Hot Melt Extrusion Processing

for the Pharmaceutical Industry

Dr Rod Bottom

Sales Account Manager, Process-Pharma

Rod.Bottom@thermofisher.com

Topics

• Introduction

• Challenges in pharmaceutical formulation development

• Overview of melt extrusion

• Solid dispersions

• Examples of HME polymers

• Laboratory and production scale extruders

• Minilab

2

• Minilab

• Pharmalab

• Process Analytics for Hot Melt Extrusion

• QBD and PAT

• NIR for PAT

• Feasibility example

• Process mastercurve example

• Conclusions and questions

What is your challenge today?

Taste masking

Poor solubilityLimited by your API

3

New delivery methods

New capsule materials

New dosageconcepts

Biopharmaceutics Classification Scheme

Class II Class ILow Solubility

High Permeability

High Solubility

High Permeability

Pe

rme

ab

ility

90%

4

Class IIIClass IVHigh Solubility

Low PermeabilityLow Solubility

Low Permeability

Pe

rme

ab

ility

Solubility

0.1 mg/ml

Why use Hot Melt Extrusion technology?

• different applications: sustained release, solubility enhancement, taste masking

• anhydrous process, no solvents

• simple process (limited number of process steps, single step?)

• short residence time

• different dosage forms (depending on shape of the die and downstream processing equipment): tablets, granules, pellets, films, ...

5

processing equipment): tablets, granules, pellets, films, ...

• continuous process (high throughput)

• in-line monitoring possibilities

• co-extrusion (e.g. manufacturing of high-precision medical devices)

Downstreaming

The Melt Extrusion Process

Compounding/Extrusion

Feeding

6

Examples of some screw elements

• For nearly all mixing applications a well dispersed and well distributed mixture is required.

• Distributive mixing can be achieved by splitting and reorienting the flow repeatedly

7

repeatedly

• Dispersive mixing can be achieved by passing the mixture through small regions of intense deformation.

Mixing and composites, M. Kontopoulous Chee 18.2. p. 390presentation Queens Univers

What are we doing by Melt Extrusion?

Polymeric thermoplastic carrier

Drug

Plasticiser

8

Filler

etc.

…we are preparing a solid dispersion

Binary Solid Dispersions by Melt processing

Extrudate is a: Solid crystalline

suspension

Solid glassy

suspension

Solid glassy solution

Polymer Phase A A A

Drug Phase is C A A

Appearance Opaque Translucent Translucent

Extrudate

9

A DSC will find Tg + Fp 2 x Tg 1 x Tg

Expected stability Thermodynamically

stable

Due to clusters of

amorphous drugs

tendency to be

instable �

recrystallization

- Dependent on

kinetic

Can be stable if drug

migration is stopped

by:

1. hydrogen bonding

2. ‘freezing” due to

high Tg

-Stable until csaturation

- Above csaturation :

kinetically controlled

Solid Dispersion – Characterisation

Global characterisation tools

• DSC/MTDSC/TGA

• PXRD

• NIR/IR/Raman

• SS-NMR

10

Localised characterization tools

• SS-NMR

• Scanning probe & imaging

based techniques

(e.g. AFM, SEM, LTA, PT-MS)

• IR/Raman imaging

Hot melt extrusion polymers

• Polymers

• e.g. methacrylate polymers, cellulose derivatives, PEO, PEG, PVA, waxes,

lipids, PVP, copovidone, PEG/PVA graft polymers, poloxamer, PVAc,

EVA, silicone, PVP/VA

• - requirements:

• - thermoplastic behaviour

• - suitable Tg

• - high degradation temperature

11

• - high degradation temperature

• - low toxicity

• Plasticisers

• - e.g. triethyl citrate, PEG, dibutyl sebacate, propyleneglycol, diethyl

phtalate,dibutyl phtalate, glycerol monostearate, ...

