Gamlen Tablet Press GTP1 World’s First Bench Top Tablet Press Unique dual mode- used as both as a tablet press and tablet hardness tester. Portable and lightweight (20kg) Welcome to the GTP1 -the world’s first bench top computer controlled tablet press. This unique instrument developed for pharmaceutical use acts both as a tablet press and also tablet hardness tester. It is both portable and lightweight making the instrument ideal for many applications in tablet research development and manufacturing. It is very easy to use.

Can be linked to any laptop or PC. Real time data recording. Computer control Can be linked to any laptop or PC. Real time data recording. Force displacement curves. Ejection force. Fracture load of compact. The instrument is fully computer controlled and can be linked to any computer running Microsoft Windows. It provides real time data recording of Force and punch displacement during material compaction. It also measures and records tablet ejection force. When used in tablet testing mode it records load and displacement during the fracture of the tablet or compact.

Force Displacement profile

Ejection force profile

Fracture profile

Simple Features and Operation Weigh powder into die. Insert die in press. Start compression cycle. Eject tablet. Quick changeover of punch sizes and mode. No special training required for set-up and operation. The press is extremely easy to use Simply weigh out powder directly into the die- in this example a powder pipette is used for accurate dispensing Insert die into the press Start compression cycle The instrument will display the F-D data in real time including max load and subsequent ejection force readings. 4. Eject the tablet once formed The simple features of the press will allow quick changeover of punch sizes and also mode change from tablet press to hardness tester. No special training is required for set up and operation making it suitable for use by all levels of staff.

Accurate control of tablet quality Control compression force OR tablet thickness. Compression force control :10N-5kN/ ±1%. Displacement Control: 0.1-1mm/s. Thickness±3µm. The Gamlen Tablet Press provides extremely accurate control of tablet quality. It will control either compression force applied or resulting tablet/ compact thickness It can control compression force in the range of 10N-5kN with force reproducibility of 1% or better. The punch speed is controlled between 0.1mm/s– 1mm/second. This is the same speed as a single punch tablet press. Compressing a tablet takes around 40 seconds. The final tablet/ compact thickness is controlled to 3 micrometers or better.

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. The Gamlen Tablet Press uses a V shape compression profile that has been shown to be the best way to generate comparative data on different materials. This test provides data which are easy to understand because the profile is fully reproducible and the strain rate is constant.

Ideal R&D, Clinical Trial and QC instrument Test product batches. Pre-formulation samples. Formulation comparison. Preclinical materials and Phase 1 CTM. Tablets 2-13mm diameter. Micro and multilayer tablets. Compress 2-400mg material. 100% yield. The advanced features of the GTP make it an ideal R&D, clinical trial and QC instrument. Its capable of making tablets between 1 and 13mm in diameter. It will compress a minimum of 2 and maximum of 400mg material with practically 100% yield saving valuable materials. Different shapes and sizes can also be accommodated including micro tablets. The photo shows an example of a microtablet made by the GTP. It can also be used to make multilayer tablets. This approach is used to keep materials separate in the tablets, and for developing extended release products.

The force needed to make the tablet. The GTP is a unique instrument able to measure material compressibility Material Compressibility is a Critical Quality Attribute which determines The force needed to make the tablet. All tablet properties- hardness, dissolution profile, friability. Currently no measure of compressibility is taken before tablet operations. The important aspect of the GTP is its capability to measure the compressibility of pharmaceutical materials. Why is this important ? Material Compressibility is a Critical Quality Attribute which determines the force needed to make a tablet from any particular material. It controls all tablet properties- hardness, dissolution profile, friability.

Risk reduction in tableting using compressibility measurements Drug substance Excipients Blending Granulation Lubricant blending Tableting As such the GTP is ideal for reducing risk in the tablet development and manufacturing process by using compressibility to measure; RM and DS quality control Post blend material quality Post granulation material quality Final blend quality prior to tableting This is because measurements taken on compacts are directly relevant to the final product and will anticipate risk of batch failure, waste of materials and expensive disposal costs.

GTP-1 scale –up to production press Major pharma compared results on a formulation with the GTP-1 and the Fette 2090 rotary press. GTP-1 -100mg 6mm flat round tablets Fette 2090- 800mg oval shaped tablets Comparable results for tensile strength from both machines

Comparison for a DC product

DC product –solid fraction

WG product

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

Tablet design and process optimisation examples Drug substance studies Formulation studies Drug salt selection for compressibility. Drug morphic form changes on compaction. Drug supplier compressibility assessments. Preparation of compacts for intrinsic dissolution testing. Formulation comparison on the milligram scale (Ranking) Multilayer tablet Dissolution studies Capping Lubricant level optimisation -ejection force and compressibility Stability studies There are various examples where the GTP has already been used in tablet dosage form design and process optimisation. These include; Drug salt selection for compressibility. Drug morphic form changes on compaction. Drug supplier compressibility assessments. Formulation comparison on the milligram scale. Preparation of compacts for intrinsic dissolution testing. Lubricant level optimisation -ejection force and compressibility.

