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Hot Melt Extrusion Processing
for the Pharmaceutical Industry
Dr Rod Bottom
Sales Account Manager, Process-Pharma
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
14
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
15
� 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
17
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
18
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
?? ?? ?? ?? ?? ?? ?? ??
19
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
20
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
22
• 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
23
• 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
28
-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
29
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
31
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
38
• Process Analytics can provide valuable real-time date to help control and maintain product quality and develop robust production processes.
•Questions?
39
•Questions?