• - reduce Tg and melt viscosity to improve workability and flexibility of

polymer

• - smooth surface of extrudate (no sharkskinning, stick/slip effect)

Hot melt extrusion polymers

Example of some BASF polymer properties

12

Equipment for hot melt extrusion

Easy handling & cleaning,track record

Formulation & Process Development, Clinical Trial, Full Production

Formulation DevelopmentProof of concept

Small amount of compounds

13

PRISM PHARMALABHAAKE MiniLab

The MiniLab

HAAKE MiniLab – suitable e.g. for

� Proof of concept studies

� Creating specimen for drug delivery systems

� Your advantages of a Micro Compounder

� Substantial cost savings for proof of concept studies due

to compounding of small quantities of ingredients (5 ml)

� Understanding of material characteristics by documenting

structural changes via integrated viscosity measurement

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structural changes via integrated viscosity measurement

� Flexible process conditions for different materials by

� Using conical counter or co- rotating screws

� Automatic bypass operation for

extrusion/recirculation

� Force feeder especially for continuous powder

feeding

Pharma MiniLab for small scale production

HAAKE Pharma MiniLab

� Allows you e.g. to produce clinical trial

samples for e.g. phase 1 when only a few

grams of clinical material is needed

� No time delay due to long process

development on a larger twin screw

extruder

� The characteristics of our GMP Version are

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� The characteristics of our GMP Version are

� Without backflow channel

� Force feeder for powder and small

pellets

� Stainless steel materials without

painted parts

� Password protected controls

Equipment for hot melt extrusion

Easy handling & cleaning,track record

Formulation & Process Development, Clinical Trial, Full Production

Formulation DevelopmentProof of concept

Small amount of compounds

16

PRISM PHARMALABHAAKE MiniLab

Pharmalab 16 and Pharma 24 Extrusion Lines

• 16 and 24mm parallel twin screw extruders

• Output 5-20 Kg/hour

• Multiple feeding ports

• Fully configurable screws

• Complete line of post-extrusion ancillary systems

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ancillary systems

Pharmalab 16 Hot Melt Extruder

Pharmalab 16 HMEProcess development studiesProducing samples for Clinical Trials

Advantages of a Pharmalab HMESubstantial cost savings for process

development from compounding of samples

(from 200g)

Significant time savings from ability to process

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Significant time savings from ability to process

multiple samples in succession.

Flexible process configurations for different

materials from segmented screws and barrels.

Opportunities for multiple feed streams to

minimise use of expensive API.

Special feeding accessories for difficult to handle

ingredients.

QbD (Quality by Design) and PAT (Process Analytical Technologies) - The Link

QbD is included in FDA‘s Pharmaceutical CGMP Initiative for the21st Century - a Risk Based Approach

Quality-by-Design

Raw

Materials

Weighing

Feeding

Extrusion Down-streaming

Product

?? ?? ?? ?? ?? ?? ?? ??

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PAT 2 PAT 5 PAT 8PAT 1 PAT 3 PAT 4 PAT 6 PAT 7

• Development: PAT supports RA to identify the risks

• Manufacturing: PAT helps to monitor quality on critical process points

?? ?? ?? ?? ?? ?? ?? ??

Likely Question to be answered by PAT ihn HME

Solid Dispersion

Modification

of Drug:Modification I

Modification II …

Drug stage:

Moisture Content

Homogeinity

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crystalline or

amorphous?

ImpuritiesExist?

Which?

Concentration?

Homogeinity

Interactions, or

modifications

during processing

On-line, In-line, At-line, Off-line…?

MFR

NIR

In-line

On-line

21

At-linebeside the line

simultanuously

Off-linein separate lab

later

• Speed: Answers in seconds / real-time information

• No offline-sampling, no sample preparation, no reagents or disposables(other techniques require making solutions or otherwise preparing a sample)

• Multiple analyses per scan (API content, moisture, ...)

Reasons for NIR as PAT for Melt Extrusion

• Provides physical and chemical picture of the process

• High instrument precision, good signal/noise ratio

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• Non invasive, non destructive(Sample and process are not influenced by the measurement)

• Ease of use

• Rugged and robust

• Adaptable to fibre optics (Instrument and sample can be hundreds of meters apart)

Near Infrared

�NIR spectral information is useful in many industries but

usually needs to be processed by a computer

�NIR analysers are simple to use and do not require a

chemist or scientist, only an operator

• Vibrational spectroscopy is made easy

• Push-button solutions for Near IR analysis

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• Push-button solutions for Near IR analysis

