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: [email protected]
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)
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