SCALEABILITY OF GTP-1 DATA WITH A FETTE 2090 ROTARY PRESS FOR A DIRECT COMPRESSION AND WET GRANULATED PRODUCTD DEY1, MJ GAMLEN1, 2KG PITT, 2RJ WEBBER, 2K HILL 1GAMLEN TABLETING LTD, BIOCITY NOTTINGHAM

NOTTINGHAM NG1 1GF UK 2GSK GLOBAL MANUFACTURING AND SUPPLY PRIORY ST WARE SG120DJ UK

ABSTRACT

A major issue in using small scale compaction studies to address manufacturing and development challenges is the validity of the data at the large scale. In this paper we present a systematic approach to address tablet manufacturing issues using a novel bench top press capable of compressing milligram quantities of material. This bench top press uniquely delivers a rapid compressibility assessment of formulations and the tensile strength of subsequent tablets, and we show that these provide an accurate prediction of tablet quality using a rotary tablet press in large scale product manufacture.

We investigated the compressibility of two formulations of well-known medicines, one produced by direct compression and the other by wet granulation. The compressibility of the two formulations on the bench top single station tablet press (Gamlen Tablet Press GTP-1) was compared with that on the rotary tablet press (Fette 2090) used in large scale manufacture. Tablets were formed using the Gamlen Tablet Press GTP-1 at various compaction pressures-1, 2, 3, 4 and 5kN. 100mg of each material was compressed to form a 6mm round faced tablet. Data was collected on the compression profile, weight and thickness of the tablet formed. The tablets were then crushed on the same instrument and the fracture profile recorded as well as peak fracture load. This was repeated for both formulations and a profile of the compressibility and tensile strength of the tablets built up.

The data was compared with data already gained from production runs of the formulations on a Fette 2090 tablet press. In this case 800mg (for the direct compression product) and 1140mg (for the wet granulated product) caplet-shaped tablets were produced, providing a great contrast to the round 100mg tablets produced on the GTP-1. Data from the two formulations compacted on the GTP-1 was comparable to production data obtained on the high speed rotary press (Fette 2090). Analysis of tablet tensile strength to compaction pressure and solid fraction demonstrated that the results obtained on the GTP-1 can be reproduced for different sizes of tablets produced on a rotary press.

PURPOSE AND HYPOTHESIS

The value in using small compacts compressed at defined compression forces for tablet preformulation and formulation is well established (Marshall 1989). We have already shown that the GTP-1 is an ideal instrument to perform such experiments quickly and accurately (Dey et al 2011, Dey et al 2012).

MATERIALS AND METHODS

FormulationsWe investigated the tablet quality of two different formulations with a high loading of drug active.Formulation A- a direct compression formulation containing 70% drug in Avicel made at a 200kg batch scale.Formulation B- a wet granulated formulation containing 80% drug in Avicel/ PVP binder made at a 300kg batch scale and dried in a fluidised bed.Both formulations were lubricated with 1% magnesium stearate.

TabletingTablets were produced from the two formulations on the Gamlen Tablet Press GTP-1 and the Fette 2090 rotary press. The GTP-1 used a 6mm flat face round punch to produce 100mg cylindrical compacts at various compression pressures ranging from 1kN to 5kN. Data was collected on the maximum compression pressure applied, weight and thickness of the tablet. Tablets were fractured on the GTP-1 using the diametral compression test. For cylindrical tablets this can be calculated from the breaking force according to the following equation first used by Fell & Newton in 1970 (1):

AN EVALUATION OF VARIOUS DIRECT COMPRESSION INGREDIENTS USING THE GAMLEN TABLET PRESS GTP-1

DIPANKAR DEY, MICHAEL GAMLEN, GAMLEN TABLETING LTD, BIOCITY NOTTINGHAM, NOTTINGHAM UK NG1 1GF

The modern tablet needs to satisfy a number of parameters that make it fit for purpose such as hardness, potency, friability and dissolution as well as be suitable for commercial manufacture using a rotary tablet press. Performing a sufficient number of experiments to optimise the formulation is often limited by the quantity of API available and the nature of the equipment used. We present here an approach to tablet formulation using a novel bench top computer controlled tablet press—the Gamlen Tablet Press GTP-1. This requires only milligram quantities of material, is objective and practical. The approach is based on establishing the compressibility of the formulation as determined by tablet tensile strength measurements using the diametral compression test (Fell &Newton) over a range of compression pressures ; Tensile strength is an objective measure of tablet strength as it takes into account both hardness and tablet thickness. As such it can be used to compare tablets of different shapes and sizes (Pitt &Heasley 2012). In addition we can also measure ejection stress associated with each formulation from the ejection force normalised with tablet thickness.

In the preliminary experiment the Galen IQ, Parteck SD and Perlitol SD grades were the most compressible whilst the Perlitol DC grades had the least. All formulations showed high ejection stress. We selected the 200 mesh size of each brand for further development with L-HPC21 in the Main experiments. The L-HPC21 substantially increased compressibility, and also reduced ejection stress and friability The drug percentage had a major effect in reducing compressibility particularly for the Galen IQ. Using The combination of results gained on compressibility combined with powder flow and ejection stress results give a useful screening method when selecting the formulation of choice. We assigned the gradient of the tensile strength v compression pressure profiles as the compressibility of the formulation. When plotted against the powder flowability for each formulation we can visualise the results as a ‘Decision Matrix’. The Galen 0.1%/1% + L-HPC21 exhibit the best combination of compressibility and flow behaviour. In this work we have shown that rapid screening of formulations using the Gamlen Tablet Press GTP-1 is a very useful approach to development of the required tablet profile using the compression gradient as a measure of compressibility. We propose that this be considered as a Critical Quality Attribute of a tablet formulation in the tablet Quality by Design paradigm.

The formulation was developed in two stages. Preliminary experiments determined the compressibility of a formulation containing the drug (acetaminophen), excipient and lubricant; ten excipients and excipient grades were evaluated on a 100g scale. In the main experiments we used the best formulations, selected using tensile fracture strength/compaction pressure profiles. To improve compressibility we added 20% L-HPC21 (Shin-Etsu). The magnesium stearate concentration was kept at 0.5%w/w. All formulations were made using the Gamlen Tablet Press GTP-1 (Nottingham UK) to produce 75mg round flat face tablets. The tablets were subjected to tensile fracture stress testing on the GTP-1, friability and disintegration measurements. Ejection stress was also recorded for each tablet.

Fell JT and Newton JM. Determination of tablet strength by the diametral compression test. J Pharm Sci 59; 688-691, 1970 Pitt & Heasley. Powder Technology 2012. http://dx.doi.org/10.1016/j.powtec.2011.12.060)

BACKGROUND AND APPROACH

APPROACH

MATERIALS AND METHODS

RESULTS

DISCUSSION AND CONCLUSION

REFERENCES

Preliminary Experiments

σt is the tensile fracture strength of the tablet, P is the fracture force (N), D is the tablet diameter, t is the overall thickness

Mannitol grade Parteck (Merck)

Mannitol grade Perlitol (Roquette)

Isomaltulose (Beneo-Palatinit)

Parteck M100

Perlitol 100SD

Galen IQ720

Parteck M200

Perlitol 200SD

Galen IQ721

Parteck M300

Perlitol 300DC

Perlitol 400DC

Perlitol 500DC

Main Experiments We have shown previously that the Gamlen Tablet Press GTP-1 can rapidly evaluate formulations for tablet development using milligram quantities of material. Uniquely for a tablet press it gives precise information on the compression force, ejection force and fracture force of an individual tablet, providing valuable information for the required target product profile, required for Quality by Design (QbD). We present in this work an evaluation of a number of different direct compression excipients in the development of a paracetamol tablet. We evaluated a number of different direct compression excipients to prepare a formulation containing 10% paracetamol. The formulations were blended for 30 minutes and lubricated with 0.5% magnesium stearate for a further 5 minutes in a blender. Each formulation was then compacted using the Gamlen Tablet Press GTP-1 to produce round flat face tablets. Tablets weresubjected to tensile strength, friability and disintegration testing, whilst the formulation was tested for flowability and LOD. The initial experiments showed clear differences between formulations in compressibility, friability, disintegration and powder flowability. Among the mannitol grades the compressibility of the SD types was better than the DC types. Very high ejection forces were recorded despite use of a lubricant. Individual ejection profiles analysed by the GTP-1 revealed the important relationship of material properties with ejection of the tablet from the die- a key determinant of suitability for rotary press manufacture. The main experiments characterised the compressibility and tablet behaviour of the most compressible excipients, with the low API% formulas performing best. Evaluation of a wide range of formulations using using the GTP-1 provided valuable information on compression force, ejection force and disintegration times of individual tablets using very small amounts of material. This enables an evaluation of the widest possible tablet quality and tablet/ material processing parameters to aid formulation development.

