Pharma Tips

EFFERVESCENT TABLETS

By: Mitul Shah | Views: 34140 | Date: 03-Jun-2010

As per revised definition proposed to US FDA, Effervescent tablet is a tablet intended to be dissolved or dispersed in water before administration.Effervescent tablets are uncoated tablets that generally contain acid substances and carbonates or bicarbonates and which react rapidly in the presence of water by releasing carbon dioxide. They are intended to be dissolved or dispersed in water before use.

EFFERVESCENT TABLETS
 
 
 
 
 
Definition
As per revised definition proposed to US FDA, Effervescent tablet is a tablet intended to be dissolved or dispersed in water before administration.
Effervescent tablets are uncoated tablets that generally contain acid substances and carbonates or bicarbonates and which react rapidly in the presence of water by releasing carbon dioxide. They are intended to be dissolved or dispersed in water before use.

Introduction
Effervescence has also proved its utility as an oral drug delivery system in the pharmaceutical and dietary industries for decades. In Europe, effervescent dosage forms are widespread, and their use is growing in the US because they offer pharmaceutical and nutraceutical companies a way to extend their market share.
A wide range of effervescent tablets have been formulated over the years. These include dental compositions containing enzymes, contact lens cleaners, washing powder compositions, beverage sweetening tablets, chewable dentifrice, dental cleansers, surgical instrument sterilizers, analgesics and effervescent candies as well as many preparations of prescription pharmaceuticals such as antibiotics, ergotamines, digoxin, methadone and L- dopa. Preparations for veterinary use have also been developed.
Storage: Effervescent products should be stored in tightly closed containers or moisture proof packs. They should be preserved in air tight containers and protected from excessive moisture.
Labeling: It should be labeled that these products are not to be swallowed directly (52). The label should state that when the tablets are packaged in individual pouches, the label instructs the user not to open until time of use andthe tablets are to be dissolved in water before being taken

Advantages Of Effervescent Tablets (54,55,56)
1. Fast onset of action
Effervescent tablets have major advantage that the drug product is already in solution at the time it is consumed. Thus, the absorption is faster and more complete than with conventional tablet. This is particularly helpful in treating acute symptoms of pain. Faster absorption means faster onset of action, critical in treating acute symptoms such as pain. Buffered preparations with adjustable stomach pH optimize formula performance characteristics.
Effervescent drugs are delivered to the stomach at a pH that is just right for absorption. Many medications travel slowly through the gastrointestinal tract or have absorption that is hampered by food or other drugs. To achieve desired absorption levels, such drugs have to be often administered as injections or with increased dosages.
2. No need to swallow tablets
Effervescent medications are administered in liquid form so they are easy to take as compared to tablets or capsules. The number of people who cannot swallow tablets or who dislike swallowing tablets and capsules is growing. Many diseased conditions require the patient or customer to swallow several tablets at a time. The elderly, in particular, have difficulty in swallowing tablets. With an effervescent dosage form, one dose can usually be delivered in just 3 or 4 ounces of water. The amount used when someone swallows a conventional tablet or capsule.
3. Good stomach and intestinal tolerance
Effervescent tablets dissolve fully in a buffered solution. Reduced localized contact in the upper gastrointestinal tract leads to less irritation and greater tolerability. Buffering also prevents gastric acids from interacting with the drugs themselves, which can be a major cause of stomach and esophageal upsets.
4. More portability
Effervescent tablets are more easily transported than liquid medication because no water is added until it's ready to use. .
5. Improved palatability
Drugs delivered with the effervescent base, taste better than most liquids, mixtures and suspensions. Superior taste masking is achieved by limiting objectionable characteristics and complementing formulations with flavors and fragrances. Effervescent pharmaceuticals retain their flavor after lengthy storage. The effervescent tablets essentially include flavorings so they taste much better than a mixture of a non-effervescent powder in water. Moreover, they produce fizzy tablets, which may have better consumer appeal than the traditional dosage forms.
6. Superior stability
Excellent stability is inherent with effervescent formulations, particularly surpassing liquid forms.
7. More consistent response
Drugs delivered using effervescent technology have predictable and reproducible pharmacokinetic profiles that are much more consistent than tablets or capsules.
8. Incorporation of large amounts of active ingredients
In many cases, one effervescent tablet will equal to three conventional tablets in active dose amounts.
9. Accurate dosing
Researchers have shown that effervescent tablets enhance the absorption of a number of active ingredients (e.g. disulfiram and caffeine), compared to conventional formulations. This is because the carbon dioxide created by the effervescent reaction can induce enhanced active-ingredient permeability due to an alteration of the paracellular pathway. The paracellular pathway is the primary route of absorption for hydrophilic active ingredients in which the solutes diffuse into the intercellular space between epithelial cells. It is postulated that the carbon dioxide widens the intercellular space between cells, which leads to greater absorption of active ingredients (both hydrophobic and hydrophilic). The increased absorption of hydrophobic active ingredients could be due to the non-polar carbon dioxide gas molecules partition into the cell membrane, thus creating an increased hydrophobic environment, which would allow the hydrophobic active ingredients to be absorbed.
10. Improved therapeutic effect
The effervescent components aid in improving the therapeutic profiles of the active ingredients. They also help in solubilization of poorly soluble drugs.

