Injection Moulding as a One-Stop-Productionto Produce ... · PDF fileSlide Outline...

of 32 /32
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 Produce Pharmaceutical Dosage Forms Karin Eggenreich, Simone Schrank, Gerold Koscher, Daniel Treffer, Eva Roblegg and Johannes G. Khinast

Embed Size (px)

Transcript of Injection Moulding as a One-Stop-Productionto Produce ... · PDF fileSlide Outline...

  • 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 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

    4

  • 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

    5

  • 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

    6

  • Slide

    Injection Moulding

    Picture Courtesy: Engel Austria

    Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms

    7

  • 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. .

    8

  • 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

    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

    Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms

    11

  • 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

    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: 13 mm x 4 mm

    Number: 6

    Type: Cold Runner System

    Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms

    13

  • 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)

    14

  • 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

    15

  • 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

    16

  • Slide

    Tablets

    Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms

    17

    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

    18

  • 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

    [-]

    19

  • Slide

    Mapping of a 10% API Tablet

    Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms

    20

  • 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

    21

  • Slide

    Comparison of Tablet with different Starting Materials

    Injection Moulding as a One-Stop-Production to Produce Pharmaceutical Dosage Forms

    Pellets 10%

    40

    30