ABSTRACT

Formulation Compressibility Index (%)

Minimum orifice size

LOD%

Parteck M100

14.5 16 0.27

Parteck M200

12.9 20 0.17

Parteck M300

7.4 14 0.19

Perlitol 100SD

13.5 20 0.16

Perlitol 200SD

11.63 18 0.11

Perlitol 300DC

8.3 10 0.14

Perlitol 400DC

6.7 8 0.11

Perlitol 500DC

8.1 5 0.14

Galen IQ720

11.25 16 4.07

Galen IQ721

13.4 12 1.5

Formulation Compressibility Index (%)

Minimum orifice size

LOD%

Parteck 0.1% 16.25 18 0.81

Parteck 1% 16.25 16 1.13

Parteck 10% 17.5 22 1.10

Perlitol 0.1% 11.25 12 0.96

Perlitol 1% 8.75 16 0.98

Perlitol 10% 16.25 18 1.32

Galen 0.1% 13.75 7 2.70

Galen 1% 16.25 8 2.65

Galen 10% 16.25 20 2.21

Scaleability of GTP-1 data with a Fette 2090 rotary press for a direct compression and wet granulated product

D Dey1, MJ Gamlen1, 2KG Pitt, 2RJ Webber, 2K Hill 1Gamlen Tableting Ltd, Biocity Nottingham Nottingham NG1 1GF UK 2GSK Global Manufacturing and Supply Priory St Ware SG120DJ UK

A major issue in using small scale compaction studies to address manufacturing and development challenges is the validity of the data at

the large scale. In this paper we present a systematic approach to address tablet manufacturing issues using a novel bench top press capable of compressing milligram quantities of material. This bench top press uniquely delivers a rapid compressibility assessment of formulations and the tensile strength of subsequent tablets, and we show that these provide an accurate prediction of tablet quality using a rotary tablet press in large scale product manufacture. We investigated the compressibility of two formulations of well-known medicines, one produced by direct compression and the other by wet granulation. The compressibility of the two formulations on the bench top single station tablet press (Gamlen Tablet Press GTP-1) was compared with that on the rotary tablet press (Fette 2090) used in large scale manufacture. Tablets were formed using the Gamlen Tablet Press GTP-1 at various compaction pressures-1, 2, 3, 4 and 5kN. 100mg of each material was compressed to form a 6mm round faced tablet. Data was collected on the compression profile, weight and thickness of the tablet formed. The tablets were then crushed on the same instrument and the fracture profile recorded as well as peak fracture load. This was repeated for both formulations and a profile of the compressibility and tensile strength of the tablets built up. The data was compared with data already gained from production runs of the formulations on a Fette 2090 tablet press. In this case 800mg (for the direct compression product) and 1140mg (for the wet granulated product) caplet-shaped tablets were produced, providing a great contrast to the round 100mg tablets produced on the GTP-1. Data from the two formulations compacted on the GTP-1 was comparable to production data obtained on the high speed rotary press (Fette 2090). Analysis of tablet tensile strength to compaction pressure and solid fraction demonstrated that the results obtained on the GTP-1 can be reproduced for different sizes of tablets produced on a rotary press.

For both formulations the tensile strength of 100mg cylindrical tablets made by the GTP-1 are consistent with the tensile strength of 800mg and 1140mg caplet shape tablets made on a Fette rotary press. For the direct compression product the values are shown in relation to the compression pressure whilst for the wet granulated product the solid fraction (relative density) is used. The results, whilst surprising, do reinforce the applicability of equations (1) and (2) to tablets of different size and shape made on different pieces of equipment. This shows the value of using small scale tableting for tablet development and manufacturing. With API costs in the range of $2000/kg, using milligram quantities of material on an instrument such as the GTP-1 provides obvious benefits. Multiple experiments may be carried out at the development stage to optimize the formulation in terms of tensile strength, with the results being directly comparable to the manufacturing scale.

Formulations We investigated the tablet quality of two different formulations with a high loading of drug active. Formulation A- a direct compression formulation containing 70% drug in Avicel made at a 200kg batch scale. Formulation B- a wet granulated formulation containing 80% drug in Avicel/ PVP binder made at a 300kg batch scale and dried in a fluidised bed. Both formulations were lubricated with 1% magnesium stearate. Tableting Tablets were produced from the two formulations on the Gamlen Tablet Press GTP-1 and the Fette 2090 rotary press. The GTP-1 used a 6mm flat face round punch to produce 100mg cylindrical compacts at various compression pressures ranging from 1kN to 5kN. Data was collected on the maximum compression pressure applied, weight and thickness of the tablet. Tablets were fractured on the GTP-1 using the diametral compression test. For cylindrical tablets this can be calculated from the breaking force according to the following equation first used by Fell & Newton in 1970 (1): (1) σt is the tensile fracture strength of the tablet, P is the fracture force (N), D is the tablet diameter, t is the overall thickness The equation takes account of the breaking load, thickness and diameter of the tablet. This formula is only correct for flat-face cylindrical tablets. 17x7mm 800mg caplet shaped tablets of Formulation A and 20x9.5mm 1140mg caplet shaped tablets of Formulation B were produced on the Fette 2090 at various compression pressures ranging from 6.5kN to 30kN- considerably more than used on the GTP-1. Tablets were collected and measured for dimensions and breaking load. From this the tensile strength of the caplet shaped tablets was determined according to the equation of Pitt & Heasley (2012) (2). (2) σt is the tensile strength, P is the fracture load (N), D is the length of the short axis, t is the overall thickness and W is the wall height of the tablet This equation is used in particular for oval and caplet-shaped tablets where the long axis (L) is at least 1.7 times that of the short axis (D), which is the case for nearly all pharmaceutical tablets. Comparison The tablet tensile strength was compared to both the compression pressure and relative density (solid fraction) for the results from the GTP-1 and Fette. The relative density was calculated from the ratio of the tablet density to the true density of the formulation.

We have shown that the tensile strength of 100mg compacts made on the GTP-1 can be successfully scaled to 800mg and 1140mg caplet shapes made on a Fette 2090 rotary press. The validity of the results at different scales provides a technique by which to optimise and troubleshoot tablet formulation development and manufacturing.

Marshall K. Monitoring punch forces and punch movements as an aid to developing robust tablet formulations. Drug Dev.Ind.Pharm. 15(13) 2153-2176(1989) Dey D, Gamlen MJ, Brown S, Thorne B. Intelligent tablet formulation using rapid compressibility assessment. Poster at AAPS 2011 Washington Dey D, Gamlen MJ. Evaluation of various direct compression excipients using the Gamlen Tablet Press GTP-1. Poster at AAPS 2012 Chicago Fell JT, Newton JM. Determination of tablet tensile strength by the diamteral compression test. J PharmSci 59: 688-691 (1970) Pitt KG, Heasley MG. Determination of the tensile strength of elongated tablets. http://dx.doi.org/10.1016/j.powtec.2011.12.060

The value in using small compacts compressed at defined compression forces for tablet preformulation and formulation is well established (Marshall 1989). We have already shown that the GTP-1 is an ideal instrument to perform such experiments quickly and accurately (Dey et al 2011, Dey et al 2012). The strength of the compact can be defined simply in terms of the compressive force required to fracture a specimen across its diameter. In the pharmaceutical industry this is referred to as a "hardness test". More complex shapes can also be crushed by this method. However the breaking load does not take into account either the dimensions and shape of the compact or the mode of failure. The conversion of a fracture load to tensile strength, which takes these factors into account, allows for ready comparisons to be made between samples of different shapes or sizes. The tensile strength of a tablet is an important attribute as the tablet needs to be mechanically strong enough to withstand further handling such as film–coating, packaging, transport and end-use by the patient, but to be weak enough to break apart in the human body and so release its contents. Generally, a tensile strength greater than 1.7 MPa will usually suffice in ensuring that a tablet is mechanically strong enough to withstand commercial manufacture and subsequent distribution. Tensile strengths down to 1 MPa may suffice for small batches where the tablets are not subjected to large mechanical stresses.The question remains though whether the results derived from such small scale studies are valid when used on a manufacturing scale typically using a rotary press. In this work we investigated whether the tensile strength could be used for comparison between tablets of different shape or size.

