54

Tableting

Innovations in Pharmaceutical Technology Issue 44

Keywords

Compaction

Tensile fracture stress

Tabletability

Ejection stress

In-die measurements

By Michael Gamlen at Gamlen Tableting

Instrumentation to accurately measure compaction behaviour during tablet formation has evolved, with the latest technology revealing some surprising results

An Instrumental Process: Tablet Compaction

Tablets have been manufactured

for well over 120 years. In an

amazingly prescient piece of

writing, Joseph Remington

Wood wrote in 1904: “The

proper manipulation of the

medicinal ingredients, and

the choice, proportioning and

manipulation of the excipients

best suited to use with the

different formulas, require a

considerable degree of skill, as

well as an intimate knowledge

of the physical and chemical

properties of the ingredients” (1).

He recognised some of the

principal components that are

used today – binders and binder

solvents, bases or diluents,

disintegrators and lubricants.

Even now, relating the physical

and chemical properties of drugs

and excipients to their processing

behaviour remains a substantial

challenge. Serious study of the

process of tablet formation

began in the 1950s, with the

publication by Brake of the first

paper on the instrumentation

of the single punch tablet

machine (2). Instrumentation of

a rotary press was

first published by

Knoechel et al in

1967. Other early

systems included

those developed

by Goodhart

(1968) and Wray

(1969) (3-5).

Compaction Analysis

The development of compaction

simulators, first published by Hunter

(1976), was intended to permit

characterisation of materials at

production speed on a small scale

and with extensive instrumentation,

but the technical limitations of

control and measurement were

substantial. Accurate simulation of

all aspects of the compaction event

is still not possible even today (6).

Clearly it is difficult to control a

process in which the relationship

between the manufacturing

process and product quality

(such as tablet properties) is

not understood. To properly

characterise the compaction

event, all phases of the process

should be examined, including

die filling, precompression,

compression, ejection, and

detachment of the tablet from the

punch. The parameters needed for

full characterisation are upper and

lower punch position, upper and

lower punch force, ejection and

detachment. Most measurements

of punch force on a rotary tablet

press are indirect (using load

detectors remote from the punch)

and are intended solely for

machine control, rather than the

study of the compaction process

itself. Many of the original systems

developed to measure actual

punch forces and position, using

on-turret force and displacement

measurement, have been found

to be inaccurate. Accuracy is

extremely important because

a very small error has a large

impact on the calculated thickness

(and therefore density) of the

tablet. Density asymptotically

approaches 100 per cent during

compression of many materials,

and so the impact of any

displacement measurement error

is disproportionately large.

For these reasons, most detailed

studies of material compaction

behaviour have been done

on either instrumented single

punch tablet machines (mostly

without measurement of punch

displacement), or on a compaction

simulator. As an alternative, the

Gamlen Tablet Press (GTP) generates

high-resolution displacement

measurements corrected for

machine compliance. Recently

the GTP has been used to make

highly accurate measurements of

compaction behaviour, with some

surprising results.

Solid Fraction

The study of compaction began in

the ceramic and powder metallurgy,

with attempts to measure material

parameters and generate equations

which described the compaction

process (7). The purpose of the

investigations was to improve

IPT 44 2013.indd 54 07/03/2013 16:22

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Prerequisites for applying

compaction equations are

accurate measurements of tablet

thickness during compression,

and accurate calculations of

tablet density. These have been

most widely applied in the

preparation of Heckel plots,

which give some information

on the compaction behaviour

of the material. Unfortunately,

the impact of measurement and

instrumentation errors make many

published Heckel plots unreliable.

A further problem with using a

Heckel plot is its susceptibility

to the impact of small errors in

density measurement.

Tensile Fracture Stress

As stated above, all tablet

properties are determined by

the solid fraction of the tablet,

including stability, dissolution

and friability. A series of key

papers by Fell and Newton

published between 1968 and

1972 provided two major

breakthroughs in the study

of compaction.

The first, and better known,

is the use of the diametral

compression test to measure

the tensile fracture stress (TFS) of

a tablet. Based on a stress analysis

of the diametral compression

test performed in the 1930s, and

confirmed in the 1950s, the TFS (σt)

of a tablet breaking in tension is

given the formula σt = 2P/πDt ,

in which P is the fracture load

of the tablet, D the diameter

and t the tablet thickness.

Fell and Newton quickly realised

the utility of the TFS. In 1970 they

understanding of which materials

will compress well and why, with

a view to minimising production

problems and maximising

production control.

A critical quality attribute of a

tablet which determines all of its

properties is the solid fraction,

or relative density. This can

range from 50 to 99.9 per cent.

The solid fraction is a function

of the pressure used to make

the tablet – as the compaction

pressure increases, so does the

solid fraction. The relationship

between compaction pressure and

solid fraction is different for each

material, and is studied by using

compaction equations. These are

largely empirical exercises in data

handling, which attempt to fit

the compaction pressure and

density curves.