Other Considerations:
• Convenient and easy administration than other liquid medicines to administer
• Less chance of misuse
• Ability to combine multiple active ingredients, if therapeutically appropriate
• Innovative, yet less risky than unproven technology

Possible Drawbacks
1. Unpleasant taste of some active ingredients Some active ingredients have unpleasant taste that cannot be masked by flavors and sweeteners. This will lead to an unacceptable product.
2. Disintegration time In a tablet form, disintegration can take up to 5 min. This depends mainly on the temperature of the water and the active ingredients present.
3. Relatively expensive to produce due to large amount of more or less expensive excipients and special production facilities.
4. Larger tablets requiring special packaging materials.
5. Clear solution is preferred for administration, although a fine dispersion is now universally acceptable.

The Effervescent Reaction (51,53)
Effervescence is the evolution of gas bubbles from a liquid, as the result of a chemical reaction. The most common reaction for pharmaceutical purpose is the acid base reaction between sodium bicarbonate and citric acid. Acid-base reactions between alkali metal bicarbonates and citric or tartaric acid have been used for many years to produce pharmaceutical preparations that effervesce as soon as water is added.

For example: the reaction of Citric acid and Sodium bicarbonate

3 NaHCO3(aq) + H3C6H5O7(aq)  - 3 H2O(l) + 3 CO2(g) + Na3C6H5O7(aq) 
252 g (3 mol)           +     192 g (1 mol)        -     54 g (1 mol)   +    132 g (3 mol)   +      258 g (1 mol) 


From this equation it can also be derived why most effervescent tablets are relatively large.
If it is assumed that a placebo tablet consisting of 192 mg H3C6H5O7 and 252 mg NaHCO3 comes into contact with 100 ml water it will react to 258 mg C3OH5(COONa)3 + 132 mg CO2 + 54 mg (of extra) H2O.

Knowing that 1 mol of CO2 is, under normal conditions, equal to 22,4 litres, which means that 132 mg of CO2 formed by the reaction of the tablet above is equal to 67,2 ml of gas. As the solubility of CO2 in water at 20 °C and 1 bar is already 90 mg of CO2 per 100 ml of water, which means that not much of the gas produced by this tablet will form bubbles, but will go directly into solution. This reaction will start even if only a very small amount of water is added, as water is also one of the reaction products. This means that during manufacturing, but also during storage, all contact with water has to be minimised as much as possible.

This reaction starts in presence of water, even with small amount as catalyzing agent, and because water is one of the reaction products, it will accelerate the rate of reaction, leading to difficulty in stopping the reaction. For this reason, the whole manufacturing and storage of effervescent products is planned by minimizing the contact with water. In such systems, it is practically impossible to achieve much more than an atmospheric saturation of the solution with respect to released CO2. If the acid dissolves first, then the bulk of the reaction takes place in the saturated solution in close proximity to the undissolved bicarbonate particles. If the bicarbonate dissolves faster, the reaction essentially takes place near the surface of the undissolved acid. Such suspension systems do not favor supersaturation with respect to carbon dioxide because the particulate solids act as nuclei for bubble formation. The physical and chemical basis of the formulation depends on essentially the total dissolution of bicarbonate salts and the acids prior to formation of free acids.




Active Ingredients (54)
There are several categories of active ingredients, which would be advantageous if formulated as effervescent tablet. These include the following:
1. Drugs difficult to digest or disruptive to the stomach
A classic example is calcium carbonate tablets, the most widely used form of calcium. In a conventional tablet or powder, the calcium carbonate dissolves in the acidic pH of the stomach and is carried into the digestive system for absorption. However, calcium carbonate releases carbon dioxide when it dissolves in the gastrointestinal tract, which usually produces gas in the stomach. On the other hand, as people age, they have less amount of acid in the stomach, and thus a calcium carbonate tablet may pass undissolved through the stomach.
That, in turn, may lead to constipation. However, if the calcium carbonate is taken in an effervescent formulation, the calcium dissolves in water, is readily available for the body to absorb, and there is no risk of excessive gas in the stomach or of constipation.
2. pH-sensitive drugs such as amino acids and antibiotics
The low pH of the stomach can cause active ingredients 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 the stomach to empty quickly—usually within 20 min into the small intestine and results in maximum absorption of the active ingredient.
3. Drugs requiring a large dose
A typical effervescent tablet (1 inch in diameter weighing 5 g in total weight) can include more than 2 g of water-soluble active ingredients in a single dose. If the required dose is larger than that, the sachet (powder form) is the common means of delivery.
Effervescent delivery can be highly beneficial in the following treatments:
• Arthritis, inflammation and pain management • Ulcers
• Allergies      • Osteoporosis
Drugs and drug compositions used as effervescent products
• Acetylsalicylic acid (Aspirin)  • Paracetamol (Acetaminophen)
• Ibuprofen     • Antacid preparations
• Ascorbic acid and other Vitamins  • Calcium
• Acetylcysteine, a mycolytic agent used as an antidote for paracetamol overdosage and Activated charcoal preparations used in the management of theophylline poisoning


