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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
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
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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
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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 g/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
EgaletEgalet technology: Two subsequent injection phases into same mold. Provides zero-order release.
Modified from: Zema et al., J. Control. Release 159:324-331.
ChronocapTMA functional container that releases API following programmed lag phases.
Vilivalam et al., Pharm. Sci. Technol. To. 3(2):64-69.
CapillAlternative to gelatin dip molding.
SeptacinTMPolyanhydride-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: 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]
Co
mp
lex
Vis
cosi
ty [P
as]
100%90/10%80/20%70/30%
170C
150C
170C
130C
110C
130C
150C
90C
110C
130C
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]
Co
mp
lex
Vis
cosi
ty [P
as]
170C 0=3000 [Pas]
170C 0=550 [Pas]
170C 0=50 [Pas]
170C 0=5 [Pas]
Concentration Temperature
0 170
10 150
20 118
30 100
Time Temperature Superposition is used to derive processing temperatures
0 10 20 3080
100
120
140
160
180
Concentration [%]
Pro
cess
ing
Tem
per
atu
re [
C]
Strong plasticizing effect by the addition of fenofibrate and decreased processing temperatures
70C
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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)
100m Laser SpotDiameter
200m 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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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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Mapping of a 10% API Tablet
Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms
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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
