Effervescent tablets are uncoated tablet preparations containing mixtures of medicinal agents with acid substances and carbonates or hydrogen carbonates, which react rapidly in the presence of water to release carbon dioxide. They are solid dosage forms which are intended to be dissolved or dispersed in a glass of water before administration.
Effervescent tablets have specific characteristics that allow rapid adsorption and dissolution of the intended drug. The availability of dosage forms based on effervescence technology gained much importance with the technology of Alka-Seltzer in the 1930s. The widespread use of effervescent tablets has been achieved as a result of their convenience and also the ease in which they can be consumed.
This article reviews the fundamentals of effervescent tablets, effervescence reaction, excipients used in effervescent tablets, production techniques, quality control tests as well as the advantages and disadvantages of effervescent tablets.
- 1 Effervescence reaction
- 2 Drugs formulated as effervescent tablets
- 3 Constituents of effervescent tablets/ Excipients used in the manufacture of effervescent tablets
- 3.1 1. Acid Components
- 3.2 2. Alkali Components
- 3.3 3. Binders
- 3.4 4. Lubricants
- 3.5 5. Disintegrants/ Dissolution aids
- 3.6 6. Sweeteners
- 3.7 7. Colourants
- 3.8 8. Surfactants
- 3.9 9. Antifoaming agents
- 4 Manufacture of effervescent tablets
- 4.1 1. Manufacture of effervescent tablets using wet granulation method
- 4.2 2. Manufacture of effervescent tablets using fusion method
- 4.3 3. Manufacture of effervescent tablets using dry granulation method
- 4.4 4. Manufacture of effervescent tablets using direct compression method
- 4.5 Evaluation/ Quality Control of Effervescent tablets
- 5 Packaging of effervescent tablets (add pics of the various packaging systems)
- 6 Packaging Integrity Testing
- 7 Stability testing of effervescent tablets
- 8 Examples of effervescent tablets
- 9 Advantages of effervescent tablets
- 10 Disadvantages of effervescent tablets
- 11 Conclusion
- 12 References
3NaHCO3 (aq) + H3C6H5O7 (aq) → 3H2O (aq) + 3CO2 (g)+ 3Na3C6H5O7 (aq)
Effervescence is the evolution of bubbles of gas (carbon dioxide) from a liquid as the result of a chemical reaction between acids and bases. The reaction proceeds spontaneously when the acid and carbonate components are mixed in water, even with a very small amount as a catalyzing agent. Because water is one of the reaction products, it will accelerate the rate of reaction, leading to difficulty in stopping the reaction.
Drugs formulated as effervescent tablets
Drugs formulated as effervescent dosage forms include:
a. Those that are difficult to digest or disruptive to the stomach
A classic example is calcium carbonate, the most widely used form of calcium. In a normal tablet or powder, the calcium carbonate dissolves in the stomach acid and is carried into the digestive system for absorption. As the calcium carbonate dissolves, however, it releases carbon dioxide, resulting in stomach gas. On the other hand, as people age, they have less acid in the stomach and thus a calcium carbonate tablet may pass through the stomach without dissolving. That, in turn, may lead to constipation. However, if the calcium carbonate is taken in an effervescent formulation, the calcium dissolves in water and is readily available for the body to absorb without the risk of excessive gas in the stomach or of constipation.
b. Those that are pH-sensitive
The low pH in the stomach can cause active ingredients (e.g., amino acids and antibiotics) to become denatured, lose activity, or cause them to remain inactive. Effervescent ingredients, however, can buffer the water-active solution so that the stomach pH increases (becomes less acidic) and thus prevent the degradation or inactivation of the active ingredient. This buffering effect (via carbonation) induces rapid emptying of the stomach (usually within 20 minutes) and the residence time of the drug in the stomach will thus be short. The result is maximum absorption of the active ingredient.
c. Those requiring a large dose
Drugs requiring large dose can be formulated as effervescent tablets. A typical effervescent tablet (1 inch in diameter, weighing 5 grams in total weight) can include more than 2,000 milligrams of water-soluble active ingredients in a single dose. If the required dose is larger than that, the powder form is a common means of delivery.
d. Those that are susceptible to light, oxygen, or moisture
Many vitamins fall into this category. Typical effervescent formulations have less than 0.5 per cent of free moisture. To maintain that level and prevent other damage from the ambient environment, the formulation’s package should be 0.001-inch-thick aluminium that completely blocks light, oxygen, and moisture.
