1. The Gamlen Tablet Press (GTP) Michael Gamlen Gamlen Tableting Ltd

2. Gamlen Tablet Press GTP1 World’s First Bench Top Tablet Press  Computer control of compaction force and compaction speed  Can be used as both as a tablet press and tablet hardness tester.  Portable and lightweight (20kg)  Simple to use

3. Computer control Can be linked to any laptop or PC. The system records:  Real time compression and punch position  Force-displacement curves  Ejection force  Able to perform multiple compactions  Easy to make layered tablets or test precompression

4. Accurate control of tablet quality  Control compression force, maximum 5kN ±1%.  Displacement rate: 0.1-1mm/s.  Can be used to control thickness±3µm.  Data capture rate 10-2000Hz

5. V Shape Compression Profile  Completely reproducible.  Provides detailed and accurate information as strain applied at a constant rate.  Established as the most sensitive way of comparing materials.

6. OPERATION OF THE PRESS IS SIMPLE AND EASY TO LEARN

7. Weigh the powder into the die using a balance

8. Place the die in the press

9. Select the compression parameters  Compression parameters are set for each compaction using the computer display  Values are carried forward to the next compaction ready for editing

11. Data display area

12. Machine display

13. Data input area

14. Select compression mode Can also use Tablet Thickness or Fracture modes

15. Select compression speed 1-60 mm/min

16. Select maximum compression force 5-500 kg

17. Die diameter and Die Height Enter values for the die in use. Dies available 2-10mm Normal size 5 or 6 mm

18. Number of compactions 1 or more as required

19. Ejection If selected, the machine will eject the tablet. If not selected, the die must be removed for ejection Used for rapid ejection.

20. Data capture rate 200Hz recommended for most purposes

21. Click on the Test button and Enter a reference for the tablet  The reference will be stored and written to the Excel data capture file  The tablet will then be compressed

22. Typical compression display Force (kg) Displacement (mm)

23. Slide the die to the ejection position

24. Eject the tablet Ejection – Polyplasdone XL

25. Eject the tablet Ejection – Avicel PH102

26. Slide the die slide back and remove the tablet from the die slide

27. Applications of the Gamlen Tablet Press

28. Ideal R&D, Clinical Trial and QC instrument  Testing product batches  Manufacture samples for compatibility tesing  Comparison of Formulations  Manufacture of preclinical materials and Phase 1 CTM  Comparison of API suppliers Formulation

29. Testing product batches

30. Comparison of GTP and Production tablet press, direct compression product Tablet strength Tablet density

31. Comparison of GTP and Production tablet press, wet granulated product Tablet strength Tablet density

32. Using the GTP-1 to scale up Performing small scale compactions on the GTP-1 have been shown to yield comparable results at the production scale Use GTP-1 to optimise tensile strength and use same compaction pressure and/ or solid fraction on scale up Considerable saving of time, materials and money using such an approach Increase speed of drug to market

33. Example Applications 1.Replacement of wet granulation with direct compression 2.API supplier evaluation 3.Lubrication studies 4.Formulation Development

34. Replacement of wet granulation with direct compression Example application 1

35. Replacing wet granulation by direct compression without changing formula Compressibility Tablet strength Compaction pressure

36. Replacing wet granulation by direct compression without changing formula Fail specification % Dissolved Time Pass specification

37. Capping prediction Example application 2

38. Capping prediction  Capping is a serious production problem, and one of the hardest to solve.  Client problem – some batches of tablets cap, but you can only tell which ones by setting up a Production tablet machine  Evaluated 4 batches on PCT (more to follow) o 2 batches which cap o 2 batches do not cap

39. Tensile strength/compaction pressure profile – batch 1

40. Tensile strength/compaction pressure profile – batches 1 and 2

41. Tensile strength/compaction pressure profile – batches 1, 2, 3 and 4

42. Capping problem - conclusions  Differences observed in compressibility between good and bad batches o Capping batches have lower peak hardness and flatter compression profiles  Need larger data set to confirm significance of results o Data being generated

43. Supplier evaluation Example application 2

44. Amoxycillin supplier evaluation Evaluation of 2 suppliers for the API amoxycillin.  Material from one supplier seems to be less compressible than the other  Material from the more compressible supplier seems more variable o Can we develop a test to distinguish between the suppliers, and see differences in compressibility?

