User-friendly solid oral
dosage forms are popular with patients and offer many benefits over conventional
tablets. Rather than being swallowed whole, these dosage forms can be chewed,
sucked, or dissolved in water and consumed as a drink. This makes them easy to
swallow, even for children, elderly people, and those with dysphagia. As they
tend to spend longer in the mouth and are tasted more thoroughly than
traditional tablets and capsules, a pleasant taste is one of the key attributes
that determines acceptability and patient compliance. However, even
conventional tablets, which are normally considered by formulation scientists
to taste neutral, are often perceived to taste unpleasant by patients and
consumers, creating a potential barrier to uptake.
Given the inherently
bitter taste of most active pharmaceutical ingredients (APIs), the challenge for
the pharmaceutical industry is how best to use flavorings and taste-masking
technologies to make oral dosage forms taste pleasant. Furthermore, the process
of assessing taste raises both practical and ethical issues when relying on human
tasting panels. One exciting alternative that is starting to gain traction in
the industry is assessment via an electronic tongue to detect and analyze all
the compounds responsible for taste within a sample. Electronic tongue
instruments, methods, and data can be qualified and validated making this
approach particularly suitable for pharmaceuticals. Electronic tongue analysis
also means that taste evaluations can be incorporated into both stability studies
and formulation development, potentially reducing drug development lead times
and reducing costs accordingly.
THE CHALLENGE WITH CONVENTIONAL TABLETS & CAPSULES
While tablets and capsules
remain a popular dosage form within the pharmaceutical industry, it is
frequently underestimated how many people struggle to swallow them. In research
recently conducted, it was discovered that more than half of the 2,000 people
surveyed reported difficulty swallowing tablets and capsules, with around a
third of these people describing the problem as serious.1 There were
a variety of reasons given for this with the most commonly cited being that
tablets/capsules are too big, that they become stuck in the throat, or that they
have an unpleasant taste or odor. Those surveyed did not experience similar difficulties
swallowing foodstuffs or liquids.
When faced with tablets or
capsules to swallow, people used various techniques to ease the process. 32%
tried breaking them, 17% crushed them and dissolved them in water, and 9%
chewed them. This is concerning as these approaches have the potential to
negatively affect release profile, bioavailability, and medical efficacy of the
API. Most worrying of all is that 8% simply resorted to not taking their
medication at all.
Some people described
other challenges with tablets and capsules. Older people often found it hard to
press them out of the blister packaging, while younger people highlighted the
inconvenience of taking them “on the go.” User-friendly solid oral dosage forms
offer a great alternative that overcome these issues (Figure 1).
Taste has been shown to be
an important factor in how people perceive medications, and a negative
experience can impact patient compliance. This is true for user-friendly dosage
forms that spend longer in the mouth but also for conventional tablets and
capsules. Thus, in order to develop a successful product, the pharmaceutical
industry must ensure it tastes good.
THE HUMAN SENSE OF TASTE
Humans rely on a
combination of appearance, smell, taste, and texture to form a sensory impression
for anything we consume. This is as true for pharmaceuticals as it is for foodstuffs.
User-friendly dosage forms spend longer in the mouth than conventional tablets,
making the sensory impression even more crucial.
For the pharmaceutical
industry, appearance and texture are relatively easy to measure using various
analytical instruments, as well as forming an assessment “by eye.” All this can
be achieved without unnecessary exposure to drug substances. Smell and taste,
on the other hand, are harder to assess. A “sniff test” works well for some
low-risk pharmaceuticals but would be unsafe for more toxic APIs. Likewise,
it’s possible, but far from ideal, to ask people to assess the taste of
The human (or indeed
mammalian) sense of taste is of evolutionary importance, and it’s no
exaggeration to say that it can be a life-saver. Toxic substances will often
taste bitter while sweetness is usually associated with safe food and energy.
Substances dissolved in the mouth stimulate taste receptors. These are located
within taste buds, which are found around small structures called gustatory
papillae on the tongue, soft palate, upper esophagus, and epiglottis. We each
have around 10,000 taste buds, although these are known to reduce in number as
we age, particularly beyond the age of 50. As a result, we taste things
differently later in life.