Preparation of Effervescent tablets
RAW MATERIALS
The effervescent tablets, when added to water, generate a gas, which causes effervescence and produces a clear and fresh tasting, sparkling solution. The gas, which gives the effervescence, is carbon dioxide, which is derived from the reaction between an acid and a base like carbonate or bicarbonate. The effervescent tablet mainly consists of three components:
• Active ingredient;
• Acid source;
• Alkaline compound, constituted by a carbonate or bicarbonate
The acid and the alkali are the essential components which provide the effervescence and the disintegration of the tablet when contacted with water. As an acidic component, the citric acid both in the hydrated and anhydrous forms is more commonly used, but other edible acids like tartaric, fumaric, adipic, and malic acid can be used as well.
The carbonate, which represents the source of carbon dioxide, which generates the effervescence, generally is a water-soluble alkaline carbonate. The choice of the carbonate is very important since, besides provoking the effervescence, it can influence the stability of the tablet. Sodium bicarbonate is one of the most used carbonate because it is very soluble and of low cost. Other physiologically acceptable alkaline or alkaline earth metal carbonates may be used, such as potassium or calcium (bi) carbonate, sodium carbonate, or sodium glycine carbonate.
Compositions of effervescent tablets may also include a lubricant which has to be necessarily selected from the totally water soluble compounds forming a clear solution. Examples of this kind of lubricants are sodium benzoate, sodium acetate, fumaric acid, polyethylene glycols (PEG) higher than 4000, alanine and glycine. Conventional excipients such as diluents, ligands, buffering agents, sweeteners, flavorings, colorings, solubilizers, disintegrants, wetting agents and other excipients of common use may be added to the formulation of effervescent tablets. However, it is also advised that the acidic and alkaline ingredients give a larger bulk to the tablets, the additives should be kept to a minimum and added only when required.
Effervescent tablets are convenient, attractive, and easy to use as premeasured dosage forms. These advantages, however, are to be balanced by some technological problems. The most important of which are hygroscopicity and lubrication. To avoid a premature effervescent reaction in the tablets, substances with low moisture content will have to be used. This is due to the fact that the effervescent reaction may also be initiated with small amounts of water bound to or adsorbed on the raw materials. Raw materials may be used in the anhydrous state but although hydrated forms are preferred as some water is essential for binding purposes, a completely anhydrous mixture has poor compressibility. The substances should be easily wetted and have good aqueous solubility. If the tablet components are not soluble, the effervescent reaction will be hindered and the tablet will take time to disintegrate. Ideally, all components should have similar rates of solubility as a slowly dissolving substance can hinder tablet disintegration and a slowly soluble residue may be produced (1). Other important characteristics, which need to be examined before selecting a material for addition to an effervescent tablet formulation, are compressibility and compactability. Poor compactability leads to retardation of the dissolution rates of the effervescent tablets.
Acid Sources
The three main acid sources are food acids, acid anhydrides and acid salts.
Food Acids
The food acids are most commonly used since they occur in nature and are ingestible.
1] CITRIC ACID 
Citric acid is most preferred among the food acids as it is available abundantly and is relatively inexpensive, has good solubility and a pleasant taste. Citric acid is available as a monohydrate and as an anhydrate form. It is available in the form of colorless, translucent crystals or as white crystalline powder. Citric acid is readily available as fine granular, free flowing powder forms of different particle – sizes such as coarse, medium, fine etc. It is odorless and has a strong acidic taste. It is freely soluble in water and alcohol (2). It produces solutions with citrus-like taste. It is very hygroscopic and precautions must be taken to prevent exposure during manufacturing and storage. The anhydrous form is less hygroscopic than the monohydrate form. The anhydrous form has a tendency to cake during storage at humidity above 70% RH. At relative humidity between 65 and 75%, citric acid monohydrate absorbs insignificant amounts of moisture but above these humidity levels, substantial amounts are absorbed whereas citric acid anhydrate absorbs insignificant amounts of moisture at RH of 25 to 50% and significant amounts at RH of 50 to 75%, with formation of monohydrate form (3). The monohydrate melts at 100°C and releases water of crystallization at 75°C, thus it can be used as a binder source in hot melt granulation.
2] TARTARIC ACID
Tartaric acid is commonly used in effervescent tablets, as it is readily available commercially. It is more soluble than citric acid, 1 part of acid in less than 1 part of water. It is available as colorless monoclinic crystals or as white crystalline powder. It is odorless with an extremely tart taste. It is also more hygroscopic than citric acid and at RH above 75% it is deliquescent. It is as strong as citric acid but must be used in higher amounts to achieve equivalent acid concentrations in the effervescent reaction since it is diprotic whereas citric acid is triprotic. In terms of compressibility, tartaric acid is comparable to citric acid.
3] ASCORBIC ACID
Ascorbic acid occurs as white to light yellow crystalline powder with a sharp acidic taste and no odour. It is freely soluble in water (1 in 3.5) and alcohol. A comparison of formation of carbon dioxide from effervescent tablets based on anhydrous citric acid, ascorbic acid or tartaric acid and sodium bicarbonate indicated that ascorbic acid and anhydrous citric acid behaved similarly. Tartaric acid formed most carbon dioxide but the disintegration time was longer. On exposure to light, ascorbic acid gradually darkens. Ascorbic acid is less hygroscopic than tartaric and citric acid and this facilitates the production of effervescent tablets. Thus, the use of ascorbic acid minimizes the need for stringent air and temperature controls during manufacturing.
4] FUMARIC ACID
Fumaric acid occurs as a white, odorless or nearly odorless granules or crystalline powder. It is a strong acid which is virtually non hygroscopic and most economical. However, it has very low solubility in water (about 1 in 33 at 20°C), which poses a problem in formulation of effervescent tablets. Fumaric acid may be used in the form of salt such as mono sodium or potassium fumarate, which have greater water solubility. Certain formulations take advantage of the lubricant properties of fumaric acid allowing to limit the quantity of additional lubricants.
5] MALIC ACID
Malic acid is available as white crystalline powder. It has a slight odor and a strongly acidic taste. It is also hygroscopic and readily soluble. It has an acid strength less than citric acid but high enough to produce sufficient effervescence when combined with a carbonate source. Malic acid can be used in effervescent formulas for a smoother aftertaste but its price is higher than that of citric acid.
6] ADIPIC AND SUCCINIC ACIDS
These are virtually non hygroscopic but are also extremely less soluble in water than citric acid. They are also less available and less economical. Both acids have been reported to possess lubricant properties.
7] ACETYL SALICYLIC ACID
Acetyl salicylic acid is a drug frequently used in effervescent form, it cannot be used as an acid source due to its low water solubility.
8] NICOTINIC ACID
Nicotinic acid was used as a drug in olden times for the treatment of hypercholesteremia. As large doses were recommended (1 g), effervescent tablets were prepared with sodium bicarbonate. Nicotinic acid is non hygroscopic but also has low solubility in water (1 in 60)
Acid Anhydrides
Acid anhydrides when mixed with water are hydrolyzed to their corresponding acid. If the rate of hydrolysis is controlled, they can give sustained high volume effervescence due to continuous acid production. Citric anhydride and succinic anhydride are commonly used anhydrides (4). Succinic anhydride has been used in a denture soak composition. They also act as internal desiccants and thus reduce caking tendencies. Glutamic anhydride has also been used but the characteristic taste of glutamic acid created problems (5). Water can not be used in the manufacture of product containing acid anhydrides, as it will cause prior conversion of acid anhydride to acid.
Acid Salts
Commonly used acid salts are mentioned below:
1] SODIUM DIHYDROGEN PHOSPATE (MONOSODIUM PHOSPATE)
It is available as granular and powdered forms. It is readily soluble in water. On dissolving in water, it readily reacts with carbonates and bicarbonates to give effervescence.
2] DISODIUM DIHYDROGEN PYROPHOSPATE (SODIUM ACID PYROPHOSPATE)
This acid salt is also readily available and is soluble in water, forming an acid solution and has been used in production of effervescent tablets.
3] ACID CITRATE SALTS
Sodium dihydrogen citrate and disodium hydrogen citrate are both readily soluble in water and produce acid solutions. They both have been used in effervescent tablets (6).
4] AMINO ACID HYDROCHLORIDES
Amino acid hydrochlorides readily release acid in solution and this reaction has been used to avoid unfavorable electrolyte concentrations in effervescent electrolyte replacements. These materials are expensive and hygroscopic also (7).
5] SODIUM ACID SULPHITE
Sodium acid sulphite or sodium bisulphite produces an acid solution but it is not suitable for ingestion. It can be used in effervescent preparations meant for other applications such as toilet cleaners. It is also a strong reducing agent and is thus incompatible with oxidizing agents.
Carbonate Sources
Dry, solid carbonate and bicarbonate salts provide effervescence in most effervescent tablets. Bicarbonates are more reactive and are used more often than the carbonates

