Download - Injection Moulding as a One-Stop-Productionto Produce ... · PDF fileSlide Outline Introduction Motivation Injection Moulding Pharmaceutical Applications Injection Moulding as a One-Stop-Production

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






� 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.


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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


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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


6

Slide

Injection Moulding

Picture Courtesy: Engel Austria


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Slide

Pharmaceutical Applications


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






� 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


10

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


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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%


12

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


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Slide

Feeding Strategies


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


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


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


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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


� 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


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


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Slide

Comparison of Tablet with different API-Concentrations


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


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)


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 .


24

Slide


Powder FeedingPellet

25

Slide

Outline

� Introduction

� Motivation






� Results

� Simulation Work

� Conclusion

26

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 ®


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Project Partner:

Johannes Kepler University Linz Institute of Polymer Injection Moulding and Process Automation

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


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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


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






� Results

� Simulation Work

� Conclusion

30

Slide

Conclusion


• 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