ABSTRACT

PURPOSE AND HYPOTHESIS

MATERIALS AND METHODS RESULTS AND DISCUSSION

CONCLUSIONS

BIBLIOGRAPHY

AM-12-02047

The strength of the compact can be defined simply in terms of the compressive force required to fracture a specimen across its diameter. In the pharmaceutical industry this is referred to as a “hardness test”. More complex shapes can also be crushed by this method. However the breaking load does not take into account either the dimensions and shape of the compact or the mode of failure. The conversion of a fracture load to tensile strength, which takes these factors into account, allows for ready comparisons to be made between samples of different shapes or sizes. The tensile strength of a tablet is an important attribute as the tablet needs to be mechanically strong enough to withstand further handling such as film–coating, packaging, transport and end-use by the patient, but to be weak enough to break apart in the human body and so release its contents.Generally, a tensile strength greater than 1.7 MPa will usually suffice in ensuring that a tablet is mechanically strong enough to withstand commercial manufacture and subsequent distribution. Tensile strengths down to 1 MPa may suffice for small batches where the tablets are not subjected to large mechanical stresses.The question remains though whether the results derived from such small scale studies are valid when used on a manufacturing scale typically using a rotary press. In this work we investigated whether the tensile strength could be used for comparison between tablets of different shape or size.

σt =2PπDt

Scaleability of GTP-1 data with a Fette 2090 rotary press for a direct compression and wet granulated product

D Dey1, MJ Gamlen1, 2KG Pitt, 2RJ Webber, 2K Hill 1Gamlen Tableting Ltd, Biocity Nottingham Nottingham NG1 1GF UK 2GSK Global Manufacturing and Supply Priory St Ware SG120DJ UK

A major issue in using small scale compaction studies to address manufacturing and development challenges is the validity of the data at

the large scale. In this paper we present a systematic approach to address tablet manufacturing issues using a novel bench top press capable of compressing milligram quantities of material. This bench top press uniquely delivers a rapid compressibility assessment of formulations and the tensile strength of subsequent tablets, and we show that these provide an accurate prediction of tablet quality using a rotary tablet press in large scale product manufacture. We investigated the compressibility of two formulations of well-known medicines, one produced by direct compression and the other by wet granulation. The compressibility of the two formulations on the bench top single station tablet press (Gamlen Tablet Press GTP-1) was compared with that on the rotary tablet press (Fette 2090) used in large scale manufacture. Tablets were formed using the Gamlen Tablet Press GTP-1 at various compaction pressures-1, 2, 3, 4 and 5kN. 100mg of each material was compressed to form a 6mm round faced tablet. Data was collected on the compression profile, weight and thickness of the tablet formed. The tablets were then crushed on the same instrument and the fracture profile recorded as well as peak fracture load. This was repeated for both formulations and a profile of the compressibility and tensile strength of the tablets built up. The data was compared with data already gained from production runs of the formulations on a Fette 2090 tablet press. In this case 800mg (for the direct compression product) and 1140mg (for the wet granulated product) caplet-shaped tablets were produced, providing a great contrast to the round 100mg tablets produced on the GTP-1. Data from the two formulations compacted on the GTP-1 was comparable to production data obtained on the high speed rotary press (Fette 2090). Analysis of tablet tensile strength to compaction pressure and solid fraction demonstrated that the results obtained on the GTP-1 can be reproduced for different sizes of tablets produced on a rotary press.

For both formulations the tensile strength of 100mg cylindrical tablets made by the GTP-1 are consistent with the tensile strength of 800mg and 1140mg caplet shape tablets made on a Fette rotary press. For the direct compression product the values are shown in relation to the compression pressure whilst for the wet granulated product the solid fraction (relative density) is used. The results, whilst surprising, do reinforce the applicability of equations (1) and (2) to tablets of different size and shape made on different pieces of equipment. This shows the value of using small scale tableting for tablet development and manufacturing. With API costs in the range of $2000/kg, using milligram quantities of material on an instrument such as the GTP-1 provides obvious benefits. Multiple experiments may be carried out at the development stage to optimize the formulation in terms of tensile strength, with the results being directly comparable to the manufacturing scale.

Formulations We investigated the tablet quality of two different formulations with a high loading of drug active. Formulation A- a direct compression formulation containing 70% drug in Avicel made at a 200kg batch scale. Formulation B- a wet granulated formulation containing 80% drug in Avicel/ PVP binder made at a 300kg batch scale and dried in a fluidised bed. Both formulations were lubricated with 1% magnesium stearate. Tableting Tablets were produced from the two formulations on the Gamlen Tablet Press GTP-1 and the Fette 2090 rotary press. The GTP-1 used a 6mm flat face round punch to produce 100mg cylindrical compacts at various compression pressures ranging from 1kN to 5kN. Data was collected on the maximum compression pressure applied, weight and thickness of the tablet. Tablets were fractured on the GTP-1 using the diametral compression test. For cylindrical tablets this can be calculated from the breaking force according to the following equation first used by Fell & Newton in 1970 (1): (1) σt is the tensile fracture strength of the tablet, P is the fracture force (N), D is the tablet diameter, t is the overall thickness The equation takes account of the breaking load, thickness and diameter of the tablet. This formula is only correct for flat-face cylindrical tablets. 17x7mm 800mg caplet shaped tablets of Formulation A and 20x9.5mm 1140mg caplet shaped tablets of Formulation B were produced on the Fette 2090 at various compression pressures ranging from 6.5kN to 30kN- considerably more than used on the GTP-1. Tablets were collected and measured for dimensions and breaking load. From this the tensile strength of the caplet shaped tablets was determined according to the equation of Pitt & Heasley (2012) (2). (2) σt is the tensile strength, P is the fracture load (N), D is the length of the short axis, t is the overall thickness and W is the wall height of the tablet This equation is used in particular for oval and caplet-shaped tablets where the long axis (L) is at least 1.7 times that of the short axis (D), which is the case for nearly all pharmaceutical tablets. Comparison The tablet tensile strength was compared to both the compression pressure and relative density (solid fraction) for the results from the GTP-1 and Fette. The relative density was calculated from the ratio of the tablet density to the true density of the formulation.

We have shown that the tensile strength of 100mg compacts made on the GTP-1 can be successfully scaled to 800mg and 1140mg caplet shapes made on a Fette 2090 rotary press. The validity of the results at different scales provides a technique by which to optimise and troubleshoot tablet formulation development and manufacturing.