Constituents of effervescent tablets/ Excipients used in the manufacture of effervescent tablets
In addition to active ingredients, effervescent tablets contain:
1. Acid Components
a. Citric acid
Citric acid is an odourless, colourless, translucent crystal with a strong acidic taste. It is the most commonly used acid component, being readily abundant and relatively inexpensive. Citric acid imparts a citrus-like taste to the product. It is very soluble in water and freely soluble in ethanol.
Citric acid is commercially available in fine granular, free-flowing, anhydrous, and monohydrate food-grade forms. It is very hygroscopic. Special care must be taken to prevent its exposure to and storage in high-humidity areas especially if it is removed from its original container and not suitably repackaged.
b. Tartaric acid
This is an odourless, colourless, monoclinic crystal or a white (almost white) crystalline powder with an extremely tart taste. It is used in many effervescent preparations, being readily available commercially.
Tartaric acid is more soluble than citric acid. It is soluble in less than 1 part of water and 1 in 2.5 of ethanol. It is as strong an acid as citric acid, but more must be used to achieve equivalent acid concentration since it is diprotic, whereas citric acid is triprotic. Tartaric acid is deliquescent at relative humidity of above 75%.
c. Ascorbic acid
This is a colourless or white to yellow coloured, non-hygroscopic, odourless, crystalline powder with a sharp acidic taste. It is freely soluble in water and ethanol but darkens on exposure to light. It is less hygroscopic than citric or tartaric acid.
d. Malic acid
Malic acid is a white or nearly white, crystalline powder or granule having a slight odour and a strongly acidic taste. It is hygroscopic and readily soluble. Although its acid strength is less than that of citric or tartaric acid, malic acid provides sufficient effervescence when combined with a carbonate source. Malic acid also has a smooth, tart taste that does not “burst” in flavour as does the tart taste of citric acid.
e. Other sources of acid components
Other sources of acid components used in the manufacture of effervescent tablets include fumaric acid, nicotinic acid, acetylsalicylic acid, succinic and adipic acids, acid anhydrides (e.g., glutaric anhydride, succinic anhydride, etc.) and acid salts (e.g., amino acid hydrochlorides, sodium dihydrogen phosphate, acid citrate salts, etc.).
2. Alkali Components
a. Sodium bicarbonate
This is the most widely used alkali source in effervescent products. It is a white, odourless, crystalline powder with a saline, slightly alkaline taste. Sodium bicarbonate has low moisture content (1 % at 80 % relative humidity), yields about 52 % carbon dioxide by weight and is soluble in water (1 in 11 parts at 20 °C) but insoluble in 96 % ethanol at 20 °C.
Sodium bicarbonate produces a clear solution after tablet disintegration and forms carbonate when treated with heat. It is commercially available in five particle size grades ranging from a fine powder to a free-flowing uniform granule.
b. Other sources of alkali components
Other sources of alkali components include sodium carbonate (soda ash) and sodium glycine carbonate. When sodium ion is undesirable or needs to be limited, as in the case of antacid products, in which the dosage is dependent on the amount of sodium recommended for ingestion. Other sources of alkali that can be used include potassium bicarbonate, potassium carbonate and calcium carbonate.
Binders are normally necessary in effervescent tablets to bring the tablets’ hardness to a point where handling is possible. These binders should be water-soluble. A binder should be used very cautiously because it can carry free moisture into the tablet, which is undesirable and can increase the disintegration time when used in large quantities. The ideal amount of binder is one that makes the tablet hard enough to handle but soft enough to disintegrate and dry enough to be stable. PEG 6000 at 3 % use level can be used as a dry binder. However, most effervescent products are formulated without a binder because of its disadvantage of carrying free moisture into the tablets.
