Presentation - Academy of Pharmaceutical Sciences

Melt processing of pharmaceutical
compounds: future developments & learnings
from the plastics industry
Adrian Kelly
Centre for Pharmaceutical Engineering Science, University of Bradford
APS Amorphous by Design 2014,University of Bradford,
Tuesday 29th April 2014
Scope
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Introduction
Polymer developments
HME and downstream technologies
Single screw extrusion
PAT
Extrusion of non-polymerics
Injection moulding & micromoulding
Molecular orientation to control drug release
Screw-free melt processing
Centre for Pharmaceutical Engineering Science
• Interdisciplinary research centre
• Combines pharmaceutical science, polymer science and
process engineering
• Research themes:
– Pharmaceutical solid dispersions
– Processing & characterisation
– Cocrystallisation, polymorphic transformation
Hot melt extrusion ISO8 clean room
Pharmaceutical extruders
Thermo Fisher Pharmalab
16mm screw diameter, 15-40:1 L:D
(50g – 10kg)
Haake Minilab
Recirculating twin screw extruder
(5g - 250g)
Materials for healthcare grant
• EPSRC Capital for Great Technologies:
Advanced Materials for Healthcare EP/L027011/1
• Recent grant award (led by Prof Phil Coates
• £3.42M from EPSRC + £2M UoB support
• Equipment, PDRA and technician posts
• Includes processing and characterisation:
– AFM + integral confocal light microscopy + nanoindentation
– TEM, Micro CT scanner, SAXS-WAXS
– Raman mapping, FTIR, GPC, APC, DSC, TGA
– Hot melt extrusion, micromoulding, biaxial stretching, die drawing, 3D
printing, ultrasonic injection moulding
Pharmaceutical extrusion (hot melt extrusion)
Courtesy: Particle Sciences Inc. USA
• Twin screw extrusion mixing of API, polymer & excipients
–
–
–
–
Surgical grade stainless steel
Tight temperature control
Complex feed (multi solid & liquid)
Downstream cooling (no water)
• Becoming an accepted process (Norvir, Kaletra, Fenoglide etc.)
Developments in polymers
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•
•
•
•
Must be FDA approved
Generally water soluble
Low processing temperature
Plasticisers may be required
Generally not formulated for melt processing
Developments?
• New polymers / copolymers formulated for melt processing,
e.g. BASF Soluplus®, Dow Affinisol®
• Shin Etsu ‘cleaning compound’
• Pre-blended mixture (dry-blend) to simplify processing and minimise
segregation & feed problems
HME – downstream processing
• Current options:
– Pelletisation
– Sheet extrusion and flaking
– Additional size reduction
steps required
• Downstream alternatives?
– Calendering directly into tablet / caplet geometry
– Micro pelletisation or on-line spheronisation
(Young et al., 2002, Int. J. Pharm.)
– Die face pelletising (air-cooled)
Single screw extrusion
• This is an extra processing step, essentially a melt pump
• Example geometries include:
–
–
–
–
–
Sheet or film (transdermal / transmucosal patches)
Hollow tube (e.g. Stents)
Fibres (sutures)
More complex geometries/profiles
Surface features (micro-channels or patterns)
• Co-extrusion
– Drug release control
– 2 or more drugs
• Foamed structures
– Floating or rapid release systems
– sCO2 a possibility
Terife et al., 2012, SPE ANTEC
HME Process monitoring of (PAT)
• In-line characterisation to measure/control product properties
• Highly relevant in pharmaceutical extrusion quality control (e.g. FDA
PAT Initiative, 2005)
• In-process monitoring techniques readily applied to HME; fits in well
with QbD approach
• Process monitoring capabilities at Bradford:
– Spectroscopy (NIR, Raman, UV-vis)
– Rheology
– Ultrasound
– Temperature field
– Energy consumption
– Flow visualisation (rheo-optics)
In-process NIR
• Thermo Fisher Antaris II with high temperature probe in
the die of a Thermo Pharmalab TSE
• Wavelength: 1000-2500nm (10,000-4,000cm-1)
• 32 scans taken every 30 seconds