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pressure and tensile fraction can

be described in three related

properties:

● Tabletability – the relationship

between compaction pressure

and TFS, described by Fell

and Newton

● Compactibility – the relationship

between solid fraction and TFS.

This is useful because it can

be implemented without the

need to measure compaction

force, in other words on an

un-instrumented tablet

press. The downside of the

measurement is that the solid

fraction calculation requires

knowing the absolute density

of the material

● Compressibility – the

relationship between

compaction pressure and solid

fraction, closely related to the

compaction equations discussed

earlier (for example, Heckel)

The three compaction parameters

described above can be plotted as

a three-dimensional space which

fully describes the compaction

behaviour of the material.

Tabletability in Practice

We regularly use tabletability

to study both formulations

and processes using the GTP.

Figure 2 is a study of the impact

of manufacturing method on

tabletability, comparing wet and dry

granulation and direct compression.

The wet granulated formulation

is shown to be substantially more

compressible than a dry granulated

product, as would be expected from

both theory and experience.

Measuring tabletability enables the

objective quantification of effects

on compaction and permits the

simple study of formulation and

process comparisons such as mixing

time, granulation conditions and

lubrication. Process and formulation

effects can be studied on the 50g

scale or less.

In formulation development study

for a clinical trial product, we

observed that there was a linear

relationship between compaction

pressure (CP) and TFS of a tablet

and used it to show differences

in the compression properties of

a range of lactose size fractions

compacted on a single punch

tablet press. Tablet TFS has

subsequently been shown to be a

fundamental property of a tablet.

Example data show that the TFS/

CP relationship for 2, 3 and 6mm

Avicel tablets clearly lie on the

same line, demonstrating that TFS

is independent of tablet size. A

further example in Figure 1 shows

a TFS study of proprietary tablet

formulations compressed as 100mg

cylindrical tablets on the GTP, and as

800mg capsule shaped tablets on

a Fette 2080 tablet machine. Again,

the tablet TFS is shown to be

independent of tablet size

and compression machine,

and a fundamental

material property.

Compaction Parameters

The complex

relationship between

the tablet properties of

solid fraction, compaction

Fette

GTP

Figure 1: Tabletability assessed on the GTP-1 and Fette production tablet presses

Source: Gamlen Tableting Ltd

3.5

3

2.5

2

1.5

1

0.5

0

Tens

ile s

tren

gth

(MPa

)

Compaction pressure (MPa)

0 50 100 150 200 250 300

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57Innovations in Pharmaceutical Technology Issue 44

As expected, ejection stress

increases with compaction force and

decreases with magnesium stearage

concentration. This work is being

extended to other lubricant systems

and other excipients. Improved

understanding of lubrication using

ejection stress measurements is a

very exciting area of research.

In-Die Measurements

The final area of research to

consider is the use of in-die

measurements under load. As far

as we know, these are impossible

to make on any rotary tablet

press currently available. The

displacement measurement

compared 10 formula variants, all

containing 25 per cent drug, wet

granulated on a 50g scale, dried,

milled and lubricated. A difference

in tabletability of over 100 per cent

was seen. Put another way, tablets

compressed at one compaction

pressure were twice as strong

made from the best formulation

as they were from the worst. This

was extremely helpful to the client,

who was looking for a high-quality

formulation for clinical trial use.

Using a good formulation allowed

minimal compaction pressure

to be used to make the tablet,

and resulted in superior

product dissolution.

Ejection Stress

Lubricity, the ability to make

tablets without product or

granule sticking to the punches

or dies, is a crucial tablet

property which is normally

only studied empirically. Very

few machines can measure

ejection stress during small-

scale formulation development;

it is possible on a compaction

simulator but very difficult on an

instrumented tablet press. The

GTP automatically collects a full

force/displacement profile for

every ejection event, which, as

far as we know, has never been

done before. The results are

very surprising. Some example

ejection profiles for direct

compression materials are shown

in Figure 3. There is substantial

variation both within and

between materials, with a wide

range of forces and profiles.

Recently Leung, a student at

King’s College, London, studied

the effect of compaction pressure

and mixing time on the ejection

stress of Avicel PH102 tablets

continuing magnesium stearate.

A pronounced minimum was seen

after five minutes of mixing in a

Turbula mixer, after which ejection

stress dramatically increased.

