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.
iptonline.com
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
iptonline.com
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)
iptonline.com
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: [email protected]
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: [email protected]
Figure 5: Compaction (top), ejection (middle) and fracture (bottom) profiles for an Avicel PH-102 tablet