1] SODIUM BICARBONATE
Sodium bicarbonate is an odorless, white crystalline powder with a saline, slightly alkaline taste. It is available in five particle- size grades from fine powders to free flowing granules. Its solubility in water is 1 in 11 parts at 20°C. It is non hygroscopic, inexpensive abundant (8). It is the most frequently used of all the bicarbonate sources. It is ingestible and is widely used as an antacid, alone or in combination.
It yields approximately 52% carbon dioxide by weight. It is the mildest of alkalies, having a pH of 8.3 in an aqueous solution of 0.85 % concentration. It is a non-elastic substance and poses problems during compression. In order to overcome the bad flowability and low compressibility of sodium bicarbonate, spray-drying technique was used for the manufacture. The directly compressible spray dried sodium bicarbonate containing additives such as polyvinyl pyrollidone and silicon oil is also available. This product possesses good compressibility and stability (9).
Normal sodium bicarbonate products are highly unstable and will react with the acid component of an effervescent formulation if any amount of moisture is present. This creates a challenge for the manufacturing company who needs to handle, manufacture and package the product in a humidity-controlled environment in order to avoid the chances of early effervescent reaction and ruination. Many times, it is necessary to pre-dry the sodium bicarbonate before using it in order to eliminate excess moisture and avoid reaction. By using Effer-Soda Sodium Bicarbonate, many of these problems can be avoided (10) Effer-Soda Sodium Bicarbonate is dried and partially desiccated to increase its stability, making it a more stable form of sodium bicarbonate. It has been manufactured to include a “desiccant skin” of sodium carbonate that surrounds the core of sodium bicarbonate. This “desiccant skin” makes up 8 to 12% of Effer-Soda’s total mass. This sodium carbonate outer layer protects the sodium bicarbonate core by absorbing moisture to form a hydrate salt (sodium sesquicarbonate), which is stable up to 70°C. When large amounts of moisture are introduced from the effervescent tablet or powder being put into a glass of water, the moisture dissolves the sodium carbonate outer layer and the sodium bicarbonate is released for reaction with the acid component.
2] SODIUM CARBONATE
Sodium carbonate is also known as soda ash and can be used as source of carbon dioxide in effervescent tablets. It is also used as an alkalizing agent due to its high pH of 11.5 in an aqueous solution of 1% concentration. It is highly water-soluble.
Sodium carbonate is commercially available as an anhydrous form and as a monohydrate or a decahydrate. Anhydrous form is preferred due to its ability to absorb moisture, preventing the initiation of effervescent reaction. It is more resistant to the effervescent reaction and is also used as a stabilizing agent.
3] POTASSIUM BICARBONATE AND POTASSIUM CARBONATE
Potassium bicarbonate and potassium carbonate are more soluble than their sodium counterparts but are also more expensive. They are used when sodium ion is undesirable or needs to be limited as in antacids in which dosage is dependent on the amount of sodium recommended for ingestion. Potassium bicarbonate absorbs substantial amounts of water at 80% RH whereas potassium carbonate is hygroscopic at RH above 2% and deliquescent at more than 40%RH. The commercially available forms are also limited. Potassium carbonate (2%) in an effervescent dosage form is reported to act as a desiccant and it accommodated total moisture levels up to 0.4%w/w and still prevents the effervescent base degradation (11).
4] SODIUM SESQUICARBONATE
Sodium sesquicarbonate consists of equimolar concentrations of sodium carbonate and sodium bicarbonate and twice the molar amount of water. It is soluble in water and 2% solution has a pH of 10.1. It is primarily used in laundry industry. However, the mixtures of sodium bicarbonate and sodium carbonate are more preferred over sodium sesquicarbonate and moreover its dihydrate form also presents stability problems.
5] SODIUM GLYCINE CARBONATE
Sodium glycine carbonate is a complex of glycine and sodium carbonate. It is more soluble in water and has less alkalinity. It is non-hygroscopic, heat resistant and stable.
Its disadvantage is its low carbon dioxide yield, only about 18% by weight. For each gram of sodium bicarbonate, almost 270 ml of carbon dioxide are released whereas Sodium glycine carbonate only releases ± 95 ml of carbon dioxide per gram. Sodium bicarbonate is also a lot cheaper than Sodium glycine carbonate, as sodium bicarbonate is one of the raw materials in Sodium glycine carbonate production (12). It was found that the use of a blend of certain acids such as fumaric acid and malic acid with sodium glycine carbonate allows preparing effervescent tablets by direct compression in normal thermo-hygrometric conditions and with standard tabletting equipment (13).
The tablets made with sodium glycine carbonate are more stable in presence of trace amounts of water. Effervescent tablets made with sodium glycine carbonate will react with acid when moist, but this reaction with acid does not release water. Effervescent tablets made with other mineral carbonates rapidly decompose upon exposure to moisture since the decomposition leads to the formation of carbonic acid and thus carbon dioxide and water, therefore accelerating the decomposition. It has good compressibility characteristics as compared to other carbonate sources, it is preferred for use in direct compression. Sodium glycine carbonate is much more soluble in water (70 g per 100 ml) than sodium bicarbonate (approximately 10 g per 100 ml). This is a distinct advantage while the sodium glycine carbonate effervescent tablets dissolve more rapidly in water, thus ensuring that the active ingredient is rapidly and effectively in solution. It is also very stable when heat is applied.
6] L-LYSINE CARBONATE
L-Lysine carbonate is a white crystalline powder, which is very soluble in water. It can be used when alkali metal ions are not desired. It produces sparkling drinks when effervescent preparations are dissolved in water.
7] ARGININE CARBONATE
Arginine carbonate and citric acid tablets provide a source of amino acid for various medicinal uses. Also, arginine carbonate may be used in an effervescent product required to be free from alkaline earth metals.
8] AMORPHOUS CALCIUM CARBONATE
Amorphous calcium carbonate is not yet available commercially, but its use has been described in literature. It produces effervescent compositions, which are free from sodium ions and are highly palatable with excellent carbonation (14).
9] CALCIUM CARBONATE
Precipitated calcium carbonate is available as fine, white, odorless and tasteless powder or crystals. It is nonhygroscopic and absorbs less than 1% moisture at 90%RH and 25°C. Calcium carbonate is a high-density material, which is not very compressible. Also its solubility in water is 1 in 50,000. These factors limit the usage of calcium carbonate in effervescent tablets.
Other Effervescent Sources
Other sources of gas have also been reported to be used as effervescence. The evolution of oxygen gas has also reported to be used as a source of effervescence in products like denture cleaners. Tablets with anhydrous sodium perborate when mixed with water liberate copious volumes of oxygen and thus produce effervescence. Tablets with a peroxygen compound such as sodium perborate and a chlorine compound such as calcium hypochlorite, when dissolved in an alkaline medium, produce effervescence due to liberation of oxygen gas. This evolution of oxygen is due to decomposition of peroxygen compound by the chlorine compound (15).
Effervescence can be produced in semisolid applications such as tooth pastes by adsorption of a gas like carbon dioxide into an anhydrous base medium composed of an inorganic oxide such as zeolite aluminosilicate. The gas is desorbed from the inorganic matrix upon contact with water and produces effervescence (16)