Heckel/ Kawakita Plots Accurate measurement of punch displacement now enables assessment of material compressibility GTL can help in generation of this data for your materials

Replacement of wet granulation with direct compression Example Applications Replacement of wet granulation with direct compression Capping prediction API supplier evaluation Sodium bicarbonate tablet formulation Intrinsic dissolution testing Formulation Development The following are examples where the Gamlen Tablet Press has been used to troubleshoot, or optimise various tableting issues.

Replacement of wet granulation with direct compression Example application 1 A manufacturer of a blood pressure medicine requested that we assist in replacing the wet granulation stage with direct compression formulations. This would have considerable impact on improving the overall efficiency of the manufacturing process by saving time material costs and labour.

Example application- replacing wet granulation with direct compression This is an example of the Gamlen Tablet Press in action. In this study we measured the tensile strength of tablets containing an API for blood pressure control prepared at different compaction pressures using a granule made by wet granulation and blends of the same powders but prepared for direct compression. From the graph you can see that the direct compression formulations were more compressible than the wet granulated formulations, showing that the development of a direct compression tablet may be possible. This work was done on only about 10 grams of material.

Dissolution results comparing the formulations Two direct compression formulations gave similar dissolution profiles compared to the wet granulation product. Simple regulatory change as the excipient is not changed. Data gathered in days with milligram quantities of material saving time cost and material. Promising technique to improve productivity of tablet manufacturing. Manufacturer is now considering replacing the wet granulation stage based on this data.

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) 2 batches which cap 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 Capping batches have lower peak hardness and flatter compression profiles Need larger data set to confirm significance of results Data being generated

Supplier evaluation Example application 3

There are 2 suppliers for the API amoxycillin. Supplier evaluation There are 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 Can we develop a test to distinguish between the suppliers, and see differences in compressibility?

Comparison of Supplier 1 batches to 400MPa Client A asked us to evaluate two raw material suppliers in respect of compressibility and batch to batch variability. Samples of two batches of Supplier 1 material were compressed (without any processing or the addition of lubricant). Compressibility of the two batches was very similar in the pressure range up to 500MPa which is the normal maximum used during tableting.

Comparison of supplier 1 batches full profile To assess the capping tendency of the different sources of material, the compaction pressure range was extended to up to 700MPa. This was possible because we were using a special 3mm punch and die set which can withstand very high pressures. The strength of the tablets made from Supplier 1 material decreased rapidly at compaction pressures above the normal range.

Batch comparison – Supplier 2 Two batches of Supplier 2 material were compressed. Their compressibility was substantially different. When Supplier 2 material was compressed above the normal range, the capping profile observed was different for the two batches.

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

Sodium bicarbonate tablet formulation Example application 4

Sodium bicarbonate tablet formulation My client required a sodium bicarbonate tablet formulation with a water soluble lubricant 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 But lubrication still inadequate – ejection forces excessive Conclusion Evaluate higher levels of lubricant 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

Prepare small “blind” dies 3mm diameter in aluminium 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

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

Dissolution results 64 117 376 191

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 6

Case study– tablet formulation Client was preparing wet granulated from a wide range of formulation types Lactose Mannitol Avicel Range of binders Needed to assess the most desirable formulation 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

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 Preferred formulation was wet granulation with no external ingredients Less preferred – significant amount of external Avicel PH102

World’s first portable bench top tablet press/ material tester. 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. In summary the Gamlen Tablet Press provides a unique capability in pharmaceutical material compressibility assessment and small scale tablet production. It features advanced data capture capability together with a unique measure of material compressibility. Use of the Gamlen Tablet Press reduces the risk of tablet problems and ultimately speeds your drug product to market.

Contact Gamlen Tableting Ltd. For further details, applications and price contact: Dr Dipankar Dey Gamlen Tableting Ltd. Biocity Nottingham Nottingham NG1 1GF UK Tel: +44 7712 632735 Fax: +44 115 912 4278 Email: dip@pharmdservices.com http://www.gamlen.co.uk For further information please contact Dipankar Dey or see our website www.compressibility.com