Marshall K. Monitoring punch forces and punch movements as an aid to developing robust tablet formulations. Drug Dev.Ind.Pharm. 15(13) 2153-2176(1989) Dey D, Gamlen MJ, Brown S, Thorne B. Intelligent tablet formulation using rapid compressibility assessment. Poster at AAPS 2011 Washington Dey D, Gamlen MJ. Evaluation of various direct compression excipients using the Gamlen Tablet Press GTP-1. Poster at AAPS 2012 Chicago Fell JT, Newton JM. Determination of tablet tensile strength by the diamteral compression test. J PharmSci 59: 688-691 (1970) Pitt KG, Heasley MG. Determination of the tensile strength of elongated tablets. http://dx.doi.org/10.1016/j.powtec.2011.12.060

The value in using small compacts compressed at defined compression forces for tablet preformulation and formulation is well established (Marshall 1989). We have already shown that the GTP-1 is an ideal instrument to perform such experiments quickly and accurately (Dey et al 2011, Dey et al 2012). The strength of the compact can be defined simply in terms of the compressive force required to fracture a specimen across its diameter. In the pharmaceutical industry this is referred to as a "hardness test". More complex shapes can also be crushed by this method. However the breaking load does not take into account either the dimensions and shape of the compact or the mode of failure. The conversion of a fracture load to tensile strength, which takes these factors into account, allows for ready comparisons to be made between samples of different shapes or sizes. The tensile strength of a tablet is an important attribute as the tablet needs to be mechanically strong enough to withstand further handling such as film–coating, packaging, transport and end-use by the patient, but to be weak enough to break apart in the human body and so release its contents. Generally, a tensile strength greater than 1.7 MPa will usually suffice in ensuring that a tablet is mechanically strong enough to withstand commercial manufacture and subsequent distribution. Tensile strengths down to 1 MPa may suffice for small batches where the tablets are not subjected to large mechanical stresses.The question remains though whether the results derived from such small scale studies are valid when used on a manufacturing scale typically using a rotary press. In this work we investigated whether the tensile strength could be used for comparison between tablets of different shape or size.

ABSTRACT

PURPOSE AND HYPOTHESIS

MATERIALS AND METHODS RESULTS AND DISCUSSION

CONCLUSIONS

BIBLIOGRAPHY

AM-12-02047

(1)σt is the tensile fracture strength of the tablet, P is the fracture force (N), D is the tablet diameter, t is the overall thicknessThe equation takes account of the breaking load, thickness and diameter of the tablet. This formula is only correct for flat-face cylindrical tablets.17x7mm 800mg caplet shaped tablets of Formulation A and 20x9.5mm 1140mg caplet shaped tablets of

Scaleability of GTP-1 data with a Fette 2090 rotary press for a direct compression and wet granulated product

D Dey1, MJ Gamlen1, 2KG Pitt, 2RJ Webber, 2K Hill 1Gamlen Tableting Ltd, Biocity Nottingham Nottingham NG1 1GF UK 2GSK Global Manufacturing and Supply Priory St Ware SG120DJ UK

A major issue in using small scale compaction studies to address manufacturing and development challenges is the validity of the data at

the large scale. In this paper we present a systematic approach to address tablet manufacturing issues using a novel bench top press capable of compressing milligram quantities of material. This bench top press uniquely delivers a rapid compressibility assessment of formulations and the tensile strength of subsequent tablets, and we show that these provide an accurate prediction of tablet quality using a rotary tablet press in large scale product manufacture. We investigated the compressibility of two formulations of well-known medicines, one produced by direct compression and the other by wet granulation. The compressibility of the two formulations on the bench top single station tablet press (Gamlen Tablet Press GTP-1) was compared with that on the rotary tablet press (Fette 2090) used in large scale manufacture. Tablets were formed using the Gamlen Tablet Press GTP-1 at various compaction pressures-1, 2, 3, 4 and 5kN. 100mg of each material was compressed to form a 6mm round faced tablet. Data was collected on the compression profile, weight and thickness of the tablet formed. The tablets were then crushed on the same instrument and the fracture profile recorded as well as peak fracture load. This was repeated for both formulations and a profile of the compressibility and tensile strength of the tablets built up. The data was compared with data already gained from production runs of the formulations on a Fette 2090 tablet press. In this case 800mg (for the direct compression product) and 1140mg (for the wet granulated product) caplet-shaped tablets were produced, providing a great contrast to the round 100mg tablets produced on the GTP-1. Data from the two formulations compacted on the GTP-1 was comparable to production data obtained on the high speed rotary press (Fette 2090). Analysis of tablet tensile strength to compaction pressure and solid fraction demonstrated that the results obtained on the GTP-1 can be reproduced for different sizes of tablets produced on a rotary press.

For both formulations the tensile strength of 100mg cylindrical tablets made by the GTP-1 are consistent with the tensile strength of 800mg and 1140mg caplet shape tablets made on a Fette rotary press. For the direct compression product the values are shown in relation to the compression pressure whilst for the wet granulated product the solid fraction (relative density) is used. The results, whilst surprising, do reinforce the applicability of equations (1) and (2) to tablets of different size and shape made on different pieces of equipment. This shows the value of using small scale tableting for tablet development and manufacturing. With API costs in the range of $2000/kg, using milligram quantities of material on an instrument such as the GTP-1 provides obvious benefits. Multiple experiments may be carried out at the development stage to optimize the formulation in terms of tensile strength, with the results being directly comparable to the manufacturing scale.

Formulations We investigated the tablet quality of two different formulations with a high loading of drug active. Formulation A- a direct compression formulation containing 70% drug in Avicel made at a 200kg batch scale. Formulation B- a wet granulated formulation containing 80% drug in Avicel/ PVP binder made at a 300kg batch scale and dried in a fluidised bed. Both formulations were lubricated with 1% magnesium stearate. Tableting Tablets were produced from the two formulations on the Gamlen Tablet Press GTP-1 and the Fette 2090 rotary press. The GTP-1 used a 6mm flat face round punch to produce 100mg cylindrical compacts at various compression pressures ranging from 1kN to 5kN. Data was collected on the maximum compression pressure applied, weight and thickness of the tablet. Tablets were fractured on the GTP-1 using the diametral compression test. For cylindrical tablets this can be calculated from the breaking force according to the following equation first used by Fell & Newton in 1970 (1): (1) σt is the tensile fracture strength of the tablet, P is the fracture force (N), D is the tablet diameter, t is the overall thickness The equation takes account of the breaking load, thickness and diameter of the tablet. This formula is only correct for flat-face cylindrical tablets. 17x7mm 800mg caplet shaped tablets of Formulation A and 20x9.5mm 1140mg caplet shaped tablets of Formulation B were produced on the Fette 2090 at various compression pressures ranging from 6.5kN to 30kN- considerably more than used on the GTP-1. Tablets were collected and measured for dimensions and breaking load. From this the tensile strength of the caplet shaped tablets was determined according to the equation of Pitt & Heasley (2012) (2). (2) σt is the tensile strength, P is the fracture load (N), D is the length of the short axis, t is the overall thickness and W is the wall height of the tablet This equation is used in particular for oval and caplet-shaped tablets where the long axis (L) is at least 1.7 times that of the short axis (D), which is the case for nearly all pharmaceutical tablets. Comparison The tablet tensile strength was compared to both the compression pressure and relative density (solid fraction) for the results from the GTP-1 and Fette. The relative density was calculated from the ratio of the tablet density to the true density of the formulation.

We have shown that the tensile strength of 100mg compacts made on the GTP-1 can be successfully scaled to 800mg and 1140mg caplet shapes made on a Fette 2090 rotary press. The validity of the results at different scales provides a technique by which to optimise and troubleshoot tablet formulation development and manufacturing.

Marshall K. Monitoring punch forces and punch movements as an aid to developing robust tablet formulations. Drug Dev.Ind.Pharm. 15(13) 2153-2176(1989) Dey D, Gamlen MJ, Brown S, Thorne B. Intelligent tablet formulation using rapid compressibility assessment. Poster at AAPS 2011 Washington Dey D, Gamlen MJ. Evaluation of various direct compression excipients using the Gamlen Tablet Press GTP-1. Poster at AAPS 2012 Chicago Fell JT, Newton JM. Determination of tablet tensile strength by the diamteral compression test. J PharmSci 59: 688-691 (1970) Pitt KG, Heasley MG. Determination of the tensile strength of elongated tablets. http://dx.doi.org/10.1016/j.powtec.2011.12.060

The value in using small compacts compressed at defined compression forces for tablet preformulation and formulation is well established (Marshall 1989). We have already shown that the GTP-1 is an ideal instrument to perform such experiments quickly and accurately (Dey et al 2011, Dey et al 2012). The strength of the compact can be defined simply in terms of the compressive force required to fracture a specimen across its diameter. In the pharmaceutical industry this is referred to as a "hardness test". More complex shapes can also be crushed by this method. However the breaking load does not take into account either the dimensions and shape of the compact or the mode of failure. The conversion of a fracture load to tensile strength, which takes these factors into account, allows for ready comparisons to be made between samples of different shapes or sizes. The tensile strength of a tablet is an important attribute as the tablet needs to be mechanically strong enough to withstand further handling such as film–coating, packaging, transport and end-use by the patient, but to be weak enough to break apart in the human body and so release its contents. Generally, a tensile strength greater than 1.7 MPa will usually suffice in ensuring that a tablet is mechanically strong enough to withstand commercial manufacture and subsequent distribution. Tensile strengths down to 1 MPa may suffice for small batches where the tablets are not subjected to large mechanical stresses.The question remains though whether the results derived from such small scale studies are valid when used on a manufacturing scale typically using a rotary press. In this work we investigated whether the tensile strength could be used for comparison between tablets of different shape or size.

