Technical Feature

Formulation Optimization
For Tabletting Applications
By Reg Freeman,
Managing Director,
Freeman Technology

Tablet production is an essential operation for the

pharmaceutical industry, considering the majority of
drugs are being delivered in this form. Tablet presses
operating on the principle of direct compression have
been developed over several decades and it is now
possible to make in excess of one million tablets per
hour. Developing formulations that process well in
these units to consistently deliver uniform tablets with
the required properties, remains an ongoing challenge.

The Challenges Posed By Tabletting

With direct compression, tablet ingredients are fed to
a press as a blended powder. The blend contains various components filler, inert carrier, active pharmaceutical ingredient (API), and lubricant each of
which fulfils a different function in terms of tablet or
processing performance. Wet or dry granulation
processes may be used to improve the flowability of
the blend.
Tablet quality is quantified in terms of strength,
weight, dimensions, and API content, the required
properties being produced through control of the
flowability and compressibility of the mix. This is
achieved by manipulating variables such as particle
size and shape, surface texture, and water content, and
by addressing fundamental issues such as excipient
choice and the concentration of each component in
the final formulation. Quality may be highly dependent on processing speed so productivity may be
adversely affected if flow properties are not optimal.
The aim is to develop a formulation that flows easily into the die, releasing air to form a strong tablet
during compression. Segregation must be avoided to
ensure uniform tablet composition. These goals
require careful optimization of the properties of the
blend. For example, small particles with high surface
roughness tend to produce strong tablets. While this is
an advantage, they may not flow well within the press.
Fundamental correlations between particle properties and tabletting performance remain elusive
because of the complexity of powder behavior1. As a
result, researchers still tend to rely to some extent on
art and experience when developing a completely

22

The Pharmaceutical Solutions Update

new tabletting process, or predicting the likely behavior of a new formulation in an existing press.
Compaction simulators are also used, to assess how
formulations will perform under different tabletting
conditions. Tools that can provide information at an
earlier stage, simply through analysis of a material, are
obviously a cost-effective, time-saving alternative; the
powder rheometer is one such tool.
Powder Rheometer Measurements
A unique feature of powder rheometers is dynamic
characterization, measurement of a powder in motion.
The energy required to induce or to maintain a particular flow pattern is determined from measurements of
force and torque, recorded as a blade rotates through
the sample at a certain speed. A conditioning step
before analysis ensures that the initial packing state of
the material, and hence the measurement, is reproducible. This single traverse of the blade up and down
through the sample produces a loosely packed bed,
the gentle slicing and lifting action allowing the particles to come to rest in a homogenously packed state.
The baseline energy measurement recorded for a
conditioned bed, is highly differentiating and, therefore, valuable in its own right for assessing differences
between samples (QC applications). For example,
pharmaceutical manufacturers have found that with a
powder rheometer they can differentiate between
batches of material of the same grade. This permits the
selection of those with the preferred flow properties,
without changing the validated formulation.
In combination with other experiments, this baseline measure can also be used to systematically investigate the impact on flow properties of variables such
as consolidation, aeration, moisture content, flow rate,
and composition. Modern powder rheometers now
also measure shear and bulk properties, which can be
correlated to different stages of the process.
Permeability measurements, for example, indicate the
ability of a powder to aerate and de-aerate, while compressibility data is relevant to processing steps where
the powder is consolidated. Cohesivity, measured by
shear testing, provides insight into a powders ability
to flow from a static storage condition and also its
www.pharmaceuticalonline.com

Technical Feature

capacity to stick together in tablet form. Wall friction

tests indicate the likelihood of the material adhering
to the die walls in the tablet press.
For tabletting, segregation, de-aeration, and
flowability characteristics are particularly important.
The following case studies show how powder
rheometry can be used to investigate these aspects
of behavior.

stability testing), or making measurements as

described above, are both effective and practical
ways of assessing the propensity of a sample to segregate. These data can be used to directly determine
the likelihood of an associated problem occurring
during processing.
Air Release
If air is compressed in the die with the blend, rather
than being released prior to or during compression,
when pressure is removed the air will expand, rupturing the tablet3. A blend that releases air relatively
easily is therefore preferable in order to avoid lamination or splitting; materials that retain air are much
more likely to result in catastrophic tablet failure.
Powders pick up and release air at different rates,
some aerating easily and releasing entrained air
rapidly, others behaving very differently.
The ease with which a powder is aerated can be
quantified by measuring flow energy as air flows
through the sample. The ability of a material to

