Application Studies using the GTP at an Excipient Manufacturer s Laboratory

Transcription

1 Application Studies using the GTP at an Excipient Manufacturer s Laboratory Dr. Andreas Sauer andreas.sauer@se-pfmd.com Gamlen User Meeting

2 Outline Shin-Etsu excipients and application laboratory Considerations for the use of a powder compaction analyzer at an excipient manufacturer Use of a powder compaction analyzer at SE-PFMD 2

3 SE Excipient Product Portfolio Metolose HPMC/MC Thickening HPMC Matrix tablets (extended release) Metolose SR Tylopur SR Shin-Etsu Product Portfolio Pharmacoat / Tylopur HPMC Coating, Granulation Binder HPMCP Enteric Coating Shin-Etsu AQOAT HPMC-AS Enteric Coating Solid Dispersion Tylopur grades produced in Germany L-HPC Binder/Disintegrant SmartEx TM ODT 3

4 Technical Service at Shin-Etsu Shin-Etsu hosts application laboratories world-wide Application laboratory in Wiesbaden (Germany) on-site with production plant Our mission Application development Satisfy customer requests Customer training Technical data 4

5 Technical Service at Shin-Etsu 2 Offers a lab space of 75 m² Solid dose capabilities Tablets Pellets Films 5

6 Development Capabilities at Shin-Etsu Laboratory scale equipment for solid dosage forms Granulation High shear mixer (Glatt TMG 1-6) Fluid Bed Processor (Diosna mini lab XP) Roller Compactor (Alexanderwerk WP-120) Tablets Rotary Tablet Press (Romaco Kilian Pressima B16) Single Station (Gamlen D Series) Coating Fluid Bed Processor for Pellets (Diosna Minilab XP) Drum Coating (Bosch Solidlab 1) 6

7 SE PFMD: Requirements for a Single Punch Tablet Press 1) Easy to use Different operators using the machine 2) Small machine Limited lab space No installation requirements Little material required 3) Scalability Results should give indication about performance on the rotary tablet press 4) Further powder and granule analysis when necessary Analysis of elastic recovery of materials, ejection forces etc. 7

8 Considerations for Powder Compaction Compaction Simulator + Automated production + Analytical data (Ejection force, statistics) - Large machine - Very expensive - Expertise Hydraulic Press + Easy to operate + Inexpensive + Small machine - Dwell time control - Analytical data 8

9 Considerations for Powder Compaction Compaction Simulator + Automated production + Analytical data (Ejection force, statistics) - Large machine - Very expensive - Expertise Hydraulic Press + Easy to operate + Inexpensive + Small machine - Dwell time control - Analytical data Gamlen GTP 9

10 Gamlen GTP at Shin-Etsu Main Motivation: Formulation screening before transfer to rotary press (saving material) 1. Correlation of GTP and Romaco Kilian Pressima Rotary Press 2. Application in formulation development (lubricant optimization) 3. Analysis of SiO 2 addition to excipient and testing tablet hardness 4. Analysis of elastic recovery and ejection forces in L-HPC formulations 10

11 Study 1: Correlation of GTP and Rotary Press = N (12 mm, round, 3.43 mm thickness) Calculation of tensile strength for comparison of different punch sizes Flowlac 99%, MgSt 1% Correlation of GTP and rotary press observed = kn/cm 2 In depth study: K. G. Pitt, R. J. Webber, K. A. Hill, D. Dey, M. J. Gamlen Powder Technology Part B 2015, 270,

12 Study 1: Punch Size Conversion Range of the GTP (5 mm punch) F = Pπr F = Force in kn P = Pressure in MPa r = punch radius (in mm) Only valid for round, flat face punches Gives an estimation on the compaction pressure to use on the rotary press 12

13 Study 1: Scalability, Unit Conversions Top: Calculating compaction forces for rotary press Bottom: Calculation of tablet tensile strength 13

14 Study 2: Work on Herbal Formulations 1 Boswellia Green Tea St. Johns Worth 6 mm punch & die set Scheme property of Gamlen Tableting Ltd. Compaction Pressure [MPa] Tensile Strength Detachment [kg] Ejection [kg] Boswellia Green Tea St. Johns Worth Boswellia formulation will not be working on rotary tablet press. 82.5% Extract 12.5% L-HPC 4% Lactose 1% MgSt 14