ABSTRACT

PURPOSE AND HYPOTHESIS

MATERIALS AND METHODS RESULTS AND DISCUSSION

CONCLUSIONS

BIBLIOGRAPHY

AM-12-02047

US_Letter_Poster2.indd 1 06/10/2012 12:29

Scaleability of GTP-1 data with a Fette 2090 rotary press for a direct compression and wet granulated product

D Dey1, MJ Gamlen1, 2KG Pitt, 2RJ Webber, 2K Hill 1Gamlen Tableting Ltd, Biocity Nottingham Nottingham NG1 1GF UK 2GSK Global Manufacturing and Supply Priory St Ware SG120DJ UK

A major issue in using small scale compaction studies to address manufacturing and development challenges is the validity of the data at

the large scale. In this paper we present a systematic approach to address tablet manufacturing issues using a novel bench top press capable of compressing milligram quantities of material. This bench top press uniquely delivers a rapid compressibility assessment of formulations and the tensile strength of subsequent tablets, and we show that these provide an accurate prediction of tablet quality using a rotary tablet press in large scale product manufacture. We investigated the compressibility of two formulations of well-known medicines, one produced by direct compression and the other by wet granulation. The compressibility of the two formulations on the bench top single station tablet press (Gamlen Tablet Press GTP-1) was compared with that on the rotary tablet press (Fette 2090) used in large scale manufacture. Tablets were formed using the Gamlen Tablet Press GTP-1 at various compaction pressures-1, 2, 3, 4 and 5kN. 100mg of each material was compressed to form a 6mm round faced tablet. Data was collected on the compression profile, weight and thickness of the tablet formed. The tablets were then crushed on the same instrument and the fracture profile recorded as well as peak fracture load. This was repeated for both formulations and a profile of the compressibility and tensile strength of the tablets built up. The data was compared with data already gained from production runs of the formulations on a Fette 2090 tablet press. In this case 800mg (for the direct compression product) and 1140mg (for the wet granulated product) caplet-shaped tablets were produced, providing a great contrast to the round 100mg tablets produced on the GTP-1. Data from the two formulations compacted on the GTP-1 was comparable to production data obtained on the high speed rotary press (Fette 2090). Analysis of tablet tensile strength to compaction pressure and solid fraction demonstrated that the results obtained on the GTP-1 can be reproduced for different sizes of tablets produced on a rotary press.

For both formulations the tensile strength of 100mg cylindrical tablets made by the GTP-1 are consistent with the tensile strength of 800mg and 1140mg caplet shape tablets made on a Fette rotary press. For the direct compression product the values are shown in relation to the compression pressure whilst for the wet granulated product the solid fraction (relative density) is used. The results, whilst surprising, do reinforce the applicability of equations (1) and (2) to tablets of different size and shape made on different pieces of equipment. This shows the value of using small scale tableting for tablet development and manufacturing. With API costs in the range of $2000/kg, using milligram quantities of material on an instrument such as the GTP-1 provides obvious benefits. Multiple experiments may be carried out at the development stage to optimize the formulation in terms of tensile strength, with the results being directly comparable to the manufacturing scale.

Formulations We investigated the tablet quality of two different formulations with a high loading of drug active. Formulation A- a direct compression formulation containing 70% drug in Avicel made at a 200kg batch scale. Formulation B- a wet granulated formulation containing 80% drug in Avicel/ PVP binder made at a 300kg batch scale and dried in a fluidised bed. Both formulations were lubricated with 1% magnesium stearate. Tableting Tablets were produced from the two formulations on the Gamlen Tablet Press GTP-1 and the Fette 2090 rotary press. The GTP-1 used a 6mm flat face round punch to produce 100mg cylindrical compacts at various compression pressures ranging from 1kN to 5kN. Data was collected on the maximum compression pressure applied, weight and thickness of the tablet. Tablets were fractured on the GTP-1 using the diametral compression test. For cylindrical tablets this can be calculated from the breaking force according to the following equation first used by Fell & Newton in 1970 (1): (1) σt is the tensile fracture strength of the tablet, P is the fracture force (N), D is the tablet diameter, t is the overall thickness The equation takes account of the breaking load, thickness and diameter of the tablet. This formula is only correct for flat-face cylindrical tablets. 17x7mm 800mg caplet shaped tablets of Formulation A and 20x9.5mm 1140mg caplet shaped tablets of Formulation B were produced on the Fette 2090 at various compression pressures ranging from 6.5kN to 30kN- considerably more than used on the GTP-1. Tablets were collected and measured for dimensions and breaking load. From this the tensile strength of the caplet shaped tablets was determined according to the equation of Pitt & Heasley (2012) (2). (2) σt is the tensile strength, P is the fracture load (N), D is the length of the short axis, t is the overall thickness and W is the wall height of the tablet This equation is used in particular for oval and caplet-shaped tablets where the long axis (L) is at least 1.7 times that of the short axis (D), which is the case for nearly all pharmaceutical tablets. Comparison The tablet tensile strength was compared to both the compression pressure and relative density (solid fraction) for the results from the GTP-1 and Fette. The relative density was calculated from the ratio of the tablet density to the true density of the formulation.

We have shown that the tensile strength of 100mg compacts made on the GTP-1 can be successfully scaled to 800mg and 1140mg caplet shapes made on a Fette 2090 rotary press. The validity of the results at different scales provides a technique by which to optimise and troubleshoot tablet formulation development and manufacturing.

Marshall K. Monitoring punch forces and punch movements as an aid to developing robust tablet formulations. Drug Dev.Ind.Pharm. 15(13) 2153-2176(1989) Dey D, Gamlen MJ, Brown S, Thorne B. Intelligent tablet formulation using rapid compressibility assessment. Poster at AAPS 2011 Washington Dey D, Gamlen MJ. Evaluation of various direct compression excipients using the Gamlen Tablet Press GTP-1. Poster at AAPS 2012 Chicago Fell JT, Newton JM. Determination of tablet tensile strength by the diamteral compression test. J PharmSci 59: 688-691 (1970) Pitt KG, Heasley MG. Determination of the tensile strength of elongated tablets. http://dx.doi.org/10.1016/j.powtec.2011.12.060

The value in using small compacts compressed at defined compression forces for tablet preformulation and formulation is well established (Marshall 1989). We have already shown that the GTP-1 is an ideal instrument to perform such experiments quickly and accurately (Dey et al 2011, Dey et al 2012). The strength of the compact can be defined simply in terms of the compressive force required to fracture a specimen across its diameter. In the pharmaceutical industry this is referred to as a "hardness test". More complex shapes can also be crushed by this method. However the breaking load does not take into account either the dimensions and shape of the compact or the mode of failure. The conversion of a fracture load to tensile strength, which takes these factors into account, allows for ready comparisons to be made between samples of different shapes or sizes. The tensile strength of a tablet is an important attribute as the tablet needs to be mechanically strong enough to withstand further handling such as film–coating, packaging, transport and end-use by the patient, but to be weak enough to break apart in the human body and so release its contents. Generally, a tensile strength greater than 1.7 MPa will usually suffice in ensuring that a tablet is mechanically strong enough to withstand commercial manufacture and subsequent distribution. Tensile strengths down to 1 MPa may suffice for small batches where the tablets are not subjected to large mechanical stresses.The question remains though whether the results derived from such small scale studies are valid when used on a manufacturing scale typically using a rotary press. In this work we investigated whether the tensile strength could be used for comparison between tablets of different shape or size.

