Delivery and Formulation

Inno

vatio

ns in

Pha

rmac

eutic

al T

echn

olog

y is

sue

42. ©

Sam

edan

Ltd

. 201

2

Keywords

Tableting

Tablet hardness

Compression force

Compaction pressure

Tensile fracture stress

By Michael Gamlen and Dipankar Dey at Gamlen Tableting Ltd

The hardness of a tablet has traditionally been used as a measure of quality; however, tensile strength is more appropriate when comparing tablets of different composition, shape and size, and compressed on different pieces of equipment.

Tablets Under Pressure

The modern tablet is a complex

drug delivery system in which

the drug substance is combined

with a number of excipients to aid

formulation of the desired product;

these include bulking agents,

binders, disintegrants and coatings,

all of which have some function

to aid processing of the drug

substance into the end-product. The

excipients and drug substance are

processed through a number of unit

operations such as mixing, blending,

granulation, tableting and often

coating to form the final product.

The final tablet has to fulfil a

number of characteristics, including

the ability to deliver the correct

amount of drug substance into the

patient’s system at the required

rate, as well as physicochemical

properties that make it easy to

handle, administer and store. For

dispensable products, these include

a suitable size, hardness, texture and

stability, as well as taste and smell.

Process and formulation

development of the desired tablet

form is time-

consuming and

complex because

knowledge of

excipient/drug

substance material

properties and

their relationship

to processing

parameters is limited

– preventing a priori prediction

of quality.

This causes manufacturers

particular problems in developing

and producing the ideal tablet

that fulfils its therapeutic purpose,

and can be manufactured both

efficiently and economically.

Even small variations in material

properties or process parameters

can have profound effects on final

tablet quality.

Measuring the Correct Tablet Properties

To assess the impact of

starting material properties and

manufacturing conditions on

tablet properties, it is important

to ensure that the correct

characteristics are used when

making comparisons between

tablets comprising different

formulations or made on different

pieces of equipment. In fact, it

is actually very difficult to make

scientifically robust comparisons

between formulations and

processes for a number of reasons.

Tablet hardness, or breaking

strength, is an important and

widely used parameter to control

the tablet manufacturing process.

In many cases, it is used as a

surrogate measure for compression

force during manufacture – often

because the tablet machine is

unable to measure compression

force. It is a very important control

parameter because compression

affects every tablet property,

including disintegration, dissolution

and friability. In some cases stability

is also affected. However, tablet

hardness (or breaking force)

comparisons are applicable to

one tablet size and shape only. If

the size, shape or thickness of a

tablet is materially changed, then

all tablet hardness comparisons

will become incorrect. It is obvious

that it is more difficult for a small

tablet to withstand a given fracture

load than a larger tablet. Simple

hardness measurements are thus

not a valid basis for comparison in

this situation.

In fact, there are two factors at work

here. One is the area across which a

tablet breaking force is applied, as

clearly the strength of the tablet will

be proportional to the area across

which the force is distributed.

The second factor is that, if the

same compaction force is applied

to (say) a 6mm circular tablet and

a 3mm circular tablet, the force

per unit area on the small tablet

will be four times that on the large

tablet (because area is proportional

to the square of the diameter of a

circle). So the material in the 3mm

tablet will experience a compaction

pressure four times that of the 6mm

tablet at the same load.

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It is essential that these factors

are taken into account when making

comparisons between tablets.

Instead of comparing breaking

loads (measured in Newtons or

kg), tablets should be compared

using breaking stress (‘pressure’),

which in engineering terms is

called the tensile fracture stress

(TFS) (1). Rather than comparing

compaction force, we should

compare fracture stress based on

the work of Newton et al (2). When

we do this, the results make much

more sense.

In Figure 1, 3mm and 6mm tablets

appear to have a similar hardness

(measured by breaking force);

however, this takes no account of

the differences in tablet thickness,

or the effect of differences in

compaction pressure (see Figure 2).

Only the applied compression force

is quoted, which does not take

into account the punch diameter,

and hence the area over which the

compaction force is applied.

Making Valid Comparisons

Comparing formulations using

only compression force and

hardness does not reveal all of the

information available in the data.

To make the proper comparison,

the tablet punch diameter,

thickness of the tablet and

compression force must also

be taken into account so that a

graph of TFS versus compaction

pressure can be prepared.

The differences in tablet thickness,

diameter and compression

force for circular tablets can

then easily be accounted

for by calculating the tablet

tensile fracture strength

and tablet compaction

pressure.

Tablet Tensile Fracture StressFor cylindrical tablets, TFS can be

calculated from the breaking force

according to the following equation,

first used by Fell and Newton in

1970 (1):

2Pσ

t = —

Dt

where σt is the tensile fracture

strength of the tablet, P is the

fracture force (N), D is the tablet

diameter and t is the overall

thickness. The equation takes

account of the breaking load,

thickness and diameter of the

tablet, and effectively divides the

breaking load by the area of the

fracture surface.

0 1 2 3 4

Figure 1: Comparison of a 3mm and 6mm tablet

Figure 2: Thickness and diameter need to be accounted for in any tablet hardness quote

Hardness of 3mm and 6mm diameter Avicel PH-102 tablets

Tabl

et h

ardn

ess

(N)

200

180

160

140

120

100

80

60

40

20

0

6mm tablets

3mm tablets

Compression force (kN)

ThicknessThickness

3mm

6mm

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appropriate formula must be used to

calculate the TFS for the comparison

to be valid.

Compaction PressureFor a flat-faced tablet, compaction

pressure is calculated simply by

dividing the force applied by the

die area:

PCp

= —

A

where Cp is the compaction

pressure and A is the area of the die.

