The document discusses hot melt extrusion technology for pharmaceutical applications. It provides an overview of extrusion systems and processes, including different types of extruders and their components. Hot melt extrusion is described as a beneficial processing technology for manipulating ingredients to create materials with unique properties. Key benefits of hot melt extrusion for pharmaceuticals include enhanced solubility, bioavailability and specific drug release characteristics of active pharmaceutical ingredients. Process parameters and considerations for optimizing hot melt extrusion are also reviewed.

1. Hot Melt Extrusion
Technology
Kurt Kortokrax
Sales Account Manager
Thermo Fisher Scientific

2. Agenda
1 Introduction and Review of Extrusion
2 Pharmaceutical Grade Extrusion Systems
3 HME as a Beneficial Technology
4 Summary and Discussion
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3. Application of Extrusion Technology
Extrusion is a well-known processing technology which
has been developed over the last century and has found
beneficial application in many diverse industrial fields.
• Polymer
• Ceramic / Metal
• Food
• Cosmetic
• Pharmaceutical
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4. Application of Extrusion Technology
Extrusion is a well-known processing technology which
has been developed over the last century and has found
beneficial application in many diverse industrial fields.
• Polymer
• Ceramic / Metal
• Food
• Cosmetic
• Pharmaceutical
4/58 1 2 3 4 Introduction and Review of Extrusion

5. Application of Extrusion Technology
Extrusion is a well-known processing technology which
has been developed over the last century and has found
beneficial application in many diverse industrial fields.
• Polymer
• Ceramic / Metal
• Food
• Cosmetic
• Pharmaceutical
5/58 1 2 3 4 Introduction and Review of Extrusion

6. Application of Extrusion Technology
Extrusion is a well-known processing technology which
has been developed over the last century and has found
beneficial application in many diverse industrial fields.
• Polymer
• Ceramic / Metal
• Food
• Cosmetic
• Pharmaceutical
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7. Application of Extrusion Technology
Extrusion is a well-known processing technology which
has been developed over the last century and has found
beneficial application in many diverse industrial fields.
• Polymer  Troglitazone® (Parke Davis)*
• Ceramic / Metal  Kaletra® Meltrex® (Abbott)
 NuvaRing® (Oragnon)
• Food  Implanon® (Schering-Plough)
• Cosmetic  Zoladex® (AstraZeneca)
• Pharmaceutical  Ozurdex® (Allergan)
…
* Removed from market in March of 2000
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8. Types of Extrusion Systems
Extrusion is a process which is used to create new materials
with desirable properties by manipulating additive ingredients
through a number of staged unit operations and forcing the
product through a defined die geometry.
Ram Single Screw Twin Screw
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9. Hot Melt Extrusion is Extrusion Compounding
Two or more ingredients which have been combined in defined
proportions, distinguishable from their original state in that the
characteristics of the whole is unique from that of the original
constituents.
• Mechanical Properties
• tensile strength, bending strength, hardness, fracture toughness
• Physical Properties
• color, odor, density, melting/freezing/boiling point, glass transition, solubility
• Electrical Properties
• electrical resistance, dielectric constant
• Chemical Properties
• flammability, biodegradability
• Thermal Properties
• thermal conductivity, specific heat, thermal shock resistance
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10. Types of Extrusion Compounding Systems
• Design
• Conical
• Parallel
• Screw Rotation
• Co-Rotating
Twin Screw Classifications • Counter-Rotating
• Degree of Contact
• Co/Counter Intermeshing
• Counter Non-
Intermeshing
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11. Extrusion Detail
Extrusion is a process which is used to create new materials
with desirable properties by manipulating additive ingredients
through a number of staged unit operations…
Dosing – Metering – Melting – Mixing – Venting – Pumping – Forming – …
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12. Extrusion Detail - Dosing
Extrusion is a process which is used to create new materials
with desirable properties by manipulating additive ingredients
through a number of staged unit operations.
Dosing – Metering – Melting – Mixing – Venting – Pumping – Forming – …
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13. Extrusion Detail - Dosing
• Type of Feeding System
• Single Screw (pellet, flake, granule, powder)
• Twin Screw (powder, …)
• Liquid Injection (fluid, solution, …)
• Piston (paste, rubber, …)
• Forcefeeder / Stuffer (downstream)
• Design of Feeding System
• Volumetric
• Operate at Constant Screw Speed to delivery a Constant Volume per
Unit Time
• Accuracy +/- 2% of Set Point
• Mass Flow can be Subject to Variation due to Material Density, Refilling
Stages, Batch Variation/Homogeneity, etc.