NIR Spectra: Glipizide and PeO physical mixtures
• 2nd derivative used to more clearly highlight differences
GPZ
PeO
PM 1:2
PM 1:4
PM 1:6
NIR Spectra: In-line effect of drug loading
(110°C)
• Drug loading can be detected during extrusion
GPZ
PeO
1:6 100°C
1:4 100°C
1:2 100°C
Transflectance NIR
• Systems which may be transparent or opaque in the melt state are
difficult to measure
• A transflectance method has been developed, using a reflectance
probe and highly polished opposing surface
• Attempt to measure Carbemazepine and PEG in a PVP-VA matrix;
transparent below ~15% API content
NIR probe
Polished surface
31
NIR calibration of CBZ and PEG in PVP-VA matrix
5% C BZ 10% PEG
0.00 25 10 % C BZ 10 % PEG
15 % C BZ 10 % PEG
0.00 20 20 % C BZ 10 % PEG
CBZ
RMSEC: 0.788 Corr. Coeff.: 0.9936
RMSEP: 0.672 Corr. Coeff.: 0.9982
4 factors used
0.00 15
0.00 10
Calculated
0.00 05
Ab s or ba nc e
0.00 00
- 0.000 5
- 0.001 0
- 0.001 5
- 0.002 0
CBZ
- 0.002 5
- 0.003 0
Calibration
Validation
Correction
5064 cm-1
Cross-correction
Ignore
3
- 0.003 5
- 0.004 0
3
- 0.004 5
620 0
600 0
580 0
560 0
540 0
520 0
500 0
Actual
31
480 0
W av enu mber s ( c m- 1)
20
0.00 25 20 % C BZ 5% PEG
20 % C BZ 15 % PEG
0.00 20
20 % C BZ 7.5 % PEG
20 % C BZ 20 % PEG
0.00 15
PEG
RMSEC: 0.633 Corr. Coeff.: 0.9864
RMSEP: 1.06 Corr. Coeff.: 0.9677
6 factors used
0.00 10
0.00 05
Calculated
0.00 00
Ab s or ba nc e
- 0.000 5
- 0.001 0
- 0.001 5
- 0.002 0
- 0.002 5
- 0.003 0
PEG
Calibration
Validation
Correction
- 0.003 5
Cross-correction
Ignore
5
- 0.004 0
- 0.004 5
5
600 0
580 0
560 0
540 0
W av enu mber s ( c m- 1)
520 0
500 0
480 0
Actual
20
Loading (wt %)
NIR tracking a step change in API and plasticiser
Time
22.5% CBZ >> 17.5% CBZ;
7.5% PEG >> 12.5% PEG
In-process rheometry using instrumented slit die
• Plasticising effect of API on shear viscosity
• Low cost, simple PAT tool
Shear Viscosity (Pa.s)
10000
20% API
1000
30% API
40% API
100
10
100
Wall Shear Rate (s-1)
(API = Bristol Myers Squibb development drug)
Ultrasonic monitoring of HME
Raw voltage-time data
3.93E+11
2.40E+04
transmit
20% MPT
30% MPT
40% MPT
3.92E+11
1.60E+04
3.91E+11
8.00E+03
receive
3.90E+11
Transit time (µs)
Peak height
0.00E+00
Metoprolol tartrate (MPT) in Eudragit®
Peak height (V)
Transit time (µs)
10% MPT
Non-polymeric HME applications
• Twin screw extrusion can be used as a continuous
method of providing shear and heat to materials
• Not necessarily melting the components
• Same advantages of HME – continuous, scalable
• Examples include:
– Granulation (wet, melt)
– Cocrystallisation
– Polymorphic transformation
Cocrystallisation by twin screw extrusion
Co-former
Drug
Co-crystal
Agglomerated
co-crystals
Patent Application WO 2010/013035
Dhumal et al., 2010, Pharm. Res., 27, 2725
SEM images of
agglomerated cocrystals
Polymorphic transformation by TSE
(Chaitrali Kulkarni)
Pure Drug A
Artemisinin
Piracetam
Chlorpropamide
Patent application:
PCT/GB/1208489.3
Drug A’
Carbamazepine
100
e.g. Artemisinin – stable triclinic form produced
140°C
Orthorhombic form
Triclinic form
Drug release (%)
80
60
40
20
0
0
5
10
15
Time in hours
Orthorhombic form
Triclinic form
20
Injection moulding – a batch process
1. Injection
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Screw acts as piston, rapidly forcing
melt into the mould cavity
2. Packing
–
Screw applies a fixed pressure as the
moulded polymer cools
3. Plasticisation + cooling
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Screw rotates and moves backwards
to prepare next melt shot
4. Part ejection
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Clamps move apart and part is ejected
or taken by robot
Injection moulding of pharmaceuticals
• Two cavity injection mould tool for Fanuc Roboshot
5 tonne injection moulding machine
• Feasibility of injection moulding solid dispersions / challenges
• Effect of processing conditions on structure and release rate