As mentioned earlier, at the same

compression force, punch diameter

has an exponential effect on

compaction pressure. For example,

400kg of compression force on a

3mm punch produces four times the

pressure as 400kg on a 6mm punch.

For tablets that are not flat-faced,

the cross-sectional area of the die

is still normally used.

TFS/Compaction Pressure Comparisons

When TFS and compaction pressure

are reviewed, the data reveals

its full value. By using the tensile

strength for tablets and normalising

the applied force with the punch

diameter to give the compaction

pressure, we can see the impact of

tablet size and compaction pressure

on TFS, and the effect of tablet size

on compressibility.

The effect of increasing compaction

pressure on tablet tensile strength

is shown in Figure 3. There is an

area of overlap of around 150MPa

of compaction pressure where

the tensile strength of a 6mm

tablet is similar to that of a 3mm

tablet. Normalising the data in this

way provides an objective way to

measure tablet physical properties

over a wide range of compaction

pressures and using a small amount

of material. The data shows that the

behaviour of Avicel PH-102, when

compressed into a 30mg tablet

of 3mm diameter, is completely

scalable to the behaviour of a

100mg tablet of 6mm diameter.

Similar results have been obtained

for other materials (2).

This formula is only correct for

flat-faced cylindrical tablets; for

convex-faced round tablets, the

formula becomes:

10P

σt

= t t W (2.84 — – 0.126 — + 3.15 — + 0.01) D W D

where σt is the tensile strength, P

is the fracture load, D is the tablet

diameter, t is the overall thickness

and W is the wall height of

the tablet.

Both of these

equations are also

listed in monograph

1217 of the United

States Pharmacopeia.

Similarly, an equation

for a wide range of

elongated tablets has

been derived by Pitt et

al (3). Hence if tablets

of different shape are

to be compared, the

0 100 200 300 400 500 600

Figure 4: The Gamlen Tablet Press GTP-1

Images: Gamlen Tableting Limited

Figure 3: The tablet tensile strength comparison for a 3mm and 6mm tablet

Tensile fracture stress for 3mm and 6mm diameter Avicel PH-102 tablets

14

12

10

8

6

4

2

0

6mm tablets

3mm tablets

Compaction pressure (MPa)

Tens

ile fr

actu

re s

tres

s (M

Pa)

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TFS Measurement in Formulation Development

Tensile fracture stress

measurement is an

important material property

independent of tablet size.

Any statement requiring a

specific hardness to pass

a friability test or survive

a coating operation is not

universally applicable as it

would apply to one specific

size only. Normalising the

data would remove that

barrier and help in comparing

formulations of different

tablet sizes and shapes, or

compressed on different

equipment.

Comparison of tablet TFS is

relatively straightforward

if tablets are made at a

controlled compaction

pressure. At Gamlen, we

have developed a bench-top,

computer-controlled tablet

press (the GTP-1, Figure 4)

that is well-suited for this

purpose as it is both a tablet press

and a tablet fracture tester. For the

measurement of tablet breaking

load, the press records both force

and displacement during both

compression and fracture, and also

provides the ejection force profile

associated with tablet ejection

(see Figure 5).

In the scale-up of tablet

production, the press can be used

to determine the relationship

between tablets developed at

the bench-top scale using a few

grams of material (often at the

early development stage) and the

final tablet manufactured on a

rotary tablet press. The latter uses

hundreds of kilograms of material,

making process development

difficult because of practical

difficulties in experimentation;

smaller and different shaped

tablets can, however, be scaled

to the final desired tablet

design if TFS is used as the

basis for comparison.

Conclusion

While tablet development

has traditionally used tablet

hardness as a measure of the

physical attribute of a tablet,

tensile strength is in fact more

appropriate when comparing

different formulations and tablets

compressed on different pieces of

equipment and at different scales.

References1. Fell JT and Newton JM,

Determination of tablet strength by the diametral compression test, J Pharm Sci 59, pp688-691, 1970

2. Newton JM, Rowley G, Fell JT, et al, J Pharm Pharmacol 23 Suppl 195S-201S, 1971

3. Pitt KG and Heasley MG, Determination of the tensile strength of elongated tablets, Powder Technol, in press, http://dx.doi.org/10.1016/j.powtec.2011.12.060

Michael Gamlen is Managing Director of Gamlen Tableting Limited (Nottingham, UK), a leading provider of expertise, equipment and services in the design, development and manufacturing of pharmaceutical tablet dosage forms. Awarded a first class honours degree in pharmacy, specialising in pharmaceutical engineering, he studied for a PhD at Nottingham University (UK). He was Head of Tablet Development at the The Wellcome Foundation for 15 years, and has since

worked for Vanguard Medica Limited and as a consultant. Michael has over 30 years’ experience of tablet development and specialises in managing product development, formulation, tablet and process development studies. He has been teaching professional tableting courses for many years and his courses are highly rated, often exceeding the expectation of participants. Email: michael@gamlen.co.uk

Dipankar Dey is an Oxford-educated doctoral graduate with extensive senior management experience in the pharmaceutical and medical diagnostics industries. Dipankar joined Gamlen Tableting Ltd from Oystar Manesty (Liverpool, UK) where he was Head of Process Development. He has particular expertise in manufacturing solid dose and biopharmaceuticals, and has worked in a number of different functions including technology transfer, new product development, training and

manufacturing. He also has experience in film coating and the implementation of Process Analytical Technology (PAT). Email: dip@gamlen.co.uk

Figure 5: Compaction (top), ejection (middle) and fracture (bottom) profiles for an Avicel PH-102 tablet