• Gravimetric
• Automatic Adjustment of Feeder Speed based upon Feedback of
Incorporated Load Cell
• Accuracy +/- 0.5% of Set Point
• Control in Feeding of a Twin Screw Extruder is Critical!
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14. Extrusion Detail - Metering
Extrusion is a process which is used to create new materials
with desirable properties by manipulating additive ingredients
through a number of staged unit operations.
Dosing – Metering – Melting – Mixing – Venting – Pumping – Forming – …
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15. Extrusion Detail – Melting & Mixing
Extrusion is a process which is used to create new materials
with desirable properties by manipulating additive ingredients
through a number of staged unit operations.
Dosing – Metering – Melting – Mixing – Venting – Pumping – Forming – …
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16. Extrusion Detail – Melting & Mixing
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17. Extrusion Detail – Melting & Mixing
• Shear Stress brings about the reduction in particle size
of the ingredient (i.e. active component)
 Dispersion
• Division and recombination of the materials brings about
general homogenization of the complete product
 Distribution
• For a given screw speed, the highest shear stress occurs when the
viscosity of the material is at its highest, thus promoting dispersive mixing
• Blending and cross-flow action in low shear environments can promote
distributive mixing
• Proper screw design in terms of element selection, configuration, and
orientation enables both dispersive and distributive mixing
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18. Extrusion Detail – Melting & Mixing
Distributive and Dispersive
Additive has been
well distributed
Initial Materials
Polymer Excipient
Homogeneous
Additive (API) Compound
Additive has been
well dispersed
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19. Extrusion Detail - Venting
Extrusion is a process which is used to create new materials
with desirable properties by manipulating additive ingredients
through a number of staged unit operations.
Dosing – Metering – Melting – Mixing – Venting – Pumping – Forming – …
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20. Extrusion Detail – Pumping & Forming
Extrusion is a process which is used to create new materials
with desirable properties by manipulating additive ingredients
through a number of staged unit operations.
Dosing – Metering – Melting – Mixing – Venting – Pumping – Forming – …
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21. Standard or Pharmaceutical Grade?
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22. Standard or Pharmaceutical Grade?
Parallel Co-Rotating Twin Screw Extrusion Systems
• Barrel Diameter – 16 mm
• Barrel Length – 25:1 L/D
• Typical Output – 0.5 – 5.0 kg/hr
• Modular Clamshell Barrel, Modular Screw Design
•…
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23. Where are the differences?
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24. Specialized Materials of Construction, Design
• Stainless Steel Shrouding
• Smooth Edges / Minimal
Contamination Points
• Non-Painted Surfaces
• Sealed Access Panels
• Touchscreen Controls
• Pressurized Internal
Compartments
• Spray-Down Capability
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25. Specialized Materials of Construction, Design
• Specific MoC for all Parts
in Contact with Product
• Barrel (top/bottom)
• Screws
• Hoppers, Funnels
• Dies
• Specialized Clamping
Mechanisms
• Quick-Release Interlocks
for Heating, Cooling
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26. Disassembly – Accessibility to all Wetted Components
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27. Disassembly – Accessibility of all Wetted Components
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28. Disassembly – Accessibility to all Wetted Components
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29. Disassembly – Accessibility to all Wetted Components
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30. Mobility and Scale
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31. Modularity – Barrel, Screw Design
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32. Incorporation of Process Monitoring Technologies
In-Line
On-Line
At-Line
Off-Line
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33. Post Extrusion Handling – Air Cooling (Conveyor)
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34. Post Extrusion Handling – Pelletizing
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35. Post Extrusion Handling – Chill Roll, Flaker
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36. Why Melt Extrusion?