Injection moulding of HPMCAS based systems
(Shivprasad Deshmukh)
Thermal characterisation
TGA, DSC, MDSC
Biopharmaceutical
Evaluation
Drug release kinetics and
mechanism
Spectroscopic
characterisation
Surface properties
Raman, FTIR, FT-NIR
Contact angle
AFM
Mechanical properties
DMA
Tensile properties
HPMCAS and Ibuprofen
• Gradual change in surface appearance
• Ibuprofen crystal growth
40o C
75% RH
% Crystallisation
70
70
Injection moulded system
60
60
50
50
40
40o C
60% RH
25o C
60% RH
Extruded system
40
40C 75 %RH
40C 75% B-07
30
25C 60% B-07
20
40C 60% B-07
10
40C 60%RH
30
25C 60%RH
20
10
0
0
10
20
Time (Days)
30
Post extrusion
0
0
10
20
Crystallisation of 33% Ibu, measured by MDSC
30
HPMCAS and Ibuprofen
• Size and amount of crystals are monitored
ambient
0.2
–––––––
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–––––––
–––––––
–––––––
–––––––
DSC
40°C, 75% RH
B-02 I 33 Bar 0 day
B-02 I 33 Bar 1 day
B-02 I 33 Bar 2 day
B-02 I 33 Bar 3 day
B-02 I 33 Bar 7 day
B-02 I 33 Bar 21 day
B-02 I 33 Bar 28 day
Heat Flow (W/g)
0.0
-0.2
-0.4
-0.6
-20
Exo Up
0
20
40
60
80
Temperature (°C)
100
120
140
160
Universal V4.5A TA Instruments
NIR
Micromoulding – small scale injection moulding
Applications in healthcare, electronics, optics
Micromoulding medical examples
Moulded DRFP ProPoint core
(radio-opaque, rigid)
Moulded microneedles
Orientation & crystallinity to control drug release
• Can the morphology of the polymer matrix be tailored to
control drug release?
•Capillary effect?
•Different permeation?
•Different function groups
available for drug – polymer
interaction?
amorphous
semi-crystalline
semi-crystalline
+ oriented
• Different crystal morphologies have different packing of
amorphous and crystalline regions of the polymer chains
•
•
Crystal density and size may vary
Drug - polymer interaction
•
Barrier properties/ water penetration
PeO modified with small percentage of high Mw
(Rohan Ambardekar)
• PeO (Mw 2x105) Injection moulded blends with different
additions of high Mw (2x106) PeO
• Retardation of drug release with small
amounts of higher molecular weight
component
• Negligible change in % crystallinity
• Release may be linked to orientation
and/or crystal size
Injection moulded system at 1 bar
Percentage cumulative release
120
100
80
Blank
60
Below C*
0.25%
0.50%
40
Near C*
1.25%
20
Above C*
0
0
50
100
150
Time (minutes)
200
Cooling
Biaxial stretching of drug loaded films
Draw ratio
1
2
3
4
Orientation
factor
0.006328
0.012091
0.034217
0.044984
700
Drug released (µg/ml)
600
Day 1 burst release + individual
release every week
500
400
Draw ratio 1
300
Draw ratio 2
Draw ratio 3
200
Draw ratio 4
100
0
1
7
14
Days
21
28
Cumulativel Drug released (µg/ml)
WAXS view
Cumulative drug release
900
800
700
600
Draw ratio 2
500
400
Draw ratio 1
300
Draw ratio 3
200
Draw ratio 4
100
0
0
10
20
Days
30
Screw-less melt processing technologies
• Screw processing causes high shear and residence
times
• Alternative techniques include:
– Ultrasonic injection moulding (Ultrasion)
– Kinetisol process
(high friction & shear)
– High shear pan milling (UoB & Sichuan SKLPME, China)
Summary comments
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New pharmaceutical polymers can be expected
•
Process analytics will become more widely used
•
Moulding techniques and extruded products are likely to
generate more interest
•
Morphology of the polymer matrix could be used to
control drug release
•
Screw-free (low residence time) processing alternatives
are being explored
Acknowledgements
PhD Students:
Hrushikesh Karandikar, Shivprasad Deshmukh
Rohan Ambardekar, Prafulla Apshingekar, Sachin Korde,
Clive Wood, Abdolati Alwati
Colleagues:
Tim Gough, Elaine Brown, Ben Whiteside,
Anant Paradkar, Chaitrali Kulkarni, Suyog Aher
Fin Caton-Rose, Phil Coates
Industrial collaborators:
Shilpa Mistry (Shin Etsu)
Sheelagh Halsey, Rod Bottom (Thermo Fisher)
John Jones (BMS)