Of all the excipients compounded into effervescent tablets, the lubricant is one of the most important because, without this material, production of effervescent tablets on high-speed equipment would not be possible. Lubrication of effervescent granulation has historically been the main stumbling block to an acceptable, marketable product partly due to the nature of the raw materials used and partly due to the rapid tablet disintegration usually required. Many substances are effective lubricants in certain concentrations but inhibit tablet disintegration at these same concentrations. When the concentration is lowered to permit proper disintegration of the tablet, the lubricating efficiency of these materials are lost or so greatly diminished that they are no longer useful.
A perfect lubricant (or auxiliary agent, in general) for effervescent products must be water-soluble, non-toxic and tasteless. Typical lubricants such as magnesium stearate and stearic acid are of limited use due to their insolubility in water and thus, they tend to float on the surface, creating an unattractive “oil slick”. This can sometimes be remedied by adding emulsifiers such as lecithin or dioctyl sodium sulfosuccinate. Most formulators have to use water-soluble lubricants such as sodium benzoate, polyethylene glycol, and adipic acid. These are minimally effective and depend heavily on the granulation method used. Sodium chloride, sodium acetate, and D, L-leucine (water-soluble lubricants) have also been suggested for effervescent tablets lubrication.
5. Disintegrants/ Dissolution aids
Disintegration of effervescent tablets is enhanced by the carbon dioxide released during effervescence reaction. Common disintegrants used in conventional granules and tablets are not used in effervescent tablets because disintegrants are selected in such a manner that a clear solution should be obtained within five minutes after adding the tablet to a glass of water.
Effervescent formulations often contain sweeteners e.g., sorbitol, sucrose, aspartame or other natural sweeteners. Saccharin sodium can be used with sodium cyclamate in a 9:1 ratio. Water-soluble flavours may be added to mask unpleasant taste and make the product palatable.
Dyes or lake pigments may be included in the formulation to produce coloured solutions or products. Colour stability is also important and thus, colourants should be chosen as anhydrous material. Dried flower bud, herbs, chamomile extract may be used for this purpose.
These are added to effervescent formulations to increase wettability.
9. Antifoaming agents
In some cases, antifoaming agents (e.g. Polydimethylsiloxane) may be included in the formulation to reduce foam formation, and consequently, reduce the tendency of drugs to stick to the wall of the glass above the water level.
Note: The constituents of effervescent dosage forms or excipients used in the manufacture of effervescent tablets are required to have low moisture content and should be easily soluble.
Manufacture of effervescent tablets
The manufacture of effervescent dosage forms is similar in many ways to that of conventional granules or tablets, although due to the hygroscopicity and potential onset of the effervescence reaction in the presence of water, environmental control of relative humidity and water levels is of major importance during manufacture. A maximum of 25 % relative humidity or less is sufficient to avoid problems of atmospheric moisture. Moderate to cool temperatures (25 ºC) in the manufacturing areas are also essential to prevent the granulations or tablets from sticking to the machinery and from picking up moisture from the air, which may cause product instability.
Effervescent tablets are manufactured by both direct compression method and by compaction via granulation. In the latter case, traditional wet granulation is seldom used; instead, granules are formed by the fusion of particles as a result of their partial dissolution during wet massing of a moistened powder.
The equipment used in the manufacture of effervescent tablets are also the same as that for conventional tablets; the only difference is that it uses the rotatory press with special adaptations for compression.
