Hot Melt ExtrusionTechnology

Kurt Kortokrax

Sales Account Manager

Thermo Fisher Scientific

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Agenda

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Introduction and Review of Extrusion

Pharmaceutical Grade Extrusion Systems

HME as a Beneficial Technology

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Summary and Discussion4

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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

1 2 3 4 Introduction and Review of Extrusion

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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

1 2 3 4 Introduction and Review of Extrusion

Application of Extrusion Technology

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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

1 2 3 4 Introduction and Review of Extrusion

Application of Extrusion Technology

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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

1 2 3 4 Introduction and Review of Extrusion

Application of Extrusion Technology

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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

Troglitazone® (Parke Davis)*

Kaletra® Meltrex® (Abbott)

NuvaRing® (Oragnon)

Implanon® (Schering-Plough)

Zoladex® (AstraZeneca)

Ozurdex® (Allergan)

…

* Removed from market in March of 2000

1 2 3 4 Introduction and Review of Extrusion

Application of Extrusion Technology

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Types of Extrusion Systems

Ram Single Screw Twin Screw

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.

1 2 3 4 Introduction and Review of Extrusion

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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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Types of Extrusion Compounding Systems

Twin Screw Classifications

• Design• Conical• Parallel

• Screw Rotation• Co-Rotating• Counter-Rotating

• Degree of Contact• Co/Counter Intermeshing• Counter Non-

Intermeshing

1 2 3 4 Introduction and Review of Extrusion

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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 – …

1 2 3 4 Introduction and Review of Extrusion

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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 – …

1 2 3 4 Introduction and Review of Extrusion

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Extrusion Detail - Dosing

1 2 3 4 Introduction and Review of Extrusion

• 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• VolumetricVolumetric

• 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.

• GravimetricGravimetric• 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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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 – …

1 2 3 4 Introduction and Review of Extrusion

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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 – …

1 2 3 4 Introduction and Review of Extrusion

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Extrusion Detail – Melting & Mixing

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Extrusion Detail – Melting & Mixing

• Shear Stress brings about the reduction in particle size of the ingredient (i.e. active component)

DispersionDispersion

• Division and recombination of the materials brings about general homogenization of the complete product

DistributionDistribution

• 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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Initial Materials

Polymer ExcipientPolymer Excipient

Additive (API)Additive (API)

Additive has been well distributed

Additive has been well dispersed

Homogeneous Compound

Distributive and Dispersive

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Extrusion Detail – Melting & Mixing

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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 – …

1 2 3 4 Introduction and Review of Extrusion

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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 – …

1 2 3 4 Introduction and Review of Extrusion

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Standard or Pharmaceutical Grade?

1 3 4 Pharmaceutical Grade Extrusion Systems2

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Standard or Pharmaceutical Grade?

1 3 4 Pharmaceutical Grade Extrusion Systems2

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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Where are the differences?

1 3 4 Pharmaceutical Grade Extrusion Systems2

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Specialized Materials of Construction, Design

1 3 4 Pharmaceutical Grade Extrusion Systems2

• 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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Specialized Materials of Construction, Design

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• 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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Disassembly – Accessibility to all Wetted Components

1 3 4 Pharmaceutical Grade Extrusion Systems2

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Disassembly – Accessibility of all Wetted Components

1 3 4 Pharmaceutical Grade Extrusion Systems2

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Disassembly – Accessibility to all Wetted Components

1 3 4 Pharmaceutical Grade Extrusion Systems2

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Disassembly – Accessibility to all Wetted Components

1 3 4 Pharmaceutical Grade Extrusion Systems2

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Mobility and Scale

1 3 4 Pharmaceutical Grade Extrusion Systems2

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Modularity – Barrel, Screw Design

1 3 4 Pharmaceutical Grade Extrusion Systems2

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Incorporation of Process Monitoring Technologies

On-LineIn-Line

At-Line

Off-Line

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Post Extrusion Handling – Air Cooling (Conveyor)

1 3 4 Pharmaceutical Grade Extrusion Systems2

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Post Extrusion Handling – Pelletizing

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Post Extrusion Handling – Chill Roll, Flaker

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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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Hot Melt Extrusion Parameters

Optimize Formulation• Excipient Ingredients

• Polymeric Binders• Plasticizers and Lubricants• Glidants• Fillers and Dilutents• Disintigrants• Antioxidants• etc.