• One of the reasons Near IR succeeds in process where others fail

Sampling Points on the Extruder

NIR probe at the

extruder end

NIR probe in feeder hopper

and liquid feeding system

24

NIR probe at the

spheronization

and compression

Custom Probe

• Custom reflectance probe commissioned to fit the standard

thread (1/2”-20 UNF) on outlet of continuous extruder

25

Pharma 16 HME Twin-screw extruder with coupled ThermoFisher Antaris MX FT-NIR spectrometer

26

Feasibility Study

• Base mix of Kollidon (polyvinyl acetate/polyvinyl pyrrolidone) and lactose

• Drug blend added at 10% increments

• Extruder run at 140oC

27

• Six readings taken at each concentration change – several readings required before mixture stabilised

Spectra Raw Materials – Room Temperature

• Raw material powders scanned with probe at room temperature

blend batch 1

collidon

lactose

-0.20

-0.15

-0.10

-0.05

Drug blend

Kollidon

Lactose

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-0.55

-0.50

-0.45

-0.40

-0.35

-0.30

-0.25

Log(1

/R)

5000 6000 7000 8000 9000 10000

Wavenumbers (cm-1)

Second Derivative Spectra Raw Materials

blend batch 1

kollidon

lactose

-0.0006

-0.0005

-0.0004

-0.0003

-0.0002

-0.0001

0.0000

0.0001

0.0002

0.0003

0.0004

0.0005

0.0006

0.0007

Lo

g(1

/R)

Drug blend

Kollidon

Lactose

Cal Range 6772-6584 cm-1

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blend batch 1

kollidon

lactose

10

-6.0

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

Lo

g(1

/R)

6600 6620 6640 6660 6680 6700 6720 6740 6760 6780

Wavenumbers (cm-1)

-0.0008

-0.0007

5000 6000 7000 8000 9000 10000

Wavenumbers (cm-1)

Cal Range 6772-6584 cm

NIR Spectra of Extrudate

lac-koll 5

lac-koll 6

10% drug 3

10% drug 4

20% drug 5

20% drug 6

30% drug 5

30% drug 6

40% drug 5

40% drug 6

50% drug 5

50% drug 6

1.6

1.8

2.0

2.2

2.4

2.6

Lo

g(1

/R)

30

0.4

0.6

0.8

1.0

1.2

1.4Lo

g(1

/R)

5000 6000 7000 8000 9000 10000

Wavenumbers (cm-1)

Region of interest

Expanded Second Derivative Spectra Extrudate

lac-koll 5

lac-koll 6

10% drug 3

10% drug 4

20% drug 5

20% drug 6

30% drug 5

30% drug 6

40% drug 5

40% drug 6

50% drug 5

50% drug 6

0.0

0.2

0.4

0.6

0.8

Lo

g(1

/R)

20% Drug Blend

10% Drug Blend

0% Drug Blend

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10

-0.8

-0.6

-0.4

-0.2Lo

g(1

/R)

6600 6650 6700 6750 6800

Wavenumbers (cm-1)

50% Drug Blend

40% Drug Blend

30% Drug Blend

20% Drug Blend

PLS Regression

Corr. Coeff.: 0.99

RMSEC: 2.22%

PLS Range: 6772-6584 cm-1

Factors: 2

32

Process Mastercurve…by Similarity Match

33

Screw speed impacts product

Screwspeed set from

100 rpm to 400 rpm

Impact on NIR-Signal

34

Throughput matters less

Impact on NIR-Signal

35

Feeder empty

Temperature impacts product

Impact on NIR-Signal

36

Temp. 160°C ↗ 180°C

Temp. 180°C ↘ 140°C

One NIR-Mastercurve to monitor the whole process

37

�Monitor one Mastercurve only instead of xx different curves.

�Only when the Similarity Match shows an alert is the

analysis of other curves necessary

• Hot Melt Extrusion provides pharmacists with new possibilities for formulation development

• Systems are available for producing materials at very early stage right up to full scale production

• Process Analytics can provide valuable real-time date to help control

Conclusions

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• Process Analytics can provide valuable real-time date to help control and maintain product quality and develop robust production processes.

•Questions?

39

•Questions?