1. Manufacture of effervescent tablets using wet granulation method
This is basically the same as for conventional tablets. In this technique, the acid and bicarbonate components can be granulated either separately or as a mixture with ethanol, ethanol-water mixture, isopropanol, etc. Usually, water is not used because of product instability in water. Citric acid which normally dissolves in ethanol or isopropanol serves as a binder when the solvent is evaporated. However, wet granulation of the effervescent base can be performed by carefully adding 0.1 to 1.0 per cent water (weight-to-weight basis) to a blend of raw materials that possess the uniformity, compressibility, and flowability needed to produce good-quality tablets, but which lacks the needed binding properties. The free water which is usually added in the form of a fine spray to selected formulation components while mixing in a suitable blender acts as a binder. The granulation steps must be precisely timed and the ingredients mixed thoroughly to distribute the granulating fluid evenly in the blend. The mix is then quickly discharged to drying ovens. Because variations in drying times and temperatures can affect the finished product, operational parameters of all equipment, especially drying equipment, must be constantly monitored. While stable granulations will ultimately be made, differences in tablet hardness and disintegration times may result from either over- or under-reacting the granulation. After drying, the granules are sized, and a final mix is performed. The granules are then compressed into tablets using tablet machines that can deliver high compression forces. If the tablets are to be wrapped in foil or placed into a tube, careful attention needs to be given to the tablet parameters during compression. Also, the tablet thickness needs to be monitored to ensure the wrapping or packaging equipment can handle the tablets.
2. Manufacture of effervescent tablets using fusion method
In this method, the effervescent mixture is heated up to 100 °C so that the water of crystallization or hydration from the hydrated citric acid is released, after which it is moistened with ethanol and added to the sodium bicarbonate. Partial fusion occurs and granules are formed by kneading in a suitable mixer. The granules are tableted while still damp with the moist citric acid acting as a lubricant. The compressed tablets are transferred immediately to ovens where they are dried continuously at 70 – 75 °C. The tablets harden on drying and are packed in aluminium foil lined with polyethylene.
3. Manufacture of effervescent tablets using dry granulation method
Manufacture of effervescent tablets using dry granulation method can be accomplished with the use of special processing equipment known as a “roller compactor” or “chilsonator”. These machines compress premixed powders between two counterrotating rollers under extreme pressure. Depending on the configuration of the roller, the feed material may be compacted into dense ribbon-like materials known as flakes (smooth rolls) or dense briquettes (almond or stick-shaped) if the rollers have grooved or etched surfaces. The compressed material is reduced to the proper size for tablet granulation purposes.
Another dry granulation procedure is slugging, in which the powder particles are compressed into large flat tablets or pellets using a tablet press or more usually, a heavy-duty tablet-compacting equipment. The resulting tablet or slug are milled to yield the desired granule characteristics.
Both of these processes are used for materials that ordinarily will not compress using the more conventional wet granulation techniques and require precompression to increase density or exclude entrapped air due to porosity.
4. Manufacture of effervescent tablets using direct compression method
In this method, effervescent tablets are compressed directly from powder blends of the active ingredient and suitable excipients (including the acid and alkali components) without an intermediate granulating step. Direct compression normally requires careful selection of raw materials to achieve a free-flowing, non-segregating, compressible powder blend. Measurements have been made of the mechanical properties of effervescent raw materials and mixtures to predict compressibility when directly compressed. Fumaric acid had the best compression properties among the acids tested, while sodium bicarbonate was the best among the carbonates. Acetylsalicylic acid and ascorbic acid effervescent tablets are typical examples of effervescent tablets produced by the direct compression method.
Evaluation/ Quality Control of Effervescent tablets
The quality control parameters mentioned in pharmacopoeias for the effervescent tablets are similar to those mentioned under conventional tablets. These include:
- Uniformity of Content
- Uniformity of Weight
- Disintegration time test
- Dissolution time test
Other parameters include:
- Thickness of tablets
- Crushing strength test
- Friability test
- pH of the solution
- Appearance of the tablets
- Determination of the carbon dioxide content (using gravimetric, colourimetric and volumetric methods)
- Water content (using the Karl Fischer’s method)
Packaging of effervescent tablets (add pics of the various packaging systems)
Effervescent tablets are packaged in such a way that they are protected against moisture. This is accomplished with waterproof containers e.g., glass, plastic, metal tubes or individual foil pouches joined to form a conveniently sized strip of tablets.
