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Putting the Fizz into Formulation

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.


1. Bhosle M, Benner JS, DeKoven M and Shelton J, Difficult to swallow: patient preferences for alternative valproate pharmaceutical formulations, Patient Prefer Adherence 3: pp161-171, 2009

2. Hussain MZ, Effect of shape of medication in treatment of anxiety states, Br J Psychiatry, 120(558): pp507-509, 1972

3. Ogata I, Yamasaki K, Tsuruda A et al, Some problems for dosage form based on questionnaire surveying compliance in patients taking tamsulosin hydrochloride, Yakugaku Zasshi (Journal of the Pharmaceutical Society of Japan), 128(2): pp291-297, 2008

4. Andersen O, Zweidorff O, Hjelde T and Rodland E, Problems when swallowing tablets. A questionnaire study from general practice, Tidsskr Nor Laegeforen, 115(8): pp947-9, 1995

5. Boswell KA, Cook CL, Burch SP, Eaddy MT and Cantrell CR, Associating medication adherence with improved outcomes: A systematic literature review, Am J Pharm Benefits, 4(4): e97-e108, 2012

6. Williams A, Manias E and Walker R, Interventions to improve medication adherence in people with multiple chronic conditions: A systematic review, J Adv Nurs, 63(2): pp132-143, 2008

7. Schmidt PC and Christin L, Brausetabletten – Eine fast vergessene Arzneiform, Pharmazie, 45: pp89-101, 1990

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Detlev Haack is Director of R&D at Hermes Pharma, a division of Hermes Arzneimittel GmbH. 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, Detlev was Manager of Sales and Business Development at Hermes Arzneimittel, before becoming Associate Director and then Director of R&D.

Detlev Haack
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