ABSTRACT

PURPOSE AND HYPOTHESIS

MATERIALS AND METHODS RESULTS AND DISCUSSION

CONCLUSIONS

BIBLIOGRAPHY

AM-12-02047

Formulation B were produced on the Fette 2090 at various compression pressures ranging from 6.5kN to 30kN- considerably more than used on the GTP-1. Tablets were collected and measured for dimensions and breaking load. From this the tensile strength of the caplet shaped tablets was determined according to the equation of Pitt & Heasley (2012) (2).

L

D W T

(2)

σt is the tensile strength, P is the fracture load (N), D is the length of the short axis, t is the overall thickness and W is the wall height of the tabletThis equation is used in particular for oval and caplet-shaped tablets where the long axis (L) is at least 1.7 times that of the short axis (D), which is the case for nearly all pharmaceutical tablets.

ComparisonThe tablet tensile strength was compared to both the compression pressure and relative density (solid fraction) for the results from the GTP-1 and Fette. The relative density was calculated from the ratio of the tablet density to the true density of the formulation.

RESULTS AND DISCUSSION

For both formulations the tensile strength of 100mg cylindrical tablets made by the GTP-1 are consistent with the tensile strength of 800mg and 1140mg caplet shape tablets made on a Fette rotary press.

For the direct compression product the values are shown in relation to the compression pressure whilst for the wet granulated product the solid fraction (relative

CONCLUSIONS

We have shown that the tensile strength of 100mg compacts made on the GTP-1 can be successfully scaled to 800mg and 1140mg caplet shapes made on a Fette 2090 rotary press. The validity of the results at different scales provides a technique by which to optimise and troubleshoot tablet formulation development and manufacturing.

density) is used.The results, whilst surprising, do reinforce the

applicability of equations (1) and (2) to tablets of different size and shape made on different pieces

of equipment.This shows the value of using small scale tableting for

tablet development and manufacturing. With API costs in the range of $2000/kg, using milligram quantities of material on an instrument such as the GTP-1 provides obvious benefits. Multiple experiments may be carried out at the development stage to optimize the formulation in terms of tensile strength, with the results being directly comparable to the manufacturing scale.

Scaleability of GTP-1 data with a Fette 2090 rotary press for a direct compression and wet granulated product

D Dey1, MJ Gamlen1, 2KG Pitt, 2RJ Webber, 2K Hill 1Gamlen Tableting Ltd, Biocity Nottingham Nottingham NG1 1GF UK 2GSK Global Manufacturing and Supply Priory St Ware SG120DJ UK

A major issue in using small scale compaction studies to address manufacturing and development challenges is the validity of the data at

the large scale. In this paper we present a systematic approach to address tablet manufacturing issues using a novel bench top press capable of compressing milligram quantities of material. This bench top press uniquely delivers a rapid compressibility assessment of formulations and the tensile strength of subsequent tablets, and we show that these provide an accurate prediction of tablet quality using a rotary tablet press in large scale product manufacture. We investigated the compressibility of two formulations of well-known medicines, one produced by direct compression and the other by wet granulation. The compressibility of the two formulations on the bench top single station tablet press (Gamlen Tablet Press GTP-1) was compared with that on the rotary tablet press (Fette 2090) used in large scale manufacture. Tablets were formed using the Gamlen Tablet Press GTP-1 at various compaction pressures-1, 2, 3, 4 and 5kN. 100mg of each material was compressed to form a 6mm round faced tablet. Data was collected on the compression profile, weight and thickness of the tablet formed. The tablets were then crushed on the same instrument and the fracture profile recorded as well as peak fracture load. This was repeated for both formulations and a profile of the compressibility and tensile strength of the tablets built up. The data was compared with data already gained from production runs of the formulations on a Fette 2090 tablet press. In this case 800mg (for the direct compression product) and 1140mg (for the wet granulated product) caplet-shaped tablets were produced, providing a great contrast to the round 100mg tablets produced on the GTP-1. Data from the two formulations compacted on the GTP-1 was comparable to production data obtained on the high speed rotary press (Fette 2090). Analysis of tablet tensile strength to compaction pressure and solid fraction demonstrated that the results obtained on the GTP-1 can be reproduced for different sizes of tablets produced on a rotary press.

For both formulations the tensile strength of 100mg cylindrical tablets made by the GTP-1 are consistent with the tensile strength of 800mg and 1140mg caplet shape tablets made on a Fette rotary press. For the direct compression product the values are shown in relation to the compression pressure whilst for the wet granulated product the solid fraction (relative density) is used. The results, whilst surprising, do reinforce the applicability of equations (1) and (2) to tablets of different size and shape made on different pieces of equipment. This shows the value of using small scale tableting for tablet development and manufacturing. With API costs in the range of $2000/kg, using milligram quantities of material on an instrument such as the GTP-1 provides obvious benefits. Multiple experiments may be carried out at the development stage to optimize the formulation in terms of tensile strength, with the results being directly comparable to the manufacturing scale.

Formulations We investigated the tablet quality of two different formulations with a high loading of drug active. Formulation A- a direct compression formulation containing 70% drug in Avicel made at a 200kg batch scale. Formulation B- a wet granulated formulation containing 80% drug in Avicel/ PVP binder made at a 300kg batch scale and dried in a fluidised bed. Both formulations were lubricated with 1% magnesium stearate. Tableting Tablets were produced from the two formulations on the Gamlen Tablet Press GTP-1 and the Fette 2090 rotary press. The GTP-1 used a 6mm flat face round punch to produce 100mg cylindrical compacts at various compression pressures ranging from 1kN to 5kN. Data was collected on the maximum compression pressure applied, weight and thickness of the tablet. Tablets were fractured on the GTP-1 using the diametral compression test. For cylindrical tablets this can be calculated from the breaking force according to the following equation first used by Fell & Newton in 1970 (1): (1) σt is the tensile fracture strength of the tablet, P is the fracture force (N), D is the tablet diameter, t is the overall thickness The equation takes account of the breaking load, thickness and diameter of the tablet. This formula is only correct for flat-face cylindrical tablets. 17x7mm 800mg caplet shaped tablets of Formulation A and 20x9.5mm 1140mg caplet shaped tablets of Formulation B were produced on the Fette 2090 at various compression pressures ranging from 6.5kN to 30kN- considerably more than used on the GTP-1. Tablets were collected and measured for dimensions and breaking load. From this the tensile strength of the caplet shaped tablets was determined according to the equation of Pitt & Heasley (2012) (2). (2) σt is the tensile strength, P is the fracture load (N), D is the length of the short axis, t is the overall thickness and W is the wall height of the tablet This equation is used in particular for oval and caplet-shaped tablets where the long axis (L) is at least 1.7 times that of the short axis (D), which is the case for nearly all pharmaceutical tablets. Comparison The tablet tensile strength was compared to both the compression pressure and relative density (solid fraction) for the results from the GTP-1 and Fette. The relative density was calculated from the ratio of the tablet density to the true density of the formulation.

We have shown that the tensile strength of 100mg compacts made on the GTP-1 can be successfully scaled to 800mg and 1140mg caplet shapes made on a Fette 2090 rotary press. The validity of the results at different scales provides a technique by which to optimise and troubleshoot tablet formulation development and manufacturing.

