Post on 25-Mar-2018
K1 Competence Center - Initiated by the Federal Ministry of Transport, Innovation and Technology (BMVIT). and the Federal Ministry of Economy, Family and Youth (BMWFJ)Funded by the Austrian Research Promotion Agency (FFG), Land Steiermark and the
Styrian Business Promotion Agency (SFG).
Injection Moulding as a One-Stop -Production to ProducePharmaceutical Dosage Forms
Karin Eggenreich, Simone Schrank, Gerold Koscher, Daniel Treffer, Eva Roblegg and Johannes G. Khinast
Slide
Outline
� Introduction
� Motivation
� Injection Moulding
� Pharmaceutical Applications
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
� Experimental Work
� Materials & Methods
� Results
� Simulation Work
� Conclusion
2
Slide
Outline
� Introduction
� Motivation
� Injection Moulding
� Pharmaceutical Applications
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
� Experimental Work
� Materials & Methods
� Results
� Simulation Work
� Conclusion
3
Slide
MotivationThe solubility challenge
Up to 90% of the drugs
under development
are classified in Class 2 or 4
Biopharmaceutics Classification System (BCS)
Solution Volume [ml]
100
10
1 Cel
lPer
mab
ility
[*10
-6cm
/s]Class 1
(5%)Class 2:(70%)
Class 3:(5%)
Class 4:(20%)
1 10 102 103 104 105 106Source: BASF
Example: Venus de Milo vs. Itraconazole
Itraconazole
Marble
Solubility : 10 µg/mL
Itraconazole
1 ng/mL
The Venus De Milo is
10,000 time more soluble
than itraconazole.
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide
Motivation
API Molecule(Active Pharmaceutical Ingredient)
Amorphous Matrix Material
Source: BASF Hot-Melt Extrusion with BASF Pharma Polymers
Production: Solution or melt methodology (e.g. Spray Drying or Melt Extrusion)
Mechanism: Increased surface to volume ratio and elimination of the lattice energy
Solid Dispersions: Solubility enhancement by the formation of solid dispersions lead to improved bioavailability
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide
Extrusion & Downstream Processing
PRODUCTS
MELT EXTRUSION
• Tablets • Tablets• Implants• Etc.
• Cylindricalpellets
• Spherical orcylindrical
pellets
• Flakes• Powder
• Films
Picture sources: Soliqs, Automatik Plastics Machinery GmbH, BBAInova
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide
Injection Moulding
Picture Courtesy: Engel Austria
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide
Pharmaceutical Applications
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
http://egalet.com
Egalet ®
Egalet® technology: Two subsequent injection phases into same mold. Provides zero-order release.
Modified from: Zema et al., J. Control. Release 159:324-331.
Chronocap TM
A functional container that releases API following programmed lag phases.
Vilivalam et al., Pharm. Sci. Technol. To. 3(2):64-69.
Capill ®
Alternative to gelatin dip molding.
Septacin TM
Polyanhydride-based implantable system containing gentamicinsulfate for the treatment of osteomyelitis.
Li et al., Adv. Drug Delivery Rev. 54(7):963-986. .