15 Study 2: Work on Herbal Formulations 2 Green Tea Extract 6 mm punch and die set 2% of MgSt reduces Ejection/detachment load at excellent hardness No sticking on punches observed during tableting Classification of Herbal Extracts? 15

16 Study 3: Glidant for High Viscous Tylopur High viscous Tylopur used for example in direct compression of extended release formulations Glidant used in formulations to improve powder flow Silicon dioxide most common Might increase tensile strength Study Aim: Investigate effect of silicon dioxide on high viscous Tylopur HPMC powder flow and tensile strength of tablets. 16

17 Study 3: Addition of Glidant to Tylopur 2 Hydrophobic modified SiO 2 showed best performance in lowering the angle of repose 17

18 Study 3: Addition of Glidant to Tylopur 3 Tablets compressed on the GTP 5 mm, 100 mg, 250 kg compaction Aerosil 200 Ph optimum glidant in about 0.2% addition to Tylopur HPMC 18

19 Study 4: Analysis of Elastic Recovery: L-HPC L-HPC (low substituted hydroxypropyl cellulose) Water insoluble and swells upon water contact Utilized as binder and disintegrant in a single excipient (5-20% in formulation) LH-11 LH-21 NBD-021 NBD grade developed to reduce elastic recovery and provide more plastic deformation Fibrous app. 55 mm Regular app. 45 mm L/D: 3.0 narrower PSD app. 45 mm L/D: 2.2 Anti-Capping Standard Grade Optimized for DC 19

20 Study 4: Addition as DC Binder High API load formulation with Acetaminophen? Effect also observed? 100% Excipient. Elastic Recovery 0.5 min after compression (150 MPa, SE brochure data) 20

21 Study 4: Challenging Formulation Material F1 w/w [%] F2 w/w [%] F3 w/w [%] F4 w/w [%] F5 w/w [%] F6 w/w [%] Paracetamol Lactose LH LH NBD MCC MgSt Direct compression grades of excipients utilized Paracetamol dense powder, usually used in WG, poor binding Direct compression with the GTP after blending 5 mm, 80 mg, 400 kg (200 MPa, 3.9 kn) 6 Tablets prepared / formulation 21

22 Study 4: In- and Out of Die Elastic Recovery Calculation of ER: Tablet height at 400 kg Tablet height at zero load Tablet height after 24 h ER highest for API only formulation after 24 hours In die recovery: LH-11 and NBD grade on the level of MCC Out of die recovery NBD equivalent to MCC 22

23 Study 4: Tablet Peak Ejection Load 15% excipient content L-HPC reduces the peak ejection load by 20% Lowering tablet stress Less lubricant Less capping 23

24 Study 4: Tablet Tensile Strength API only and lactose 90 formulation performed poorly TS acceptable: all L-HPC grades and MCC Highest TS for LH-11 and NBD

25 Study 4: L-HPC Grades LH-21 vs. NBD-021 LH-21 NBD-021 Regular app. 45 mm L/D: 3.0 NBD-021 Same Chemistry as LH-21 narrower PSD app. 45 mm L/D: 2.2 BET Surface Area 100% Excipient (SE brochure data) Increased surface area, more narrow particle size distribution, less long fibers Higher tensile strength, less elastic recovery, better flow 25

26 Study 4: LH-11, Anti-Capping Grade LH-11 Fibrous app. 55 mm High fiber content Lowering Ejection Force Reducing die wall pressure Fibers of LH-11 form a interlocking network providing tensile strength to the tablet Anti- Capping MCC does not feature fibers and lower tensile strength is observed. Mostly plastic deformation L-HPC an Enabler for API with poor compression properties 26

27 Summary Scale Up Performance Formulation Analysis Excipient Performance Indication for performance on the rotary tablet press Lubrication study Glidant study Example using Shin-Etsu L-HPC Detailed study on ER, EF, TS Next? Compaction analysis of milled solid dispersion Granule analysis after roller compaction 27

28 Your Partner for Pharmaceutical Excipients Shin-Etsu Technical Seminar on Solubility Enhancement 13 th - 14 th of June, University of Bradford, UK Demonstration and Lectures Register at

29 What is L-HPC? Anhydroglucose unit Hydroxypropoxy L-HPC is Low subsituted Hydroxypropylcellulose MS 0.2 Insoluble in Water Binder & Disintegrant Same CAS Number, but different HPC (Hydroxypropylcellulose) Water-soluble binder MS