18 Alternative solution All coefficients, processing variables are a function of (z) Continuous Variables p (z), 0 < z < L T (z), 0 < z < L Discrete Point Values p i, i = 0, 1, 2, N T i, i = 0, 1, 2, N Extrusioneering International, Inc. 18

19 Alternative solution Boundary condition 1 Boundary condition 2 p N = p DIE T 0 = T F Bi pi q= AN i +, for i= 1,2,3,... N η z i i Ti 2 q = C ( ) iφη i in DU i iti TB, for i = 1,2,3,... N z i Extrusioneering International, Inc. 19

20 Iteration procedure step 1 Assume temperature profile T i, (i = 0, 1, 2, N) Extrusioneering International, Inc. 20

21 Iteration procedure step 2 Compute pressure drop through die/orifice (P DIE ) Extrusioneering International, Inc. 21

22 Iteration procedure - step 3 Pressure equation solved from i = N-1 to i = 1 Initial condition at i = N Compute viscosity at assumed T Compute screw fill level Extrusioneering International, Inc. 22

23 Iteration procedure step 4 Step 4: Temperature equation solved from i = 1 to i = N 1 Initial condition at i = 0 Based on computed screw fill level Extrusioneering International, Inc. 23

24 Compare computed results Computed T(z) compared to assumed T(z) If T, P profiles are within specified tolerance criteria Iteration ends Compute residence time, power, etc. Extrusioneering International, Inc. 24

25 Compare computed results Computed T(z) compared to assumed T(z) If T, P profiles do not meet specified tolerance criteria Assume new temperature profile Repeat calculations until convergence Extrusioneering International, Inc. 25

26 Simulation case study 34mm lab-scale extruder Leistritz LSM34, L/D = rpm screw speed 12.5 kg/hr feed rate Raw materials pre-granulated Polymer Plasticizer Surfactant API Extrusioneering International, Inc. 26

27 Define geometry Machine type Free volume Available power Geometric parameters Feeding and venting positions Screw configuration Die geometry Extrusioneering International, Inc. 27

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31 Define 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 Extrusioneering International, Inc. 31

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37 Define extrusion process Screw speed Feed position Feed temperature Feed rate Temperature profile Extrusioneering International, Inc. 37

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39 Analyze results Specific energy Discharge temperature Discharge pressure Residence time Extrusioneering International, Inc. 39

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41 Calibration of model Practical use of 1D simulation requires calibration of model results using empirical coefficients to match actual process data Melting Specific energy Melt temperature Extrusioneering International, Inc. 41

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43 Axial profiles Degree-of-fill Melting Pressure Temperature Specific energy Residence time Viscosity Mixing Extrusioneering International, Inc. 43

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53 Correlation of results 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 Pressure Ref: Bernhard Van Lengerich, PhD Thesis, Technical University of Berlin Physical Properties Crystallinity Morphology Bioavailability Rheology Mol. weight Mw Distribution Other Dissolution Color Extrusioneering International, Inc. 53

54 Scale-up Lab-scale process from 34mm machine was transferred to 50mm production line Leistritz ZSE50 extruder, L/D=36 Volume difference = 4X = 50 kg/hr Production machine different D o /D i Product requirement = 100% amorphous API has extreme thermal sensitivity, degradation level not to exceed lab scale Extrusioneering International, Inc. 54

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65 Prediction of position where melting is completed = 547.5mm Extrusioneering International, Inc. 65

66 Material temperature where melting is completed = 136 C Extrusioneering International, Inc. 66

67 Melt residence time can be identified (23 sec) Extrusioneering International, Inc. 67

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70 Prediction of position where melting is completed = 920mm Extrusioneering International, Inc. 70

71 Material temperature where melting is completed = 135 C Extrusioneering International, Inc. 71

72 Melt residence time can be identified (33.6 sec) Extrusioneering International, Inc. 72

73 Summary Commercial process successfully launched Lower discharge temperature and narrower RTD than lab-scale process (also lighter color) Different extruder geometry and screw design Specific energy same as lab-scale Product specifications (crystallinity, degradation products, dissolution) can be correlated with specific energy, residence time and thermal history Extrusioneering International, Inc. 73

74 Summary 1D process simulation for hot melt extrusion applications is commercially available and provides a cost-effective tool to probe deeper inside the extruder Expensive and scarce API s (kg quantities) Scale-up (translation between OEM machinery) Product and process optimization These simulation tools can be used to model both solid dispersion and controlled release oral solid dosage forms Extrusioneering International, Inc. 74

75 Summary Rheological characterization for polymer/api compositions remains a challenge for any simulation/modeling technique Extrusioneering International, Inc. 75

76 Thank You! Extrusioneering International, Inc. 76