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

Transcription

1 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 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).

2 Outline Introduction Motivation Injection Moulding Pharmaceutical Applications Experimental Work Materials & Methods Results Simulation Work Conclusion Slide 2

3 Outline Introduction Motivation Injection Moulding Pharmaceutical Applications Experimental Work Materials & Methods Results Simulation Work Conclusion Slide 3

4 Motivation The solubility challenge Biopharmaceutics Classification System (BCS) Up to 90% of the drugs under development are classified in Class 2 or 4 Example: Venus de Milo vs. Itraconazole Source: BASF Marble Solubility: 10 µg/ml Itraconazole 1 ng/ml Class 1 (5%) Class 3: (5%) Class 2: (70%) Class 4: (20%) Solution Volume [ml] Cell Permability [*10-6 cm/s] The Venus De Milo is 10,000 time more soluble than itraconazole. Itraconazole Slide 4

5 Motivation Solid Dispersions: Solubility enhancement by the formation of solid dispersions lead to improved bioavailability API Molecule (Active Pharmaceutical Ingredient) Amorphous Matrix Material Source: BASF Hot-Melt Extrusion with BASF Pharma Polymers Mechanism: Increased surface to volume ratio and elimination of the lattice energy Production: Solution or melt methodology (e.g. Spray Drying or Melt Extrusion) Slide 5

6 Extrusion & Downstream Processing MELT EXTRUSION PRODUCTS Picture sources: Soliqs, Automatik Plastics Machinery GmbH, BBAInova Tablets Tablets Implants Etc. Cylindrical pellets Spherical or cylindrical pellets Flakes Powder Films Slide 6

7 Injection Moulding Picture Courtesy: Engel Austria Slide 7

8 Pharmaceutical Applications Egalet Egalet technology: Two subsequent injection phases into same mold. Provides zero-order release. Capill Alternative to gelatin dip molding. Vilivalam et al., Pharm. Sci. Technol. To. 3(2): Chronocap TM A functional container that releases API following programmed lag phases. Modified from: Zema et al., J. Control. Release 159: Septacin TM Polyanhydride-based implantable system containing gentamicin sulfate for the treatment of osteomyelitis. Li et al., Adv. Drug Delivery Rev. 54(7): Slide 8

9 Outline Introduction Motivation Injection Moulding Pharmaceutical Applications Experimental Work Materials & Methods Results Simulation Work Conclusion Slide 9

10 Experimental Work Two Step Production One Stop Production Matrix API Tablets Pellets Tablets Implants Implants Injection Moulding Machine Injection Moulding Machine Slide 10

11 Materials (1/2) Fenofibrate as Active Pharmaceutical Ingredient (API) Molecular Weight: g/mol Melting Point: T M = C BCS: - Applications: Class II Practically insoluble in acidic media (ph 1.2) and water Primary and secondary hyperlipoproteinaemia Slide 11

12 Materials (2/2) Soluplus Matrix Carrier Type of polymer Molecular Weight: Graft Co Polymer PVCL-PVAc-PEG Glass Transition T g ~ 70 C Solubility Applications Formulations: # Soluplus Fenofibrate 1 90% 10% 2 80% 20% 3 70% 30% g/mol Soluble in water Solubility enhancement Slide 12

13 Methods 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 ENGEL e-mac 50/50, Source: ENGEL Austria GmbH Slide 13

14 Feeding Strategies Feeding Section: Plasticing Unit: Homogeneous Pellets (Matrix + API) Funnel Matrix Powder Feeding API Volumetric or Loss in Weight Feeders Advantages: Disadvantages: Homogeneous Melt Forced Feeding Easy Handling Additional Processing Steps Requires good flowability Higher Thermal Load (2 steps) 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 Slide 14

15 Basic Engineering: Rheology Oscillatory Measurements Anton Paar MCR 301 Cone Plate System D=25 mm Complex Viscosity [Pa s] Flow Curves of Soluplus and Fenofibrate Solutions C 90 C 170 C 130 C 110 C 150 C 130 C 150 C 110 C 170 C Angular frequency [1/s] 100% 90/10% 80/20% 70/30% Time Temperature Superposition Slide 15