• Active Pharmaceutical Ingredients

Optimize Process• Extrusion System

• System Scale• Length-to-Diameter Ratio• Barrel Configuration• Screw Configuration• Extrudate Forming Devices• Post-Extrusion Ancillaries

• Ingredient Introduction• Sequence of Addition• Rate of Addition

• Process Conditions• Screw Speed• Temperature Profile

• Monitoring Technology• On / In / At / Off - Line

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Extrusion System – System Scale

Chemistry MedicinalMedicinal Kilogram, Lab Process Chemistry Production Site Production Site

Process Batch

10 g10 g

(or less)(or less)

1 - 5 kg 5 – 50 kg 100 - 500 kg 500 kg

Process Outputs

10 g10 g

(or less)(or less)

0.5 – 2.5 kg/hr 0.5 – 2.5 , 5 – 50 kg/hr 5 - 50 kg/hr 5 – 50, 25 – 100 kg/hr

System Micro –Micro –

CompounderCompounder

16 mm HME 16, 24 mm HME 24 mm HME 24, 36 mm HME

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Extrusion System – System Scale

Chemistry Medicinal Kilogram, Lab Process ChemistryProcess Chemistry Production Site Production Site

Process Batch

10 g

(or less)

1 - 5 kg 5 – 50 kg5 – 50 kg 100 - 500 kg 500 kg

Process Outputs

10 g

(or less)

0.5 – 2.5 kg/hr 0.5 – 2.5 , 5 – 50 kg/hr0.5 – 2.5 , 5 – 50 kg/hr 5 - 50 kg/hr 5 – 50, 25 – 100 kg/hr

System Micro –

Compounder

16 mm HME 16, 24 mm HME16, 24 mm HME 24 mm HME 24, 36 mm HME

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Extrusion System – System Scale

Chemistry Medicinal Kilogram, Lab Process Chemistry Production Site Production Production SiteSite

Process Batch

10 g

(or less)

1 - 5 kg 5 – 50 kg 100 - 500 kg 500 kg500 kg

Process Outputs

10 g

(or less)

0.5 – 2.5 kg/hr 0.5 – 2.5 , 5 – 50 kg/hr 5 - 50 kg/hr 5 – 50, 25 – 5 – 50, 25 – 100 kg/hr100 kg/hr

System Micro –

Compounder

16 mm HME 16, 24 mm HME 24 mm HME 24, 36 mm 24, 36 mm HMEHME

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Extrusion System – Length-to-Diameter Ratio

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Extrusion System – Barrel Configuration

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16mm TSE, Single Feed at Main

24mm TSE, Feed at Main with Downstream Vertical

Stuffer Feeder and Peristaltic Liquid Injection

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Extrusion System – Barrel Configuration

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Extrusion System – Screw Configuration

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Extrusion System – Basic Screw Elements

• Conveying ElementsFeedingPumping, PressurizationBlending

• Mixing ElementsBlendingDispersive MixingDistributive Mixing

• Special ElementsZoning – Material and TemperatureRestrictive ElementsIncrease Residence Time

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Extrusion System – Forming Devices and Ancillaries

Granules

Pellets

Spheres

Powders

Tablets

Films

Sheets

Tubing

Plugs

Implants

Devices

…

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Ingredient Introduction - Processing Example

• Polymer Excipient & API at Primary Feed

• Low Temperature Application

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• Polymer Excipient at Primary Feed, API Introduced Downstream

• Thermally Sensitive API

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Ingredient Introduction - Processing Example

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• Polymer Excipient 1 at Primary Feed along with Plasticizer

• Polymer Excipient 2 Introduced Downstream

• API Introduced Downstream

• Vacuum Venting Applied

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Ingredient Introduction - Processing Example

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Process Conditions – Temperature Profile

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Process Conditions – Temperature Profile

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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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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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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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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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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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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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Thank you all for your attention.

Questions?Questions?

Kurt KortokraxSales Account ManagerMaterial CharacterizationThermo Fisher ScientificChemical Analysis Division

 tel. (817) 444-7848cell (817) 694-0027

Kurt.kortokrax@thermofisher.comwww.thermo.com/mc

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