Segregation
Segregation of a blend can lead directly to inconsistencies in tablet composition and rejection of a complete batch of product on the grounds of uneven
API distribution. Furthermore, segregation of a lubricant can be detrimental to powder flow, and ultimately to tablet strength. If lubricant is poorly distributed within a tablet then capping can occur
where the tablet splits or shears along the layer of
lubricant that has formed within it.
The mechanisms of segregation are fairly well
understood and are related to specific material properties. Particle size and distribution, the
ease with which the material flows
(segregation is less of a problem with
cohesive powders), and the way in
which the material behaves when aerated, are all important factors2.
Data collected during a test designed
to investigate segregation are shown in
Figure 1. Repeat measurements of flow
energy are made using the standard
test cycle. Each measurement is preceded by five segregation cycles
involving rotation of the blade once
through the sample in a three-dimensional, low-stress flow pattern,
designed to promote segregation. The
highly repeatable nature of the blades
movement during the segregation cycle Figure 1: Flowability energy as a function of segregation for a coarsely
milled lactose which had previously been subjected to attrition to produce
allows easy comparison of the vulnera- fines
bility of different blends. Observed
changes are due to segregation and not
attrition.
The results show successive increases
in flow energy consistent with ongoing
segregation of the sample. In the
absence of segregation the measured
flow energy would be constant. The
final data point on the graph was measured after the sample had been
returned to its initial state, by tumbling
and mixing to homogenize. It provides
confirmatory evidence that the
observed changes are due to segregation.
Repeatedly carrying out the basic flow
energy measurement (referred to as Figure 2: De-aeration of three different lactose materials

24

The Pharmaceutical Solutions Update

www.pharmaceuticalonline.com

Technical Feature
release air (de-aerate) can also be determined by carrying out successive measurements once the air has
been switched off. Powder rheometers uniquely allow
measurement of materials in an aerated state and are
therefore especially valuable for investigating this
aspect of behavior. Figure 2 shows de-aeration data for
three different lactose materials.
It is evident from the data that spherical, spray-dried
lactose de-aerates readily, achieving 100% recovery to
BFE in just three de-aeration cycles. The comparably
sized coarsely milled lactose also de-aerates readily,
but does not fully return to its baseline state until the
fifth cycle. The finely-milled lactose, on the other hand,
releases air much less easily the cohesive nature of
the fine particles encouraging entrainment.
Interestingly, the materials show a similar degree of
recovery when the air is simply turned off (n=0), yet
when the powder is disturbed mechanically, the properties are quite different.
Results from tests such as these, correlate directly
with the likelihood of producing tablets that will fail
catastrophically following compression as a result of
air release. They rapidly identify potential problems
with a new formulation.
Flowability
Poorly flowing blends can result in improper filling of
the tablet die, leading to inconsistencies in tablet
weight. Materials vary in terms of their flowability and
consequently their optimum processing rate; formulation and processing speed therefore need to be carefully matched for each application. Poor flow properties, resulting from the use of cohesive materials for
example, may also result in flow stoppages, and an
unacceptable amount of downtime.
Additives are often used to improve the flow properties of a tablet formulation. A common example from
the pharmaceutical industry is magnesium stearate,
which in addition to improving flow behavior, provides lubrication between the die and the tablet, so

that less ejection force is needed. The impact of this

additive on flow energy can be observed from Figure
3, which shows measurements for a range of lactose/magnesium stearate blends.
These data show that while 0.1% magnesium stearate
provides some improvement in flow behavior, the
optimum dosing level lies between 0.15 and 0.20%.
Concentrations above this level yield no further
enhancement in flow properties. High concentrations
are more likely to cause segregation problems and, as
discussed earlier, increase the likelihood of capping, so
this information is extremely useful.
Conclusion
Optimizing a formulation for an existing or new tabletting process requires careful consideration of the factors affecting processability. Powder rheometry is an
excellent option for such investigations, providing
information that directly correlates with processing
behavior. It allows researchers to predict the likely performance of a formulation at an early stage, yielding
valuable data for process design and optimization.
Particularly critical is the ability of such devices to
dynamically characterize powders in aerated, conditioned, and consolidated states.
By matching the critical flow properties of new formulations with those known to process well in a specific press, or by understanding the likely impact of differences between formulations, researchers are more
able to develop effective tabletting processes. This has
a direct impact on product quality and on productivity. Such process relevance, which is far from unique to
tabletting, explains why powder rheometry, although a
relatively new analytical technique, is increasingly
widely used by those who recognize its potential to
provide new insight into powder behavior.
About The Authors
Reg Freeman is founder and managing director of
Freeman Technology. He is a mechanical engineer
with extensive experience in designing
testing systems for evaluating the physical
properties of liquids and solids, and in
the mid 1990s conceived an innovative
approach to powder testing that is now
patented worldwide.

Figure 3: Flow energy measurements for different blends of lactose and

magnesium stearate

26

The Pharmaceutical Solutions Update

References
1. The future of compaction B.A.C
Carlin Pharmaceutical Technology. June
2004.
2. Maintaining product uniformity
and uninterrupted flow to direct compression tableting presses J. Prescott and
R.Hossfeld Pharmaceutical Technology 18
(6), 1994 p99-114.
3. A day in the life of a tablet T. Lewis
PMPS Spring 2002.
www.pharmaceuticalonline.com