Formulation Ingredients Of Effervescent Tablets
Diluents
There is usually no need for diluents in effervescent products. The effervescent materials themselves are usually present in quantities large enough to achieve the desired tablet bulk. If a denser tablet is desired, sodium bicarbonate is the ingredient of choice because of its low cost, no effect on the change in pH and also improved effervescent reaction. Other materials, which are readily soluble such as sodium chloride and sodium sulphate, can be used. They are high-density crystalline powders and exhibit good compatibility with the ingredients of the effervescent reaction. The diluents used need to be highly water soluble, have particle size in range of other effervescent ingredients and possess good compressibility. Diluents may also be selected from lactose, mannitol, sorbitol or mixtures thereof and spray-dried lactose is also commonly used. As a diluent, spray dried lactose is particularly preferred as it facilitates the blend flowability and thus, improves compressibility and tabletting of the formulation.
Binders
Binders are added in conventional tablets to assist in the formulation of a granulation suitable for tablet compression. Mostly, binders are added to prevent the rapid disintegration and dissolution of tablet. Also the binder, if used, must be completely soluble in water and must not leave behind any insoluble residue. It must also have low residual moisture content. Binders such as the natural and cellulose gums, gelatin and starch paste are not very effective due to their low water solubility or high residual water content. Polyvinyl pyrolidone is an effective binder for effervescent tablets. It can be added as dry powder or in a wet form as an aqueous, alcoholic or hydroalcoholic solution. It is also effective at low percentages, which is advantageous for effervescent formulation. Maltilol was also found to be a suitable binder for vitamin C effervescent tablets, which acted, by formation of crystal bridges. Polyethylene glycol 6000 has also been used both as a binder and as a lubricant. The solvents like isopropanol and ethanol may be used as granulating fluids but they do not have any binding effects themselves. The effervescent reaction is only started when the materials come into contact with water, and not if they come into contact with organic solvents, one possibility is to use such solvents as a granulation fluid. Water in small amounts is also very effective as a binder as it causes partial dissolution of raw materials followed by re-crystallization. An effervescent granulation composed of anhydrous citric acid and sodium bicarbonate were made with dehydrated alcohol as the granulating liquid. A portion of citric acid dissolved during the massing and acted as an effective binder. The binders commonly used for dry granulation of conventional tablets like lactose, mannitol, dextrose are not suitable for use in effervescent tablets because they need to be added in high amounts which will be inappropriate.

