Designed to dissolve in water, effervescents are
manufactured and packaged as either solid tablets or granules. Active
ingredients often taste bitter and taste masking/ flavouring is commonly
required. Upon contact with a liquid, they rapidly dissolve, releasing carbon
dioxide in the process.
This effervescent reaction is triggered due to the
chemical nature of the effervescent mixture, which contains an acidic (for
example, citric acid) and alkaline compound (such as sodium hydrogen
carbonate). The presence of water starts a chain reaction producing a salt (for
instance, sodium citrate), more water and carbon dioxide (see Figure 1).
Designed to dissolve in water, effervescents are manufactured and packaged as
either solid tablets or granules. Active ingredients often taste bitter and
taste masking/ flavouring is commonly required. Upon contact with a liquid,
they rapidly dissolve, releasing carbon dioxide in the process.
The agitation
caused by the release of the gas further stimulates the process, leading to
rapid and complete dissolution of the effervescent granules and the subsequent
release of the active pharmaceutical ingredients (APIs) into the solution.
Patients and users then simply drink this solution to easily and comfortably
ingest the medicine or dietary supplement in question.
Perfect for Patients
Effervescent dosage forms offer patients a wide range of benefits. First and
foremost, drinkable medicines are much easier to swallow than conventional
solid tablets or capsules. This is worth noting, as many patients complain that
swallowing tablets is painful and unpleasant, with factors such as tablet size
and shape significantly affecting treatment preference and regimen adherence
(1-3). Indeed, more than 25 per cent of a general practitioner’s patients can
be expected to complain of swallowing difficulties, according to one large
pan-European study (4).
Poor medical compliance is especially prevalent among
those suffering with chronic conditions that require frequent and long-term
dosing regimens, often with multiple medications (5,6). Fortunately,
effervescent formulations can also simplify treatment regimens by enabling
larger doses of API to be incorporated within a single dose, further boosting
medical adherence.
It is also possible to combine multiple APIs in a single
dose, even at very different concentrations. This means that even complex
dosing regimens requiring multiple medicines can be consolidated into one or
two drinkable doses per day. Such an approach is simply not possible using solid
dosage forms, the size and API capacity of which is restricted by the anatomy
of the human mouth and digestive tract.
Medicinally Effective
As well as being
more pleasant and convenient for patients, effervescent dosage forms offer
additional medical benefits over solid tablets. For example, as the API is
already dissolved before administration, there is no need for disintegration
and dissolution in the stomach, leading to a faster onset of action. The carbon
dioxide released during the effervescent reaction also enhances the transport
of APIs into the cells of the digestive tract, improving absorption and
bioavailability.
In addition, the solution generated by effervescent tablets is
buffered against changing pH, which in turn accelerates its passage through the
stomach and enables faster absorption in the small intestine. Furthermore, the
use of effervescent tablets tends to produce a more reliable efficacy response,
as all the agents in a dissolved effervescent tablet are evenly distributed,
preventing variability due to tablet disintegration and dissolution.
In
combination, these factors can significantly reduce the risk that the
absorption window of a given API will be missed due to slow release, incomplete
dissolution or inefficient absorption.
Industry Opportunities
Given the
widespread impact of poor treatment adherence and the additional medical
benefits of effervescent dosage forms, such user-friendly medicines would
likely be beneficial for all patients. However, they are extremely well-suited
to those with swallowing difficulties, such as the elderly, infirm, young
children or those with esophageal injuries.
With a clear medical need to
satisfy these patient groups and very few effervescent medicines currently
available, a large market opportunity exists for innovative pharmaceutical
developers and manufacturers.
One potentially ‘easy win’ for pharma companies
is to reformulate existing compounds into new user-friendly forms, targeted at
specific subsets of the market. For example, a solid dose could be converted
into a sweet-tasting effervescent dosage form for children and an instant drink
for the elderly, who are more likely to suffer from chronic disease and may
require greater flexibility in dosage concentration and frequency. This is an
excellent way to extend product lines, lengthen product lifecycles, increase
market share and move into new markets.
Patients are likely to prefer products
specially formulated to meet their needs, potentially leading to greater brand
loyalty and differentiation from competitors; in some cases, patients may even
be willing to pay higher prices for what they perceive to be better products.
By providing an even wider range of choice – for example, by introducing
several flavours – there is further opportunity to differentiate the brand and
create a group of loyal users.
Patent Protection
New effervescent formulations
of existing medicines can also provide a mechanism to protect intellectual
property. This is particularly relevant given the well-documented ‘patent cliff’,
which is having a significant impact on pharmaceutical revenues. Pharma
companies have long used minor changes in API chemical structure to apply for
extended patent protection, but recent regulatory changes that require newly
reformulated medicines to deliver significantly more benefit to patients and/or
reimbursers than the original formulation have made this approach much less
effective. In such cases, new user-friendly dosage forms that improve patient
adherence are an effective option for extending patent protection.
It is often
true that product-line extension, via the innovative modification of pharma
drugs into new formulations, can make it more difficult for rival companies to
create similar drugs, particularly where the technical parameters are difficult
to replicate and/ or can be protected by updated patents. Either way, the
ability to reformulate current medicines into new user-friendly forms provides
an effective way for pharma companies to improve therapies and protect patents.