45. Comparison of Supplier 1 batches to 400MPa

46. Comparison of two batches from supplier 1

47. Batch comparison – Supplier 2

48. Compressibility comparison Supplier 1 v Supplier 2

49. Conclusions – supplier evaluation  Supplier 1 – batches consistent  Supplier 2 – substantial differences in compressibility  Supplier 2 batches were more compressible than supplier 1  Further data needed to support definitive conclusions

50. Ejection studies – sodium bicarbonate tablet formulation Example application 3

51. Sodium bicarbonate tablet formulation Summary  My client required a sodium bicarbonate tablet formulation with a water soluble lubricant o Hard to compress, hard to lubricate  Preliminary evaluation of a proprietary compression mixture was performed  3% PEG was not found to give adequate lubrication  Each strength profile used less than 500mg of material

52. Effect of compaction pressure on sodium bicarbonate tablet strength

53. Effect of lubricant on the strength of sodium bicarbonate tablets

54. Effect of compaction pressure on tensile strength of formulated sodium bicarbonate tablets

55. Effect of lubricant on the strength of lubricated sodium bicarbonate tablets

56. Effect of lubrication on ejection force of formulated sodium bicarbonate tablets

57. Sodium bicarbonate tablet formulation conclusion  Compressibility of test formulation good  No adverse effect of lubricant on hardness profile o But lubrication still inadequate – ejection forces excessive  Conclusion o Evaluate higher levels of lubricant o Evaluate alternative lubricants

58. Intrinsic dissolution testing using the Microtest Dissolution apparatus Example application 5

59. Measurement of intrinsic dissolution rate using small amounts of material  Intrinsic dissolution rates are an important material property used in salt selection  However methods for measurement on small scale are not currently available  We are developing a test which will make this possible

60. Tablet manufacture  Prepare small “blind” dies 3mm diameter in aluminium  Compress powder samples in the dies to fixed location  Powder surface just below the die surface

61. MicroDiss apparatus Dissolution vessel

62. Microdiss test system  Online UV scanning at rapid rate o Up to 1 scan per second (? To be confirmed) o Small volumes o Can look at multiple materials o No need for specific analytical method

63. Dissolution results 64 117 191 376

64. Intrinsic dissolution rate conclusion  Dissolution rate is affected by compression force  Higher compression force=lower dissolution rate  Some work needs to be done on reproducibility  Promising technique

65. Formulation development Example application 4

66. Case study– tablet formulation  Client was preparing wet granulated from a wide range of formulation types o Lactose o Mannitol o Avicel o Range of binders  Needed to assess the most desirable formulation o Evaluated 10 formulations using compaction force/tensile strength profile

67. How to select the best tablet formulation? Some desirable tablet properties go together:  Better hardness=better friability=better film coating ability Others compete with one another:  Better (increased) hardness = worse (slower) dissolution The competition between tablet hardness and dissolution properties is often a problem. Better compressibility is always desirable  Better compressibility=lower compaction force for a given property (hardness/dissolution/friability) so the most compressible formulation normally the best The only exception to this would be if the process used to make it was itself undesirable.

68. Typical compaction force/tensile strength profile

69. All compaction force/tensile strength profiles

70. All compaction force/tensile strength profiles compared with drug substance

71. Formulation development - conclusion  Formulation improves compressibility in all cases  Some formulations/processes substantially better than others  Picked 2 of the best formulations for further evaluation o Preferred formulation was wet granulation with no external ingredients o Less preferred – significant amount of external Avicel PH102

72. Gamlen Tablet Press  World’s first portable bench top tablet press/ material tester.  Advanced data capture capability.  Unique measurement of material compressibility.  Scaleable data to rotary press  Reduces risk of failure in tablet design, development and manufacture.