Disintegrants
Disintegrants are not normally used in effervescent tablets, as it is desired that the tablet should produce a clear solution within a few minutes after addition to a glass of cold water. Dextrose and / or sucrose have been used as disintegrants in effervescent tablets of aspirin.
Lubricants
Effervescent pharmaceutical tablet formulations are inherently adhesive and tablet surfaces have much higher average surface roughness than the conventional tablets. Although formulations containing tartaric acid are less adhering to tablet tool than those containing citric acid, effervescent tablets need the use of suitable lubricants. A perfect lubricant must be nontoxic, tasteless and water-soluble. Effervescent granulations are difficult to lubricate due to the nature of raw materials and also due to the requirement of rapid tablet disintegration. The choice of the lubricant for use in effervescent tablet is to be done critically as the following factors need consideration-
1) SOLUBILITY – lubricants tend to posses low water solubility, thus it is difficult to obtain a clear transparent solution without any residue.
2) DISINTEGRATION – lubricants are generally hydrophobic in nature, so they retard the disintegration and dissolution which is required to be rapid for effervescent tablets. Lubricants in higher concentration inhibit tablet disintegration. Also most efficient lubricants are water insoluble and will leave a cloudy solution once dispersed. The lubrication of effervescent tablets may be done by intrinsic or extrinsic lubrication.
INTRINSIC LUBRICATION
Intrinsic lubrication is the most efficient and widely used method. Intrinsic lubricants are compounded directly into the tablet as the granulation is being prepared. Metal stearates such as calcium or magnesium stearate cannot be used due to their insolubility in water. They also form foamy, soapy tasting layer on the surface of a cloudy solution. Sodium stearate and sodium oleate are water-soluble lubricants, but they have a characteristic soapy taste and hence they too are not used in effervescent tablets. Lubricants reported to be suitable for use in effervescent tablets are sodium benzoate, sodium chloride, sodium acetate, Carbowax 4000 and spray dried and milled L-leucine(17). A combination of 4% PEG 6000, 2% spray dried L-leucine and 0.1% sodium fumarate was also used as a lubricant for ascorbic acid tablets made by direct compression (18). Surfactants such as sodium lauryl sulphate and magnesium lauryl sulphate also act as lubricants. However, in concentrations needed for adequate lubrication the surfactants hinder tablet disintegration. A combination of sodium lauryl sulphate and magnesium stearate has also been commercially used. Cottonseed, corn and mineral oils also have lubricating properties and will disperse in water. Addition of powdered sodium benzoate and PEG 6000 as lubricant was found to promote tablet disintegration instead of retarding (19). Effervescent tablets containing 1% sucrose ester powder with povidone and PEG 6000 were found to have significantly decreased adhesion to tablet punch faces and consequently less surface roughness and better quality of finished product (20). Aspirin crystals provide adequate lubricating properties so that effervescent analgesic formulations at effective dose levels usually do not require additional lubricants.
EXTRINSIC LUBRICATION
Extrinsic lubrication is provided by a mechanism that applies lubricating substances such as film of melted wax or paraffin oil to the tabletting tool surface. The melted wax film can be alternatively sprayed on the tool surfaces after one tablet is ejected and before the granules of the next enter the die cavity. Another method makes use of an oiled felt washer attached to lower punch below the tip. This washer wipes the die cavity with each tablet ejection. Materials such as polytetrafluoroethylene or polyurethane have also been applied to punch faces to avoid sticking of tablets.
Glidants
Glidants are usually not necessary due to large tablet diameters and free flowing granulations. Ingredients of effervescent preparations are selected in appropriate physical forms suitable for direct compression.
Antiadherants
The adherence of granulation mixture to the punch surfaces can be eliminated by using polytetrafluoroethylene or polyurethane cemented to the punch surfaces.
Sweeteners
Natural water-soluble sweeteners such as sucrose, lactose, xylitol, D-glucose, sorbitol or mannitol may be added in an effervescent product. Artificial sweeteners permitted by health regulations such as saccharin or its calcium or sodium salt, aspartame or cyclamates can also be used.
Flavors
Water-soluble flavors may be added to make the preparation more palatable as sweeteners alone do not suffice the taste masking. Natural and artificial fruity flavors in dry form such as orange, lemon, pineapple etc. are commonly preferred to improve the organoleptic properties.
Colors  Improving the appearance and for identifying the preparation
Surfactants added to increase the wetting and dissolution rate of drugs. However, they may cause problems due to formation of foams.
Antifoaming Agents