16 Basic Engineering: Rheology Time Temperature Superposition is used to derive processing temperatures Complex Viscosity [Pa s] C η 100% Soluplus 0 =3000 [Pa s] 90/10% 80/20% /30% 170 C η 0 =550 [Pa s] C η 0 =50 [Pa s] 170 C η 0 =5 [Pa s] Angular frequency [1/s] 70 C Processing Temperature [ C] Concentration Temperature Concentration [%] Strong plasticizing effect by the addition of fenofibrate and decreased processing temperatures Slide 16

17 Tablets Mouldings Tablets Slide 17

18 Methods: Raman Mapping Surface Mapping (Perkin Elmer Raman Station 400) Raman Station µm Laser Spot Diameter 200µm Lattice (75x75 Points) 3s Integration Time 10h per Tablet Mapping of a Tablet 785 nm Laser Raman Shift: cm -1 Chemometric Model Tablet on the Sample Tray Slide 18

19 Raman Spectra of Fenofibrat Soluplus (Injection Moulded Tablets) Model Region 30% 20% Intensity [-] 10% 0% Wave number [1/cm] Wave number [1/cm] 30% Fenofibrate in Soluplus Fenofibrate in Soluplus Slide 19

20 Mapping of a 10% API Tablet Slide 20

21 Comparison of Tablet with different API-Concentrations Starting Material: Homogeneous Pellets % API 10% 20% API 30% API 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 Slide 21

22 Comparison of Tablet with different Starting Materials Pellets 10% Powder mixture 10% Tablet Average SD RSD Pellets 9.9% 0,62% 6,3% Powder Mixture 10,7% 0,69% 6,4% Powder Feeding Leads to similar concentration distributions Slide 22

23 Preparation of an Amorphous System by Injection Molding Tablet (powder) Tablet (pellets) Pellets (HME) physical blend Soluplus Fenofibrate The physical mixture still contained the crystalline fenofibrate peak. HME and IM yielded in pellets and tablets that contained fenofibrate and Soluplus in the amorphous state -> formation of a solid dispersion. DSC thermograms (first cooling cycles) of primary powders and pharmaceutical products. All samples, were investigated with a heat flow rate of 10 K/min, except for Soluplus, which was investigated with 60 K/min. 23 Slide

24 Dissolution Improvement by Injection Molding In-vitro dissolution profiles generated in 0.1 N HCl during 2 h. Simply blending Soluplus with fenofibrate did not yield improved dissolution profiles. Pellets prepared by HME showed rapid release due to the formation of a solid dispersion and large surface area. Tablets prepared by IM showed improved release characteristics (due to the formation of a solid dispersion), which were slower due to lower surface area and high hardness. Slide 24

25 Outline Introduction Motivation Injection Moulding Pharmaceutical Applications Experimental Work Materials & Methods Results Simulation Work Conclusion Slide 25

26 Simulation Openfoam & SIGMASOFT 1. CFD set-up: Tablet Injection Mould Objectives: Distribution behavior of API during injection into the cavaties 2. CFD set-up: Plasticizer unit Objectives: Distribution behavior of API in polymer during processing in metering zone and screw antechamber Project Partner: ENGEL e-mac 50/50, Source: ENGEL Austria GmbH Johannes Kepler University Linz Institute of Polymer Injection Moulding and Process Automation Slide 26 26

27 CFD set-up: Tablet Injection Mould Software: Open source code OpenFOAM and SIGMASOFT 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 Slide 27 27

28 CFD set-up: Tablet Injection Mould Results: Wall shear stresses along the mould gate 150 C 160 C T = 10 C : Reduction of wall shear stress in critical area: 50% C Wall shear stress as a function of shear rate Slide 28 28

29 Outline Introduction Motivation Injection Moulding Pharmaceutical Applications Experimental Work Materials & Methods Results Simulation Work Conclusion Slide 29

30 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. Slide 30

31 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 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).