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

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

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

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 Hz

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.

OPERATION OF THE PRESS IS SIMPLE AND EASY TO LEARN

Weigh the powder into the die using a balance

Place the die in the press

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

Data display area

Machine display

Data input area

Select compression mode Can also use Tablet Thickness or Fracture modes

Select compression speed 1-60 mm/min

Select maximum compression force kg

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

Number of compactions 1 or more as required

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

Data capture rate 200Hz recommended for most purposes

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

Typical compression display Force (kg) Displacement (mm)

Slide the die to the ejection position

Eject the tablet Ejection – Polyplasdone XL

Eject the tablet Ejection – Avicel PH102

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

Applications of the Gamlen Tablet Press

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

Testing product batches

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

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

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

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

Replacement of wet granulation with direct compression Example application 1

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

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

Capping prediction Example application 2

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

Tensile strength/compaction pressure profile – batch 1

Tensile strength/compaction pressure profile – batches 1 and 2

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

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

Supplier evaluation Example application 2

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?

Comparison of Supplier 1 batches to 400MPa

Comparison of two batches from supplier 1

Batch comparison – Supplier 2

Compressibility comparison Supplier 1 v Supplier 2

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

Ejection studies – sodium bicarbonate tablet formulation Example application 3

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

Effect of compaction pressure on sodium bicarbonate tablet strength

Effect of lubricant on the strength of sodium bicarbonate tablets

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

Effect of lubricant on the strength of lubricated sodium bicarbonate tablets

Effect of lubrication on ejection force of formulated sodium bicarbonate tablets

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

Intrinsic dissolution testing using the Microtest Dissolution apparatus Example application 5

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

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

MicroDiss apparatus Dissolution vessel

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

Dissolution results

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

Formulation development Example application 4

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

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.

Typical compaction force/tensile strength profile

All compaction force/tensile strength profiles

All compaction force/tensile strength profiles compared with drug substance

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

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.