Manufacturing
The effervescent tablets are generally manufactured in same way as conventional tablet manufacturing process, but need controlled environmental conditions. Thus, humidity and temperature control in production area is an essential step in the manufacturing of these tablets. The cost of temperature and humidity control equipments and energy required for its operation are high, thus environmental control area needs to be kept to a minimum
Environmental Conditions
The prerequisite for controlled environment is due to the hygroscopic nature of the raw materials used for its production and chances of initiation of an effervescent reaction due to uptake of moisture by these materials. Low relative humidity (maximum of 25% or less) and moderate to cool temperatures (25ºC) in the manufacturing areas are essential to prevent the granulations or tablets from sticking to the machinery and from picking up moisture from the air, which may cause product degradation. The whole process is generally carried out in a completely closed and integrated handling system, consisting of intermediate bulk containers (IBCs), tumblers for IBCs, docking and dosing stations. Effervescent granulations can be mixed in conventional blending equipments, such as ribbon, twin-cone, and V-type blenders. Complete drying of all the equipments after a cleaning process is essential to prevent erratic granulation and lost batches. All these equipments must also allow proper venting of air with sufficiently low moisture content. This method is particularly useful for potent drugs, which require a high level of personal protection for operators. The alternative is the open handling of the product, which allows the use of much simpler types of equipment, but manufacturing area must have maximum tolerable moisture levels.
Methods For Manufacturing
Commercial tablet formulations are compressed using high-speed rotary tablet presses and thus it is necessary that material fed in these tablet presses should have some special characteristics, not only to avoid segregation, but also to assure homogeneous filling of the dies for maintaining weight homogeneity. To prepare tablets with desirable characteristics, granulation approach is most widely used. Many different granulation technologies are available, ranging from dry granulation and wet granulation methods which include two-step granulation (granulating acid and alkali phase separately) to one-step granulation using water or organic solvents. The general schematic diagram for manufacturing of effervescent tablets is as shown in Figure .

