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Continuous Granulation using Twin Screw Extruders A modular approach to increase your yield in pharmaceutical production. Dirk Leister, TFS, Leader Application Group Raoul Pila, Glatt, Product Development Engineer

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Combine Expertise for your success

•$ 10+ billions in revenue • 37.000 employees • 350.000 customers

• Establishing extrusion technologies in thepharmaceutical industry

• Hot Melt Extrusion • Wet Granulation

• Glatt group 1.500+ employees • represented in 20+ companies worldwide

• Market leader in integrated process solutions for solid dosage forms

• Drying • Granulation • Coating

One stop shop for tablet production

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Content

• Granulation Technology • Purpose and batch technologies

• Continuous Granulation

• From blending to tableting • Modular Approach • Benefits

• Core Technology

• Twin Screw Granulator • Continuous Fluid Bed Dryer

• Experimental Data

• Achema 2012

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Purpose of Granulation

• Granulation is a size enlargement process of particles

• To prevent segregation of the constituents of the powder mix

• Aid downstream processing by improving the physical characteristics of the mix in terms of:

• Flow • Density • Dustiness • Compressibility • etc.

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Granulation

Wet granulation involves the agglomeration of a mix of dry primary powder particles using a granulating fluid.

The fluid, which is added during the granulation step, must be pharmaceutically safe and volatile enough so that it can be evaporated by a subsequent drying step.

In Melt granulation the binding fluid is created by heating

the formulation and causing one or more of the dry ingredients to become molten. Cooling the mix at the end of the granulation step solidifies the molten binder.

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Batch Granulation Technology

• Traditional batch processes • High shear mixers • Roll Compaction • Fluidised bed granulation

• Risks of Batch to batch variation require careful and complex procedures and controls. • Method and order of charging ingredients • Time and technique for introduction of binders • Definition of end point

• Large scale equipment needed in development to reduce risk of scale-up.

• Large quantities of expensive API (Active Pharmaceutical Ingredient) required

• Difficulty to produce small samples on production scale equipment.

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Comparison of materials – example of batch mixed granules

0

5

10

15

20

25

30

35

40

45

50

0 53 75 90 150 250 355 500 710 850 1000

Sieve size (microns)

Wt %

on

siev

e

Variable quantities of coarse material Between 2-14% @ 500 micron

characteristic peak @ 90-150 microns

Fines variable 2-18%

Source ISPE Conference John Robertson GlaxoSmithkline

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Comparison of materials – example of batch mixed granules

0

5

10

15

20

25

30

35

0 53 75 90 150 250 355 500 710 850 1000

Much lower variability at coarse end

Lower variability in fines

Potential for more consistent process ! Source ISPE Conference John Robertson GlaxoSmithkline

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Batch vs. Continuous Granulation

3-10 litre

65-150 litre

300-600 litre

Pharmalab 24mm

Phase 1

Phase 2

Phase 3

Phase 1

Phase 2 and

Phase 3

Pharmalab 16mm

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Thermo Fisher Pharmaceutical Extruders

Phase 0 Preclinical Phase

1 Phase 2 Phase 3 Regulatory

Approval Launch

Chemistry Medicinal Kilogramme Lab

Process Chemistry Development

Production Development

Commercial Manufacturing

Available API

mg - g 1-10 kg 10 – 100 kg 1,000 kg 1,000 kg

Process Batch

20 g 1 – 5 kg 5 – 50 kg 100 – 500 kg 1,000 kg

Twin screw Extruder

Pharma 11

Pharma 16 Pharma 16 Pharma 24

Pharma 24

Pharma 24 Pharma 36

Process Output

20 g 1 – 5 kg/h 1 – 5 kg/h 5 – 25 kg/h

5 – 25 kg/h

5 – 25 kg/h 25-100 kg/h

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Benefits and Advantages of a Continuous Process

• Easier to enclose the whole process • Smaller scale equipment • Small Footprint

• Flexibility of batch size • Small amount of materials in process • Improved control and consistancy

• Elimination of dispensing • Reducing risk of operator error in weighing out ingredients. • Reduced handling of / exposition to all ingredients • Reduce labour cost

• Possibility of implementing PAT • Automation • Process understanding

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How can a continuous, modular approach look like

Grav Feeding Grav liquid addition

Twin Screw Granulator Fluid Bed Dryer

Grav Feeding

Mixing

Tabletting

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Core processes for cont granulation