 Challenges
 Solubility Enhancement
− Biopharmaceutical Classification System, Class II & IV
 Bioavailability Enhancement
 Specific Release Characteristics
 Benefits
 Mechanical Shear Energy
 No Curing or Drying due to Solvent Free Process
 High Distributive / Dispersive Mixing Capability
 Stabilization of API in Defined Form
− Solid Suspensions - A / C , A / A ; Solid Solution – A / A
 Continuous Process
− Lower Batch to Batch Variation
 Process Monitoring Capabilities
 Creation of Unique Dosage Concepts / Delivery Methods
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37. Hot Melt Extrusion Parameters
Optimize Formulation Optimize Process
• Excipient Ingredients • Extrusion System
• Polymeric Binders • System Scale
• Plasticizers and Lubricants • Length-to-Diameter Ratio
• Glidants • Barrel Configuration
• Fillers and Dilutents • Screw Configuration
• Disintigrants • Extrudate Forming Devices
• Antioxidants • Post-Extrusion Ancillaries
• etc. • Ingredient Introduction
• Active Pharmaceutical • Sequence of Addition
Ingredients • Rate of Addition
• Process Conditions
• Screw Speed
• Temperature Profile
• Monitoring Technology
• On / In / At / Off - Line
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38. Extrusion System – System Scale
Chemistry Medicinal Kilogram, Lab Process Chemistry Production Site Production Site
Process 10 g 1 - 5 kg 5 – 50 kg 100 - 500 kg 500 kg
Batch (or less)
Process 10 g 0.5 – 2.5 kg/hr 0.5 – 2.5 , 5 – 50 kg/hr 5 - 50 kg/hr 5 – 50, 25 – 100
Outputs (or less) kg/hr
System Micro – 16 mm HME 16, 24 mm HME 24 mm HME 24, 36 mm HME
Compounder
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39. Extrusion System – System Scale
Chemistry Medicinal Kilogram, Lab Process Chemistry Production Site Production Site
Process 10 g 1 - 5 kg 5 – 50 kg 100 - 500 kg 500 kg
Batch (or less)
Process 10 g 0.5 – 2.5 kg/hr 0.5 – 2.5 , 5 – 50 kg/hr 5 - 50 kg/hr 5 – 50, 25 – 100
Outputs (or less) kg/hr
System Micro – 16 mm HME 16, 24 mm HME 24 mm HME 24, 36 mm HME
Compounder
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40. Extrusion System – System Scale
Chemistry Medicinal Kilogram, Lab Process Chemistry Production Site Production
Site
Process 10 g 1 - 5 kg 5 – 50 kg 100 - 500 kg 500 kg
Batch (or less)
Process 10 g 0.5 – 2.5 kg/hr 0.5 – 2.5 , 5 – 50 kg/hr 5 - 50 kg/hr 5 – 50, 25 –
Outputs (or less) 100 kg/hr
System Micro – 16 mm HME 16, 24 mm HME 24 mm HME 24, 36 mm
Compounder HME
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41. Extrusion System – Length-to-Diameter Ratio
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42. Extrusion System – Barrel Configuration
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43. Extrusion System – Barrel Configuration
16mm TSE, Single Feed at 24mm TSE, Feed at Main
Main with Downstream Vertical
Stuffer Feeder and Peristaltic
Liquid Injection
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44. Extrusion System – Screw Configuration
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45. Extrusion System – Basic Screw Elements
• Conveying Elements
Feeding
Pumping, Pressurization
Blending
• Mixing Elements
Blending
Dispersive Mixing
Distributive Mixing
• Special Elements
Zoning – Material and Temperature
Restrictive Elements
Increase Residence Time
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46. Extrusion System – Forming Devices and Ancillaries
 Granules
 Pellets
 Spheres
 Powders
 Tablets
 Films
 Sheets
 Tubing
 Plugs
 Implants
 Devices
…
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47. Ingredient Introduction - Processing Example
• Polymer Excipient & API at Primary Feed
• Low Temperature Application
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48. Ingredient Introduction - Processing Example
• Polymer Excipient at Primary Feed, API Introduced
Downstream
• Thermally Sensitive API
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49. Ingredient Introduction - Processing Example
• Polymer Excipient 1 at Primary Feed along with Plasticizer
• Polymer Excipient 2 Introduced Downstream
• API Introduced Downstream
• Vacuum Venting Applied
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50. Process Conditions – Temperature Profile
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51. Process Conditions – Temperature Profile
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52. Monitoring Technology (PAT)
• Off-Line
• A measurement with a sample which has been removed from the
process stream; analysis is not local to process stream.
• At-Line
• A measurement with a sample which has been removed from the
process stream for analysis; analysis is local to process stream.
• On-Line
• A measurement where the sample is diverted from the process
stream, analyzed, and possibly returned to the process stream.
• In-Line
• A measurement where the sample is not removed from the process
stream; analysis can be invasive or noninvasive.