There are five basic
tastes that are detected by taste receptors: saltiness, sweetness, bitterness,
sourness, and umami (which corresponds to the flavor of glutamates and means
“delicious” in Japanese and is often described as “savory” in English).
The complexity of how we
taste creates an impression that lasts a long time (compared with smells, which
are experienced for only a short time but are remembered well). This impression
allows us to differentiate between initial taste and aftertaste – wine tasting notes
provide a perfect example of this. Aftertastes may differ considerably from the
flavor of what was consumed, and pose a particular problem for medicines.
We know that people taste
differently and thus have different taste experiences of the same substance.
This is not only caused by age but can also have genetic underpinnings. Based
on an individual’s taste bud profile, some tasters may be more sensitive to
particular flavors than others. Likewise, some medicines and medical conditions
themselves can alter people’s perception of taste.
PALATABILITY OF PHARMACEUTICALS
To ensure both market
success and patient adherence, it is important that all oral pharmaceuticals –
but particularly user-friendly dosage forms – taste pleasant. When developing a
new foodstuff, it’s perfectly acceptable to ask a panel of people to assess the
taste. For pharmaceuticals, however, this is more problematic. There are
obvious ethical issues concerning giving a healthy person a medicine
unnecessarily – particularly if it could have adverse pharmacological effects.
Furthermore, molecules that are not FDA approved cannot be tested. A human
tasting panel, therefore, can essentially be considered as a clinical trial and
requires approval by an ethics committee. This makes it challenging and
time-consuming to test even a few substances.
Most APIs have a
particularly bitter taste, posing an additional obstacle for the pharmaceutical
industry. Taste-masking must be employed – through addition of sugars, sweeteners,
and flavorings, or use of coating technologies – to overcome this. At HERMES PHARMA,
we know that formulation scientists experienced in taste-masking are able to
make recommendations for which flavors to combine with which APIs and are also
aware of which flavors are preferred in different geographies. For example,
sour-tasting APIs are best taste-masked with flavors that include sour
components. This means that citrus and berry flavors are suitable options but
banana, caramel, and peach are not. Such expertise reduces the time spent in
product development compared with a solely trial-and-error approach.
Today, the most common
approach to assessing the relative success of taste-masking efforts, together
with other organoleptic properties, is via a human tasting panel that records
its immediate impressions on a questionnaire. However, due to inter-individual variability,
sensory impressions are subjective – regardless of how well you train and
calibrate your tasting panel. Most often, it is only possible to use healthy
adults, which can also affect the results. Pediatric and geriatric patients are
only permitted in exceptional circumstances.
ELECTRONIC TONGUE INSTRUMENTATION
A new instrument that is
slowly starting to be adopted by formulation development scientists is the electronic
tongue. This technology has been designed around how we know humans taste
substances and can rapidly detect all the organic and inorganic compounds responsible
for taste in a liquid sample. Sweet, salty, sour, bitter, and umami tastes are
all tested for, together with metallic, pungent, or astringent components, and a
taste profile is built accordingly.
Unlike human tasting
panels, the data generated by the electronic tongue is not subjective, making
it possible to reliably compare taste profiles between different substances. In
fact, the instruments, methods, and data can all be qualified and validated, making
this approach ideal for the pharmaceutical industry.
A significant advantage of
the electronic tongue is that many more samples can be tested than via human
tasting panels. This affords the opportunity to incorporate taste testing into
stability studies and in formulation development – both of which can help reduce
the time a product spends in development and minimize costs.
There are two electronic
tongue instruments available on the market, although a number of academic
institutions have developed their own versions for research purposes. Manufacturers
are currently working on automating the electronic tongue and optimizing it for
high throughput testing.2
comprise three key components: sensory array, signal emitting/receiving
equipment, and pattern recognition. The detection thresholds of the sensors are
similar to, if not better than, those of human taste receptors. And the
information provided by each sensor is complementary, with the combination of
all the sensors providing a unique fingerprint for the substance being tested.
Electronic signals, like those transmitted by nerves in humans, are generated
as potentiometric variations. The electronic tongue uses statistical software
as the “brain” to interpret and translate the sensor data into taste patterns. This
can be done either graphically or mathematically. A graphical approach sees the
signal from the various sensors added in a radar plot (Figure 3). Comparisons between
different plots/substances are made visually. Alternatively, data from the different
sensors can be processed mathematically via a multi-variate data analysis, such
as principle component analysis (Figure 4). Either way, it is possible to
compare the whole profile or just selected factors, such as sourness or bitterness,
between different samples.