Marshall K. Monitoring punch forces and punch movements as an aid to developing robust tablet formulations. Drug Dev.Ind.Pharm. 15(13) 2153-2176(1989) Dey D, Gamlen MJ, Brown S, Thorne B. Intelligent tablet formulation using rapid compressibility assessment. Poster at AAPS 2011 Washington Dey D, Gamlen MJ. Evaluation of various direct compression excipients using the Gamlen Tablet Press GTP-1. Poster at AAPS 2012 Chicago Fell JT, Newton JM. Determination of tablet tensile strength by the diamteral compression test. J PharmSci 59: 688-691 (1970) Pitt KG, Heasley MG. Determination of the tensile strength of elongated tablets. http://dx.doi.org/10.1016/j.powtec.2011.12.060

The value in using small compacts compressed at defined compression forces for tablet preformulation and formulation is well established (Marshall 1989). We have already shown that the GTP-1 is an ideal instrument to perform such experiments quickly and accurately (Dey et al 2011, Dey et al 2012). The strength of the compact can be defined simply in terms of the compressive force required to fracture a specimen across its diameter. In the pharmaceutical industry this is referred to as a "hardness test". More complex shapes can also be crushed by this method. However the breaking load does not take into account either the dimensions and shape of the compact or the mode of failure. The conversion of a fracture load to tensile strength, which takes these factors into account, allows for ready comparisons to be made between samples of different shapes or sizes. The tensile strength of a tablet is an important attribute as the tablet needs to be mechanically strong enough to withstand further handling such as film–coating, packaging, transport and end-use by the patient, but to be weak enough to break apart in the human body and so release its contents. Generally, a tensile strength greater than 1.7 MPa will usually suffice in ensuring that a tablet is mechanically strong enough to withstand commercial manufacture and subsequent distribution. Tensile strengths down to 1 MPa may suffice for small batches where the tablets are not subjected to large mechanical stresses.The question remains though whether the results derived from such small scale studies are valid when used on a manufacturing scale typically using a rotary press. In this work we investigated whether the tensile strength could be used for comparison between tablets of different shape or size.

ABSTRACT

PURPOSE AND HYPOTHESIS

MATERIALS AND METHODS RESULTS AND DISCUSSION

CONCLUSIONS

BIBLIOGRAPHY

AM-12-02047

Scaleability of GTP-1 data with a Fette 2090 rotary press for a direct compression and wet granulated product

D Dey1, MJ Gamlen1, 2KG Pitt, 2RJ Webber, 2K Hill 1Gamlen Tableting Ltd, Biocity Nottingham Nottingham NG1 1GF UK 2GSK Global Manufacturing and Supply Priory St Ware SG120DJ UK

A major issue in using small scale compaction studies to address manufacturing and development challenges is the validity of the data at

the large scale. In this paper we present a systematic approach to address tablet manufacturing issues using a novel bench top press capable of compressing milligram quantities of material. This bench top press uniquely delivers a rapid compressibility assessment of formulations and the tensile strength of subsequent tablets, and we show that these provide an accurate prediction of tablet quality using a rotary tablet press in large scale product manufacture. We investigated the compressibility of two formulations of well-known medicines, one produced by direct compression and the other by wet granulation. The compressibility of the two formulations on the bench top single station tablet press (Gamlen Tablet Press GTP-1) was compared with that on the rotary tablet press (Fette 2090) used in large scale manufacture. Tablets were formed using the Gamlen Tablet Press GTP-1 at various compaction pressures-1, 2, 3, 4 and 5kN. 100mg of each material was compressed to form a 6mm round faced tablet. Data was collected on the compression profile, weight and thickness of the tablet formed. The tablets were then crushed on the same instrument and the fracture profile recorded as well as peak fracture load. This was repeated for both formulations and a profile of the compressibility and tensile strength of the tablets built up. The data was compared with data already gained from production runs of the formulations on a Fette 2090 tablet press. In this case 800mg (for the direct compression product) and 1140mg (for the wet granulated product) caplet-shaped tablets were produced, providing a great contrast to the round 100mg tablets produced on the GTP-1. Data from the two formulations compacted on the GTP-1 was comparable to production data obtained on the high speed rotary press (Fette 2090). Analysis of tablet tensile strength to compaction pressure and solid fraction demonstrated that the results obtained on the GTP-1 can be reproduced for different sizes of tablets produced on a rotary press.

For both formulations the tensile strength of 100mg cylindrical tablets made by the GTP-1 are consistent with the tensile strength of 800mg and 1140mg caplet shape tablets made on a Fette rotary press. For the direct compression product the values are shown in relation to the compression pressure whilst for the wet granulated product the solid fraction (relative density) is used. The results, whilst surprising, do reinforce the applicability of equations (1) and (2) to tablets of different size and shape made on different pieces of equipment. This shows the value of using small scale tableting for tablet development and manufacturing. With API costs in the range of $2000/kg, using milligram quantities of material on an instrument such as the GTP-1 provides obvious benefits. Multiple experiments may be carried out at the development stage to optimize the formulation in terms of tensile strength, with the results being directly comparable to the manufacturing scale.

Formulations We investigated the tablet quality of two different formulations with a high loading of drug active. Formulation A- a direct compression formulation containing 70% drug in Avicel made at a 200kg batch scale. Formulation B- a wet granulated formulation containing 80% drug in Avicel/ PVP binder made at a 300kg batch scale and dried in a fluidised bed. Both formulations were lubricated with 1% magnesium stearate. Tableting Tablets were produced from the two formulations on the Gamlen Tablet Press GTP-1 and the Fette 2090 rotary press. The GTP-1 used a 6mm flat face round punch to produce 100mg cylindrical compacts at various compression pressures ranging from 1kN to 5kN. Data was collected on the maximum compression pressure applied, weight and thickness of the tablet. Tablets were fractured on the GTP-1 using the diametral compression test. For cylindrical tablets this can be calculated from the breaking force according to the following equation first used by Fell & Newton in 1970 (1): (1) σt is the tensile fracture strength of the tablet, P is the fracture force (N), D is the tablet diameter, t is the overall thickness The equation takes account of the breaking load, thickness and diameter of the tablet. This formula is only correct for flat-face cylindrical tablets. 17x7mm 800mg caplet shaped tablets of Formulation A and 20x9.5mm 1140mg caplet shaped tablets of Formulation B were produced on the Fette 2090 at various compression pressures ranging from 6.5kN to 30kN- considerably more than used on the GTP-1. Tablets were collected and measured for dimensions and breaking load. From this the tensile strength of the caplet shaped tablets was determined according to the equation of Pitt & Heasley (2012) (2). (2) σt is the tensile strength, P is the fracture load (N), D is the length of the short axis, t is the overall thickness and W is the wall height of the tablet This equation is used in particular for oval and caplet-shaped tablets where the long axis (L) is at least 1.7 times that of the short axis (D), which is the case for nearly all pharmaceutical tablets. Comparison The tablet tensile strength was compared to both the compression pressure and relative density (solid fraction) for the results from the GTP-1 and Fette. The relative density was calculated from the ratio of the tablet density to the true density of the formulation.

We have shown that the tensile strength of 100mg compacts made on the GTP-1 can be successfully scaled to 800mg and 1140mg caplet shapes made on a Fette 2090 rotary press. The validity of the results at different scales provides a technique by which to optimise and troubleshoot tablet formulation development and manufacturing.

Marshall K. Monitoring punch forces and punch movements as an aid to developing robust tablet formulations. Drug Dev.Ind.Pharm. 15(13) 2153-2176(1989) Dey D, Gamlen MJ, Brown S, Thorne B. Intelligent tablet formulation using rapid compressibility assessment. Poster at AAPS 2011 Washington Dey D, Gamlen MJ. Evaluation of various direct compression excipients using the Gamlen Tablet Press GTP-1. Poster at AAPS 2012 Chicago Fell JT, Newton JM. Determination of tablet tensile strength by the diamteral compression test. J PharmSci 59: 688-691 (1970) Pitt KG, Heasley MG. Determination of the tensile strength of elongated tablets. http://dx.doi.org/10.1016/j.powtec.2011.12.060

The value in using small compacts compressed at defined compression forces for tablet preformulation and formulation is well established (Marshall 1989). We have already shown that the GTP-1 is an ideal instrument to perform such experiments quickly and accurately (Dey et al 2011, Dey et al 2012). The strength of the compact can be defined simply in terms of the compressive force required to fracture a specimen across its diameter. In the pharmaceutical industry this is referred to as a "hardness test". More complex shapes can also be crushed by this method. However the breaking load does not take into account either the dimensions and shape of the compact or the mode of failure. The conversion of a fracture load to tensile strength, which takes these factors into account, allows for ready comparisons to be made between samples of different shapes or sizes. The tensile strength of a tablet is an important attribute as the tablet needs to be mechanically strong enough to withstand further handling such as film–coating, packaging, transport and end-use by the patient, but to be weak enough to break apart in the human body and so release its contents. Generally, a tensile strength greater than 1.7 MPa will usually suffice in ensuring that a tablet is mechanically strong enough to withstand commercial manufacture and subsequent distribution. Tensile strengths down to 1 MPa may suffice for small batches where the tablets are not subjected to large mechanical stresses.The question remains though whether the results derived from such small scale studies are valid when used on a manufacturing scale typically using a rotary press. In this work we investigated whether the tensile strength could be used for comparison between tablets of different shape or size.