1. Glass tubes
Glass offers the highest degree of moisture protection of the nonflexible packaging materials; however, inherent limitations exist, such as breakage and cost of shipping a heavy package. Since individual packaging in glass is economically infeasible, moisture-proof closures for these multiple-use containers must be used. Metal caps with a waxed, aluminium foil, pulp backed cap liner usually prove satisfactory when repeatedly opened and closed. If properly closed after each use, moisture is excluded from the interior of the package. Since moisture can enter a glass container only through the closure, desiccants are used to “bind-up” any free moisture in the tablet or in the air to prevent the effervescence reaction from starting prematurely. Once opened, however, protection from moisture is diminished because the air space becomes greater and greater as the tablets are used.
2. Plastic tubes
Plastic tubes are not as protective as glass due to the moisture vapour permeability of plastic packaging materials. Tablets with a low order of hygroscopicity can be satisfactorily packaged in plastic tubes with moisture-proof closures. Special caps can be constructed with a chamber containing silica gel or some other desiccant that will preferentially absorb moisture vapour entering through the closure.
3. Metal tubes
Extruded, seamless metal tubes, often made from aluminium, have been used commonly in Europe to package effervescent tablets. These are impervious to moisture as are glass tubes.
4. Strip Wrapping
Effervescent tablets are most frequently strip-wrapped in individual pouches, arranged in conveniently sized strips and stacked in a paperboard box. Each tablet is hermetically sealed in its own container and is not exposed to the atmosphere until the time of use. Many different flexible packaging materials are available for packaging, but few are suitable for protecting effervescent tablets from moisture vapour or physical damage.
5. Blister packs
Some effervescent tablets are packaged in thermoformed plastic blisters with foil backing. This type of packaging requires that the tablets be pushed through the foil backing by pressing on the blister. The tablets packaged in this manner must be hard enough so as not to break when they are removed from their package. Most large diameter, relatively thin effervescent tablets cannot be made hard enough to withstand the force required to remove them from this type of packaging.
6. Aluminium foils
Aluminium foil is a flexible, absolute barrier to gases, water vapour, and light. It is nontoxic and immune to microbiological attack. It has excellent heat conductivity, thereby making it an excellent choice for heat-sealing strip-packaging operations. Foil packaging should be heavy gauge to minimize risk of holes, and the surrounding pocket should be large enough to hold the tablets but minimize inclusion of air.
Packaging Integrity Testing
To ensure that effervescent tablet produced reaches the ultimate user with the same quality as originally produced and packaged, tests are performed on the seal integrity of various packaging configurations. Clearly, the integrity of any package is only as good as its closure. For effervescent tablets, an impervious package with a loose-fitting cap or imperfect heat seal is as good as if the cap were left off or the heat seal area left unbounded. Hermetic packaging is required if effervescent tablets are to attain a reasonable shelf life of 2 to 3 years. The ultimate testing procedure is to store packages for their expected shelf life under the most severe humidity and temperature conditions that they will encounter, once sold. Since this is not practical, accelerated testing procedures have been developed that simulate long-term storage in adverse environments. Packages containing effervescent tablets are stored in test chambers regulated at constant high humidity and temperatures, such as 80% relative humidity at 37°C for at least 3 months. The package is considered satisfactory if the product shows little or no moisture pickup after being stored in a chamber. Changes in moisture content with time can be monitored if the relative moisture content of the product is determined before the study is started. These changes may be due to moisture seeping into the product through the closure or through the package itself if it is made of a material not completely impervious to moisture-vapour transmission, such as polyethylene bottles or thin aluminium foil with pinholes.
Obviously, one cannot afford the expense or the time to wait 3 months to test representative samples of the packages produced on a day-to-day basis; several methods to test seal integrity rapidly (especially seals of aluminium foil laminates) have been devised and these include
- Vacuum Underwater Method (most commonly used method)
- Detection of Tracer Material Sealed Within the Pouch
- Purging with Detectable Gas
- Infrared Seal Inspection
- Electronic Airtightness Tester
Stability testing of effervescent tablets
Effervescent products are hygroscopic and unstable in the presence of moisture and as such premature exposure to moisture can lead to degradation or loss of reactivity. The elimination or inactivation of free water within the effervescent system is the key to stability, aside from manufacturing effervescent tablets in controlled environmental conditions.