Regulatory Considerations
When choosing to formulate medicines in effervescent
forms, one benefit is that dissolution data does not need to be provided, since
the effervescent dosage form is dissolved prior to swallowing. Instead, the
efficiency of the dissolution step can be confirmed and reported using a
simpler and cheaper disintegration test.
However, when producing effervescent
tablets packaged in tubes containing multiple doses, in-use stability data
illustrating that the tablets are stable after opening the tube must be shown.
Ensuring this stability is not usually a problem, providing that a suitable
packaging material has been selected, with an appropriate desiccant firmly
attached to the cap.
For those requiring more information, effervescent dosage
forms are described in all major pharmacopoeias, including those in Europe, the
US and the UK, where
additional details surrounding their characteristics, formulation and
manufacture can be found.
Low Moisture Conditions
While effervescent medicines
have the power to offer significant benefits to all stakeholders, their
development, mass manufacture and packaging require dedicated expertise, as
well as specific infrastructure, production facilities and technologies.
Perhaps the greatest challenge of their formulation is posed by their inherent
sensitivity to moisture, being designed to rapidly dissolve upon contact with
liquid.
Unless formulated under carefully controlled environmental conditions,
traces of humidity in the air, or even condensation on machinery, can accidentally
trigger the effervescent chain reaction. Once started, the process continues
rapidly due to the presence of additional water produced as part of the
reaction, and can be difficult to stop (see Figure 1 page 31). Fortunately, if
the relative humidity at 21°C stays below 20 per cent, then direct compaction,
dry granulation and granulation with fluidised granulators are possible (7).
Similar care must be taken as the tablets pass along the production line
through granulation, tableting (if required) and packaging. This final step is
often carried out ‘in-line’ directly alongside the tableting/filling process to
minimise the uptake of moisture – packaging the effervescent granules or
tablets in tightly sealed containers such as sachets or tubes to reduce the
risk of degradation during transport or storage. In other cases, the granules
are transported to the packaging line using a moisture-free, vacuum conveyor
process.
The packaging itself is frequently designed to be child-resistant,
while individually wrapping each dose can help to avoid the instability caused
by the frequent opening, closing and reopening of a tube. Individually wrapping
each dose increases patient convenience and may also extend the shelf-life of
extremely sensitive active ingredients.
Taste and Flavour
As well as moisture
sensitivity, the other major challenge when working with effervescent dosage
forms revolves around taste masking and flavouring. Most APIs have a bitter
taste: a characteristic that is reasonably well concealed by solid dosage
forms, as they are swallowed before being dissolved; they are unable to bind to
receptors and thereby cause a taste sensation on the palate.
This is unlike
effervescents, where the API is in solution and can therefore be more easily tasted
by the patient. Drinking also tends to require more than one mouthful of
medicine, meaning that they tend to spend a longer amount of time in the mouth.
For these reasons, taste masking and flavouring are a much more pressing
consideration in effervescent formulations than in solid medicines.
Conventional Formulation
Effervescent products tend to be sold in either solid
tablet or granulate form, rather than as fine powders, as this minimises
stability issues while also favouring rapid and thorough dissolution upon
contact with water. For this reason, the formulation and manufacturing of
effervescents requires granulation or compaction to generate the final product
to be used by patients.
Traditionally, effervescent dosage forms have been
formulated in one of a few ways. Direct compression has been the favoured
option for low price products, but some of the necessary excipients used can
have negative effects on dose stability and tolerance. For example, using this
method, sugar alcohol binders are often added to make tablets solid enough to
handle, but they must be used sparingly so as not to inhibit the breakdown of
the effervescent in water.
To avoid the use of such binders, it is advisable to
granulate the constituents before compression. Dry granulation aims to do just
this, and is generally an acceptable method for use with moisture-sensitive
substrates. However, it is rarely used for effervescent tablets as the final
products tend to possess low mechanical stability. The process is cost
effective due to the high turnover rate it offers, but does require the
addition of lubricants.
If used to formulate effervescent dosage forms, these
lubricants can cause problems upon dissolution, such as the development of an
unpleasant film on the top of the solution. This can be somewhat circumvented
either by using water-soluble lubricants or external lubrication, which enables
high tableting speeds while avoiding the formation of any unwanted films
following the effervescent reaction.
Fluidised bed granulation solves some of
the problems posed by dry granulation, increasing the stability of the final
product. But if the dosage form is to be formulated via the spray drying of
acid salts, products granulated using this process can have low mechanical
stability. The method also requires potentially costly and toxic organic
solvents, which are required to prevent the effervescent reaction from
triggering accidentally. This is a significant risk when granulating acidic and
alkaline constituents together, as is the case for effervescent dosage forms
(for example, citric acid and sodium hydrogen carbonate).
Widespread Adoption
Now that outsourcing partners have developed the expertise required to develop
and carefully control the manufacture and packaging of effervescent dosage
forms, they are no more difficult to produce and distribute than traditional
solid dosage forms and are ready for widespread adoption.
Given the extensive
range of benefits they offer to all stakeholders – including patients,
pharmaceutical companies, reimbursers and carers – the prevalence of
effervescent medicines will likely grow in the future, especially as patients
become conscious consumers of the medicines they require, requesting dosage
forms that meet their medical needs in a pleasant and painless way.
Acknowledgement We would like to thank Dr Martin Köberle, Senior Manager of
Analytical Development, for his significant contribution to this article.
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