Wet granulated

Dry granulated

Direct compression

Parteck M100 ejection force profile

Parteck M300 ejection force profile

Perlitol 200SD ejection force profile

Parteck M200 ejection force profile

Perlitol 100SD ejection force profile

Perlitol 300SD ejection force profile

Figure 2: Effect of manufacturing method on tabletability

Figure 3: Ejection profiles from the GTP

Ejec

tion

forc

e (k

g)

Punch position (mm)

Compression pressure (MPa)

0 50 100 150 200 250

Tens

ile fr

actu

re s

tres

s (M

Pa)

2

1.8

1.6

1.4

1.2

1

0.8

0.6

0.4

0.2

0

70

60

50

40

30

20

10

0

70

60

50

40

30

20

10

0

9876543210

70

60

50

40

30

20

10

0

70

60

50

40

30

20

10

0

70

60

50

40

30

20

10

041 41.5 42 42.5 43 43.5 44 44.5 45

41 41.5 42 42.5 43 43.5 44 44.5 45

41 41.5 42 42.5 43 43.5 44 44.5

41 41.5 42 42.5 43 43.5 44 44.5 45

41 41.5 42 42.5 43 43.5 44 44.5 45

41 42 43 44 45 46

IPT 44 2013.indd 57 07/03/2013 14:07

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Innovations in Pharmaceutical Technology Issue 44

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under the force/displacement

curve due to elastic compression

is allocated to work done on the

compact, which is returned to the

compact in the decompression

phase. The accuracy of the GTP,

when corrected for compliance,

is of the order of 1-3µm. This

compares with the typical

allowable tolerance in tablet

compression roll pin on a rotary

press of 12µm.

By using these precision

measurements we can see a

number of interesting effects

including continued deformation

after the peak compaction force

has been reached (first observed

on rotary tablet presses in the

1980s such as the Ridgway Watt

Betapress). In only two cases so

far – Pregelatinised Starch and

Polyplasdone XL – have we seen

evidence of ‘elastic recovery’.

In all other cases, including avicel,

paracetamol, lactose and sodium

chloride, the extent of elastic

recovery is minimal.

Conclusion

Study of the compaction

processes using instrumented

tablet machines such as the GTP

and the compaction simulator

generates important insights

into compaction behaviour.

Tabletability and compaction

measurements facilitate objective

material comparison using small

amounts of sample to generate

process and formulation insights

which can be applied during

the quality by design product

development process.

References1. Wood JR, Tablet manufacture –

its history, pharmacy and practice, J B Lippincott Company, 1906

2. Brake, Development of methods for measuring pressures during tablet manufacture, MS thesis, Purdue University, 1951

3. Knoechel EL, Sperry CC, Ross HE and Lintner CJ, Instrumented tablet machines 1: resign, construction and performance as pharmaceutical research and development tools, J Pharm Sci 56: pp109-115, 1967

4. Goodhart FW, Mayorga G and Ninger FC, Instrumentation of a rotary tablet machine, J Pharm Sci 57: pp1,770-1,775, 1967

5. Wray P, The instrumented rotary tablet machine, Drugs Cosmetic Ind 105: 58B-68B, pp158-160, 1969

6. Hunter BM, Disher DG Pratt RM and Rowe RC, A high speed compression simulator, J Pharm Pharmacol 28: p65P, 1976

7. Heckel RW, Density pressure relationships in powder compaction, Trans Metall Soc Aime 221: pp671-675, 1961

8. Krumme, Schabe and Fromming, Development of computerised procedures for the characterisation of the tableting properties with eccentric machines: extended Heckel analysis, Eur J Pharm Biopharm 49: pp275-286, 2000

validation technique developed

by Ridgway Watt et al was used

to compress a steel tablet while

making force and displacement

measurements during both

rising and falling compression

phases. The data obtained were

used to generate displacement

corrections. This technique

has been used to calibrate the

GTP in order to give extremely

accurate displacement

measurements.

The key parameters for in-die

compaction measurements are

force and displacement or tablet

thickness. These form the basis for

generation of compaction curves

and parameters such as Heckel,

Cooper and Eaton, and Kawakita.

Typical force-thickness curves are

shown in Figure 4. It is generally

held that a proportion of the area

Michael Gamlen is Managing Director of Gamlen Tableting Ltd. He has been working in tablet manufacturing, training and auditing for over 30 years and is the inventor of the Gamlen Tablet Press. He audits companies on a worldwide

basis against EU and US manufacturing standards, and is developing standardised development protocols to assist small companies in compliance with QbD and QRM guidance and systems. Email: michael@gamlen.co.uk

Ascorbic acid

Sodium chloride

Paracetamol N

Avicel

Paracetamol S

Paracetamol D

Supertab

Starch 1500

Polyplasdone

Figure 4: Displacement corrected thickness force curves for a range of materials

500

450

400

350

300

250

200

150

100

50

02,000 2,200 2,400 2,600 2,800 3,000 3,200 3,400 3,600 3,800 4,000

Forc

e (k

g)

Tablet thickness (mm)

IPT 44 2013.indd 58 07/03/2013 14:07