Grav Feeding Grav liquid addition

Twin Screw Granulator Fluid Bed Dryer

Grav Feeding

Mixing

Tabletting

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Pharma 16 Twin Screw Granulator

Pharma16 TSG Twin Screw Granulator

Gravimetric Screw Feeder

Liquid Feeding Pump

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Pharma 16 TSG with powder bridge braker

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Pharma 16 TSG showing discharge area

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PharmaLab 16 Barrel Close-Up

Flexible Extrusion Equipment 1 2 3

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Barrel Clamps Removed

Flexible Extrusion Equipment 1 2 3

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Barrel Top Half and Screws Removed

Flexible Extrusion Equipment 1 2 3

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Lower Barrel Front Section Removed

Flexible Extrusion Equipment 1 2 3

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All Lower Barrel Sections Removed

Flexible Extrusion Equipment 1 2 3

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flexible screw configuration

Pharma 16 HME - maximum flexibility…

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Conveying elements:

Profiles with long helix are used:

- in the feeding sections - - for degassing (venting)

Profiles with short helix are used:

- for high pressure built up - in front of kneading elements

Pharma 16 HME - Screw Elements:

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Mixing Elements :

• Mixing Elements are used to introduce shear energy to the extruded materials.

• The disks are arranged in different offset angles used for: - shearing - mixing - dispersing

Pharma 16 HME - Screw Elements:

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Distributive Flow Elements :

Pharma 16 HME - Screw Elements:

• Distributive Flow Elements are special mixing elements, used for the distribution of small quantities of additives and shear sensitive materials.

• Used to break up agglomerated granules.

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Pharma 24 Twin Screw Granulator

Pharma 24 TSG Twin Screw Granulator

Gravimetric Screw Feeder

Gravimetric Liquid Feeding

Pump

Crammer Feeder

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Pharma 24 TSG with feeder platforms

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Continuous Fluid Bed Drying

• Principle theory of continuous fluid bed drying

wet granules

process air for fluidization

and drying

dry granules

expansion chamber

processing chamber

inlet air chambers bottom screen discharge pipe

integrated filter system

process air for fluidization

and drying

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Continuous Fluid Bed Drying

• Equipment size

throughput < 15 kg/h > 10 kg/h

shape round rectangular name GF 5 GF 25, 50 & 125

implementation Insert for GPCG 2 LabSystem stand-alone machine

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Continuous Fluid Bed Drying

• Principle GF5: ring-shaped process chamber

material input

material discharge

outer wall

process chamber (annulus)

displacement body

divider partition

Homogeneous material flow

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Continuous Fluid Bed Drying

• Process development with GPCG 2 LabSystem

• Batch drying

• Top spray granulation

• Wurster coating

• CPS Pelletization

• Rotor Pelletization

• NEU: Continuous Drying

Process overview

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Continuous Fluid Bed Drying

• GPCG 2 LabSystem with GF5

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Experimental Data

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Experimental Data

Formulation : Qty (kg)

Proportions (%)*

API 8.0369 80.369

Aerosil 0.0557 0.557

Sodium starch glycolate 1.003 10.030

Cellulose MRK (microcr. Cellulose) 0.5701 5.701

Hypromellose Pharmacoat 603 (HPMC) 2.3400 3.343

Barrel Temperature 35°C Pure water as liquid addition

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Experimental Data

Parameters X1

Screw speed [rpm]

X2 Spray rate [g/min]

X3 Kneading element config.

[°]

-1 low

300 28 7x30, 1x60

0 center

450 31 5x30, 3x60

+1 high

600 35 3x30, 5x60

6 consecutive experiments DoE with Parameters X1, X2 and X3

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Experimental Data

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1,8

2,0

0 200 400 600 800 1000 1200 1400 1600 1800 2000

Ver

teilu

ngsd

icht

e / d

istr

ibut

ion

dens

ity

q3 [*

1000

/µm

]

Partikelgröße / particle size [µm]

Run 1 Run 2 Run 3 Run 4 Run 5 Run 6

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Achema 2012 Set-Up

• Achema • 18th – 22nd July, Frankfurt (Germany) • Hall 3.0 Booth F1

• Pharma 16 TSG • GPCG2 with GF-5

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Thank you for your attention !

Any questions ?

Looking forward to see you at Achema !