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Slide
Outline
� Introduction
� Motivation
� Injection Moulding
� Pharmaceutical Applications
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
� Experimental Work
� Materials & Methods
� Results
� Simulation Work
� Conclusion
9
Slide
Experimental Work
Injection MouldingMachine
Implants
Tablets
Two Step Production
Injection MouldingMachine
Implants
Tablets
Matrix API
One Stop Production
Pellets
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide
Materials (1/2)
Fenofibrate as Active Pharmaceutical Ingredient (API )
Molecular Weight: 360.8 g/mol
Melting Point: TM = 79-82 °C
BCS: Class II
-Practically insoluble in acidic media
(pH 1.2) and water
Applications:Primary and secondary hyperlipoproteinaemia
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide
Materials (2/2)
Soluplus ® Matrix Carrier
Type of polymerGraft Co PolymerPVCL-PVAc-PEG
Molecular Weight: 90 000-140 000 g/mol
Glass Transition Tg ~ 70 °C
Solubility Soluble in water
Applications Solubility enhancement
Formulations:# Soluplus Fenofibrate
1 90% 10%
2 80% 20%
3 70% 30%
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide
Methods
ENGEL e-mac 50/50, Source: ENGEL Austria GmbH
Injection Moulding Machine
Type: Engel e-mac 50
Clamping Force: 50 kN
Plasticing Unit: Single Screw 20 mm
Mould:
Cavity: Ø 13 mm x 4 mm
Number: 6
Type: Cold Runner System
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide
Feeding Strategies
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
Homogeneous Pellets Powder Feeding
Plasticing Unit:
API Matrix
Volumetric orLoss in Weight
Feeders
• Homogeneous Melt• Forced Feeding• Easy Handling
• Additional Processing Steps• Requires good flowability• Higher Thermal Load (2 steps)
Advantages:
Disadvantages:
• Direct Powder Processing• High Flexibility (e.g. Drug Content)• Works with Poorly Flowable Powders
• Requires Special Feeding Equipment & Feeding Strategies (Injection Cycle)
• Product Homogeneity Issues
Feeding Section:
Funnel
(Matrix + API)
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Slide
Basic Engineering: Rheology
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
10-1
100
101
102
103
101
102
103
104
105
Angular frequency [1/s]
Com
plex
Vis
cosi
ty [P
a·s]
100%90/10%80/20%70/30%
170°C
150°C
170°C
130°C
110°C
130°C
150°C
90°C
110°C
130°C
Flow Curves of Soluplus and Fenofibrate SolutionsOscillatory Measurements ����
Anton Paar MCR 301Cone Plate System
D=25 mm
���� Time Temperature Superposition
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Slide
Basic Engineering: Rheology
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
10-1
100
101
102
103
100
101
102
103
104
100% Soluplus90/10%80/20%70/30%
Angular frequency [1/s]
Com
plex
Vis
cosi
ty [P
a·s]
170°C ηηηη0=3000 [Pa·s]
170°C ηηηη0=550 [Pa·s]
170°C ηηηη0=50 [Pa·s]
170°C ηηηη0=5 [Pa·s]
Concentration Temperature
0 170
10 150
20 118
30 100
Time Temperature Superposition is used to derive process ing temperatures
0 10 20 3080
100
120
140
160
180
Concentration [%]
Pro
cess
ing
Tem
pera
ture
[°C
]
Strong plasticizing effect by the addition of fenofibrate and decreased processing temperatures
70°C
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Slide
Tablets
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Mouldings Tablets
Slide
Methods: Raman MappingSurface Mapping (Perkin Elmer Raman Station 400)
� 100µm Laser SpotDiameter
� 200µm Lattice (75x75 Points)
� 3s Integration Time ≈ 10h per Tablet
Raman Station 400 Tablet on the Sample TrayMapping of a Tablet
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
� 785 nm Laser � Raman Shift:
95-3500 cm-1
Chemometric Model
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Slide
Raman Spectra of Fenofibrat –Soluplus (Injection Moulded Tablets)
30% Fenofibrate in Soluplus Fenofibrate in Soluplus
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
Wave number [1/cm]
Model Region
0%
10%
20%
30%
Wave number [1/cm]
Inte
nsity
[-]
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Slide
Mapping of a 10% API Tablet
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide
Comparison of Tablet with different API-Concentrations
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
0% API 10% 20% API 30% API
Starting Material: Homogeneous Pellets 40
30
20
10
0
Tablet Average SD RSD
10% API 10,8% 0,71% 6,6%
20% API 22.5% 1,25% 5,5%
30% API 29.8% 5,24% 17,6%
Pellet Feeding� homogeneous Tablets
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Slide
Comparison of Tablet with different Starting Materials
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
Pellets 10%
40
30
20
10
0
Powder mixture 10%
Tablet Average SD RSD
Pellets 9.9% 0,62% 6,3%
Powder Mixture 10,7% 0,69% 6,4%
���� Powder FeedingLeads to similar concentration
distributions
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Slide
Preparation of an Amorphous System by Injection Molding
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DSC thermograms (first cooling cycles) of primary p owders and pharmaceutical products. All samples, were investig ated with a heat flow rate of 10 K/min, except for Soluplus ®, which was investigated with 60 K/min.