* Source: Food and Drug Administration. ‘Guidance for Industry PAT...’. 9. (generalized)
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53. Beneficial Properties of Twin Screw Extruders
Twin Screw Extruders are “Sanitary” Systems *
• Self-Wiping Screw Design
The selection of TSE type and screw orientation can ensure that material is
continuously exchanged on metal surfaces of the extruder to avoid stagnation.
• Materials of Construction Compliant with FDA Regulations
“… Equipment shall be constructed so that surfaces that contact components, in-
process materials, or drug products shall not be reactive, additive, or absorptive so as
to alter the safety, identity, strength, quality, or purity of the drug product…” **
• Unique Modifications from Standard “Plastics” Systems
Complete access to all components in contact with product; removable screws and
barrel ‘liners’ for thorough and simplistic cleaning of contact components; ability to
dedicate parts to process; etc…
* Source: Ghebre-Sellassie I, Martin C. Pharmaceutical Extrusion Technology. Marcel Dekker 2003; 69-71
** Source: Food and Drug Administration. Code of federal regulations. 21 CFR Parts 210 and 211. Fed Regist 1993
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54. Beneficial Properties of Twin Screw Extruders
Twin Screw Extruders are Continuous Systems *
• Continuous Process Run to Job Completion
The TSE facilitates continuous manufacture of a product; the quantity produced in the
run is specific as per the application requirement.
• Promotion of Process Stability and Reproducibility
A continuous, uninterrupted process has less risk of being influenced by external,
uncontrollable factors (transition between batch / unit operations, cleanliness
between batch runs, …)
• Systems Available to Match Capacity Requirements
A wide range of TSE systems are available to match the capacity requirement for the
application – from 10 grams/hr to 100 kg/hr (for example).
* Source: Ghebre-Sellassie I, Martin C. Pharmaceutical Extrusion Technology. Marcel Dekker 2003; 69-71
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55. Beneficial Properties of Twin Screw Extruders
Twin Screw Extruders Process “Small Masses” of Material *
• Mass of Material is Contained by Screw Geometries, Barrel Walls
Within a TSE small quantities of material are continually being acted upon within each
stage of the extrusion process. This intimate interaction with smaller, localized
quantities promotes the capacity to effect the material more efficiently and quickly when
compared with large mass, batch mixing vessels. In addition, the smaller localized
quantities of material provide an increase in exposed surface area to the screws and
barrel walls in comparison with exposed area in large batch vessels - the increased
surface area will result in improved heat transfer and tighter temperature control.
• Reduction of Risk in Production / Process Failure
A smaller inventory of in-process material allows for rapid reaction to production
instability or failure. Through continuous monitoring of the extrusion process and
additionally the implementation of Process Analytical Technologies (PAT), detrimental
situations can be recognized and remedied quickly and with minimal time and material
loss.
* Source: Ghebre-Sellassie I, Martin C. Pharmaceutical Extrusion Technology. Marcel Dekker 2003; 69-71
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56. Beneficial Properties of Twin Screw Extruders
Twin Screw Extruders Perform Multiple Unit Operations
• Multiple Unit Operations can be Performed
Through application-specific design selection of the TSE – including size, barrel
length, barrel configuration, and screw configuration – a number of unit operations
can be sequenced as necessary to perform many of the manufacturing steps
required for the product.
Dosing – Blending – Melting – Mixing – Venting – Pumping – Drying – …
• TSE’s are Designed for Flexibility, Modularity
Borrowing from their traditional existence in Polymer and Food applications, many
TSE’s have been designed specifically to allow for modification (unit operations
added, existing operations expanded) to improve upon the process. This feature is
inherent with modular barrel and screw designs.
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57. Concluding Remarks
• Extrusion is a well-established processing technology which
has found beneficial application in many diverse fields.
• The objective in extrusion is to modify input ingredients to
create a product with desirable properties (material, final
form).
• Extrusion combines multiple unit operations in a continuous,
uninterrupted process.
• Twin Screw Extruders are very modular and adaptive,
allowing for application-specific process design.
• Twin Screw Extruders offer many beneficial properties which
lend specifically towards pharmaceutical processing and
manufacturing.
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58. Thank you all for your attention.
Questions?
Kurt Kortokrax
Sales Account Manager
Material Characterization
Thermo Fisher Scientific
Chemical Analysis Division
tel. (817) 444-7848
cell (817) 694-0027
Kurt.kortokrax@thermofisher.com
www.thermo.com/mc
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