It is important to note
that only liquids can be analyzed using the electronic tongue. Solutions
require no pre-treatment, except perhaps filtration. Solid formulations, however,
must be at least partially dissolved before analysis. This dissolution step
should replicate the physiological process as closely as possible. For example,
as orally disintegrating granules (ODGs) will only partially dissolve in the
mouth, analysis should be made on the fraction that dissolves before
swallowing. This could be replicated in the laboratory by adding a known quantity
of artificial saliva to the ODG for say 1 minute (the time needed to salivate
and swallow the ODG in two to three gulps) and then filter to collect only the amount
of the ODG that is dissolved in that time. Electronic tongue analysis can be
performed on this sample. Aftertaste (to accommodate the few granules remaining
between the teeth, for example) can be analyzed by dissolving the complete ODG and
comparing it with the 1-minute sample. A similar approach can be used for tablets,
which spend only seconds in the mouth before being swallowed with water. Only
the film-coating is tasted with the tabletcore/API remaining undissolved.
GUIDING FORMULATION DEVELOPMENT
So, how can data generated
through electronic tongue analysis be used to direct formulation development?
One option is to identify a reference substance, one that is known to taste good,
with the aim of recreating the same taste (as closely as possible) with the
product that is under development. When data is shown on a PCA plot, the final formulation
should be as close as possible to the reference product and/or placebo and
distant from the original API. This top-down approach is ideally suited to the
development of generic formulations in which there is an existing product that
can be used as a reference substance. Ideally, there would also be supporting
data available that demonstrates the market acceptance of the original product.
Such data would be particularly advantageous if the product was targeted at a
difficult to access market segment, such as pediatric medicines.
Alternatively, if there is
no reference substance available, a pleasant-tasting placebo is created, which
can be tested both by the electronic tongue and by a human tasting panel.
Afterward, formulation scientists will attempt to re-create the same flavor in
the drug product by adding flavorings and sweeteners to the API or coating it.
Success is measured via comparing electronic tongue data with that of the
placebo. This bottom-up approach carries the additional advantage that both the
placebo and the drug product taste alike and so do not bias the results of
later clinical trials.
Regardless of whether a
top-down or bottom-up approach is used, the goal is the same – to make the
taste profile of a drug in development match that of a chosen, pleasant- tasting
drug/placebo and to provide evidence of this via electronic tongue analysis.
This analysis is more reliable and more consistent than the data generated
using a human tasting panel. Human perception of taste varies considerably from
person to person and often from day to day for an individual. It also allows
pharmaceutical companies to employ a more ethical approach to assessing taste,
by removing the need to administer medicines (that are still in development) to
healthy volunteers. In addition, electronic tongue analysis helps to provide
data for medicines targeted at hard-to-reach patient populations, such as
infants and elderly people.3 Having overcome the ethical problems of
taste tests, the electronic tongue approach enables formulation scientists to
perform more taste tests, and earlier in the formulation development process –
with the dual benefits of shortening development times and reducing costs.3
For these reasons, it is likely that we will see increased uptake of electronic
tongue technology throughout the next few years.
2. Cioseka P, et al.
Towards flow-through/flow injection electronic tongue for the analysis of
pharmaceuticals. Sensors & Actuators B: Chemical. 2015;207(Part
3. Campbell GA, et al
Evaluating the taste masking effectiveness of various flavors in a stable
formulated pediatric suspension and solution using the AstreeTM
electronic tongue. Powder Technology. 2012;224: 109-123.
Detlev Haack is the Director Research & Development at HERMES PHARMA. He
earned his PhD at the University of Hamburg on the subject of Chemical and Physical
Stability of Piroxicam in solid dispersion with PEG and PVP. In 1997, he
received approbation as a pharmacist. From 2003-2007, Dr. Haack was Manager
Sales & Business Development at Hermes Arzneimittel GmbH. He held the
position of Associate Director R&D there from 2007-2012 before becoming
Director R&D in 2013. His career includes a previous position as Head of
Production at Altana Pharma Oranienburg GmbH.