ABSTRACT

PURPOSE AND HYPOTHESIS

MATERIALS AND METHODS RESULTS AND DISCUSSION

CONCLUSIONS

BIBLIOGRAPHY

AM-12-02047

thickness

thickness

Hardness

AN EVALUATION OF VARIOUS DIRECT COMPRESSION INGREDIENTS USING THE GAMLEN TABLET PRESS GTP-1

DIPANKAR DEY, MICHAEL GAMLEN, GAMLEN TABLETING LTD, BIOCITY NOTTINGHAM, NOTTINGHAM UK NG1 1GF

The modern tablet needs to satisfy a number of parameters that make it fit for purpose such as hardness, potency, friability and dissolution as well as be suitable for commercial manufacture using a rotary tablet press. Performing a sufficient number of experiments to optimise the formulation is often limited by the quantity of API available and the nature of the equipment used. We present here an approach to tablet formulation using a novel bench top computer controlled tablet press—the Gamlen Tablet Press GTP-1. This requires only milligram quantities of material, is objective and practical. The approach is based on establishing the compressibility of the formulation as determined by tablet tensile strength measurements using the diametral compression test (Fell &Newton) over a range of compression pressures ; Tensile strength is an objective measure of tablet strength as it takes into account both hardness and tablet thickness. As such it can be used to compare tablets of different shapes and sizes (Pitt &Heasley 2012). In addition we can also measure ejection stress associated with each formulation from the ejection force normalised with tablet thickness.

In the preliminary experiment the Galen IQ, Parteck SD and Perlitol SD grades were the most compressible whilst the Perlitol DC grades had the least. All formulations showed high ejection stress. We selected the 200 mesh size of each brand for further development with L-HPC21 in the Main experiments. The L-HPC21 substantially increased compressibility, and also reduced ejection stress and friability The drug percentage had a major effect in reducing compressibility particularly for the Galen IQ. Using The combination of results gained on compressibility combined with powder flow and ejection stress results give a useful screening method when selecting the formulation of choice. We assigned the gradient of the tensile strength v compression pressure profiles as the compressibility of the formulation. When plotted against the powder flowability for each formulation we can visualise the results as a ‘Decision Matrix’. The Galen 0.1%/1% + L-HPC21 exhibit the best combination of compressibility and flow behaviour. In this work we have shown that rapid screening of formulations using the Gamlen Tablet Press GTP-1 is a very useful approach to development of the required tablet profile using the compression gradient as a measure of compressibility. We propose that this be considered as a Critical Quality Attribute of a tablet formulation in the tablet Quality by Design paradigm.

The formulation was developed in two stages. Preliminary experiments determined the compressibility of a formulation containing the drug (acetaminophen), excipient and lubricant; ten excipients and excipient grades were evaluated on a 100g scale. In the main experiments we used the best formulations, selected using tensile fracture strength/compaction pressure profiles. To improve compressibility we added 20% L-HPC21 (Shin-Etsu). The magnesium stearate concentration was kept at 0.5%w/w. All formulations were made using the Gamlen Tablet Press GTP-1 (Nottingham UK) to produce 75mg round flat face tablets. The tablets were subjected to tensile fracture stress testing on the GTP-1, friability and disintegration measurements. Ejection stress was also recorded for each tablet.

Fell JT and Newton JM. Determination of tablet strength by the diametral compression test. J Pharm Sci 59; 688-691, 1970 Pitt & Heasley. Powder Technology 2012. http://dx.doi.org/10.1016/j.powtec.2011.12.060)

BACKGROUND AND APPROACH

APPROACH

MATERIALS AND METHODS

RESULTS

DISCUSSION AND CONCLUSION

REFERENCES

Preliminary Experiments

σt is the tensile fracture strength of the tablet, P is the fracture force (N), D is the tablet diameter, t is the overall thickness

Mannitol grade Parteck (Merck)

Mannitol grade Perlitol (Roquette)

Isomaltulose (Beneo-Palatinit)

Parteck M100

Perlitol 100SD

Galen IQ720

Parteck M200

Perlitol 200SD

Galen IQ721

Parteck M300

Perlitol 300DC

Perlitol 400DC

Perlitol 500DC

Main Experiments We have shown previously that the Gamlen Tablet Press GTP-1 can rapidly evaluate formulations for tablet development using milligram quantities of material. Uniquely for a tablet press it gives precise information on the compression force, ejection force and fracture force of an individual tablet, providing valuable information for the required target product profile, required for Quality by Design (QbD). We present in this work an evaluation of a number of different direct compression excipients in the development of a paracetamol tablet. We evaluated a number of different direct compression excipients to prepare a formulation containing 10% paracetamol. The formulations were blended for 30 minutes and lubricated with 0.5% magnesium stearate for a further 5 minutes in a blender. Each formulation was then compacted using the Gamlen Tablet Press GTP-1 to produce round flat face tablets. Tablets weresubjected to tensile strength, friability and disintegration testing, whilst the formulation was tested for flowability and LOD. The initial experiments showed clear differences between formulations in compressibility, friability, disintegration and powder flowability. Among the mannitol grades the compressibility of the SD types was better than the DC types. Very high ejection forces were recorded despite use of a lubricant. Individual ejection profiles analysed by the GTP-1 revealed the important relationship of material properties with ejection of the tablet from the die- a key determinant of suitability for rotary press manufacture. The main experiments characterised the compressibility and tablet behaviour of the most compressible excipients, with the low API% formulas performing best. Evaluation of a wide range of formulations using using the GTP-1 provided valuable information on compression force, ejection force and disintegration times of individual tablets using very small amounts of material. This enables an evaluation of the widest possible tablet quality and tablet/ material processing parameters to aid formulation development.

ABSTRACT

Formulation Compressibility Index (%)

Minimum orifice size

LOD%

Parteck M100

14.5 16 0.27

Parteck M200

12.9 20 0.17

Parteck M300

7.4 14 0.19

Perlitol 100SD

13.5 20 0.16

Perlitol 200SD

11.63 18 0.11

Perlitol 300DC

8.3 10 0.14

Perlitol 400DC

6.7 8 0.11

Perlitol 500DC

8.1 5 0.14

Galen IQ720

11.25 16 4.07

Galen IQ721

13.4 12 1.5

Formulation Compressibility Index (%)

Minimum orifice size

LOD%

Parteck 0.1% 16.25 18 0.81

Parteck 1% 16.25 16 1.13

Parteck 10% 17.5 22 1.10

Perlitol 0.1% 11.25 12 0.96

Perlitol 1% 8.75 16 0.98

Perlitol 10% 16.25 18 1.32

Galen 0.1% 13.75 7 2.70

Galen 1% 16.25 8 2.65

Galen 10% 16.25 20 2.21

BIBLIOGRAPHY

Marshall K. Monitoring punch forces and punch movements as an aid to developing robust tablet formulations. Drug Dev.Ind.Pharm.15(13) 2153-2176(1989)Dey D, Gamlen MJ, Brown S, Thorne B. Intelligent tablet formulation using rapid compressibility assessment. Poster at AAPS 2011 WashingtonDey D, Gamlen MJ. Evaluation of various direct compression excipients using the Gamlen Tablet Press GTP-1. Poster at AAPS 2012 ChicagoFell JT, Newton JM. Determination of tablet tensile strength by the diamteral compression test. J PharmSci 59: 688-691 (1970)Pitt KG, Heasley MG. Determination of the tensile strength of elongated tablets. http://dx.doi.org/10.1016/j.powtec.2011.12.060

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