After packaging, effervescent products are assessed by placing the product in a stability chamber set at 40 oC and 75 % relative humidity for at least 3 months. At the end of the 3 months, physical tests (package leak test, tablet appearance, disintegration time, tablet hardness, and sensory evaluation of the product) are performed to determine whether any off-notes developed during testing. Chemical assay of the active ingredient is also performed to determine if there has been any product degradation.
Examples of effervescent tablets
- Alka-Seltzer – Anhydrous citric acid, Aspirin, and Sodium bicarbonate (Bayer)
- Histac – Ranitidine HCl (Sun Pharma)
- Pepfiz-O&L – Papain, Fungal diastase and Simeticone (Sun Pharma)
- Effcal – CaCO3, Vitamin D3 (Sun Pharma)
- Tagamet – Cimetidine (Glaxo SmithKline)
- Zantac – Ranitidine (Glaxo SmithKline)
- Vitalmag – Magnesium citrate, Folic acid, Vitamin B6 (ICN Hungary)
- Calcium Sandoz – Calcium (ICN Hungary)
- Ca-C 1000 – Calcium, Ascorbic acid (ICN Hungary)
- Hangoverz – Aspirin, Caffeine (Pious Pharma. Ltd)
- Solpado – Paracetamol, Codeine phosphate (Sanofi-Aventis)
- Prolyte fizz – Glucose + Potassium Chloride + Sodium Bicarbonate + Sodium Chloride + Anhydrous Citric Acid (Cipla)
- Effer-K – Potassium citrate (Nomax Inc)
- Aspirin C – Acetylsalicylic acids (Bayer)
Advantages of effervescent tablets
- It is administered as a palatable sparkling solution.
- It can be administered to patients who have problem in swallowing tablets and capsules.
- It is readily absorbed and the bioavailability is high because it is administered as a solution.
- Drugs that are unstable when stored as aqueous solutions are more often stable in the effervescent granules or tablet forms.
- Buffered effervescent aspirin tablets have a less irritant effect on the gastric mucosa and cause less gastrointestinal tract blood loss than conventional tablets.
- Incorporation of large amounts of active ingredients.
- The product is typically self-mixing and flavourful.
- Better dosing.
Disadvantages of effervescent tablets
- Most excipients used are relatively expensive.
- It requires special production facilities.
- Its high sodium or potassium content makes it unsuitable for administration to patients with heart failure or cardiac insufficiency.
- Some are bulky in relation to tablets or capsules.
- It is sometimes difficult to make drugs with unpleasant taste sufficiently palatable as an effervescent product.
- Sometimes in a tablet form, disintegration can take up to 5 minutes. This depends mainly on the temperature of the water and active ingredient present.
Effervescent technology provides a novel dosage form for nutritional supplements and pharmaceuticals. In a more scientific way, the logic behind the technology can be said to be entirely based on the chemical incompatibility between its acidic and bicarbonate sources. The reaction is, of course, an autocatalytic reaction which ends up generating carbon dioxide in the presence of water.
- Mohrle, R. (1989). Effervescent Tablets. In H. Lieberman, L. Lachman and J. Schwartz (Eds), Pharmaceutical Dosage Forms: Tablets, Volume 1 (pp.285-328), New York: Marcel Dekker, Inc.
- Ofoefule, S. I. (2002). Textbook of Pharmaceutical Technology and Industrial Pharmacy. Nigeria: Samakin (Nig) Enterprise.
- Patel, S. and Siddaiah, M. (2018). Formulation and Evaluation of Effervescent Tablets: A Review. Journal of Drug Delivery and Therapeutics, 8(6):296-303.
- Shayne, C. G. (2008). Pharmaceutical Manufacturing Handbook: Production and Processes. New Jersey: John Wiley & Sons, Inc.