Fenofibrate
Soluplus ®
physical blend
Pellets (HME)
• The physical mixture still contained the crystalline fenofibratepeak.
• HME and IM yielded in pellets and tablets that contained fenofibrate and Soluplus® in the amorphous state -> formation of a solid dispersion.
Tablet (pellets)Tablet (powder)
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
Slide
Dissolution Improvement by Injection Molding
In-vitro dissolution profiles generated in 0.1 N HC l during 2 h.
• Simply blending Soluplus ®
with fenofibrate did not yieldimproved dissolution profiles.
• Pellets prepared by HMEshowed rapid release due tothe formation of a soliddispersion and large surfacearea.
• Tablets prepared by IMshowed improved releasecharacteristics (due to theformation of a soliddispersion ), which wereslower due to lower surfacearea and high hardness .
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
Powder FeedingPellet
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Slide
Outline
� Introduction
� Motivation
� Injection Moulding
� Pharmaceutical Applications
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
� Experimental Work
� Materials & Methods
� Results
� Simulation Work
� Conclusion
26
Slide 27
ENGEL e-mac 50/50, Source: ENGEL Austria GmbH
Objectives:
Distribution behaviorof API in polymer
during processing in metering zone andscrew antechamber
Objectives:
Distribution behavior of API during injection
into thecavaties
2. CFD set-up: Plasticizer unit
1. CFD set-up: Tablet Injection Mould
SimulationOpenfoam & SIGMASOFT ®
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Project Partner:
Johannes Kepler University Linz Institute of Polymer Injection Moulding and Process Automation
Slide 28
Software:Open source code OpenFOAM® andSIGMASOFT®
Results:� Filling time, volume flow and filling
pressure at the gate � Shear heating in the mould
(from sprue to cavity) � Wall shear stresses and strain rates� Residence Time distribution
Objective of simulations:Distribution behavior of API in cavities
Injection Mould
fixed nozzle side
Mesh of tablet mould gate
CFD set-up: Tablet Injection Mould
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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Slide 29
Results: Wall shear stresses along the mould gate
∆T = 10°C :Reduction of wall shearstress in critical area: 50%
CFD set-up: Tablet Injection Mould
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
0 800
0 400
0 1500
Wall shear stress as a function of shear rate
150°C
160°C
170°C
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Slide
Outline
� Introduction
� Motivation
� Injection Moulding
� Pharmaceutical Applications
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
� Experimental Work
� Materials & Methods
� Results
� Simulation Work
� Conclusion
30
Slide
Conclusion
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
• The investigated formulation showed good processability.
• Soluplus® is strongly plasticized by fenofibrate.
• Powder feeding is feasible and leads to almost identical release profile and
concentration mappings compared to pellet feeding.
• Overall, injection moulding combines the advantages of both hot melt extrusion
(solubility enhancement) and direct shaping technologies (direct tableting).
• Injection moulding is a lean process which allows a transfer of raw material into
final product within approx. 2 minutes.
• Injection moulding is a flexible technology with a high potential for the application
in especially personalized medicine.
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K1 Competence Center - Initiated by the Federal Ministry of Transport, Innovation and Technology (BMVIT). and the Federal Ministry of Economy, Family and Youth (BMWFJ)Funded by the Austrian Research Promotion Agency (FFG), Land Steiermark and the
Styrian Business Promotion Agency (SFG).
Injection Moulding as a One-Stop -Production to ProducePharmaceutical Dosage Forms
Karin Eggenreich, Simone Schrank, Gerold Koscher, Daniel Treffer, Eva Roblegg and Johannes G. Khinast