1. Wet Granulation Method
Despite some disadvantages, wet granulation is still the most preferred method for effervescent granulation. This method gives homogeneous granules suitable for compression, and is able to provide uniform tablets either in terms of weight or active ingredient content.
TWO-STEP GRANULATION METHOD
Wet granulation involving two separate granulation steps is a useful alternative to dry granulation. The acidic and basic components are separately granulated and subsequently followed by dry mixing, before adding the lubricant for tabletting. This can be done using high shear granulator (with subsequent drying), in a single pot or in a fluid bed spray granulator. This method requires only conventional equipment which can be used for granulation and drying of other materials. Alternatively a common procedure is to granulate only one of the effervescent sources and add the other as powder form during the final blending. Other additives like flavors and lubricants are added to it and mixed. This approach increases productivity and reduces cost by saving the cost of an entire granulation step.
ONE STEP GRANULATION METHOD
One-step granulation process provides dry effervescent granules directly by granulating the acid sources and the alkaline materials together. This is done by using limited amount of water, which initiates but controls the effervescent reaction, thus forming granules. Granulation is also done by using organic solvents like alcohol (diluted with water), isopropanol or other solvents with binder. The effervescent and other ingredients of the formulation should be insoluble in organic solvent.
Using organic solvents
The use of organic solvents as a granulating fluid is another approach for granulation. It is preferable to use solvents with little amount of moisture so it can initiate effervescent reaction and have better control of the reactions. This is possible when raw materials are dry and solvent has minimum moisture and the process is performed in a low humidity atmosphere. Moreover, citric acid partly dissolves in the solvent and functions as a binder when the solvent is evaporated. This process is also done in a high shear granulator, a single pot processor or in a fluid bed spray granulator. An accessory solvent recovery utility that limits the emission of vapors in the atmosphere is also required. Certain high-shear granulator-dryers are equipped for solvent recovery by installing a tank to collect the condensate and by bringing down the possible residual exhaust with a shower of water. This method requires complex equipments with fully explosion-proof equipment to handle these granulating liquids, particularly in case of fluidized bed drier where system for exhaust gas treatment is essential. This system can be applied easily in a tray drier or a single pot as only the organic vapor has to be handled. In single-pot processor, this can be easily and accurately achieved by switching on the vacuum-drying system (possibly supplemented with gas-assisted drying or microwave drying. The typical single pot system is shown in Figure  (24). It allows mixing, granulation and drying in one vessel. The other advantages of this method include possibility of drying at low temperature, a high throughput and freedom to use a lot of different excipients to achieve the desired product characteristics. This is due to the lower heat of evaporation of organic solvents in comparison to water (25).

Using water
A very small amount of water, less than 1% of the batch size, can be used to initiate the effervescent reaction. This will start the pre-effervescent reaction by which some of the carbon dioxide is already released during the granulation phase, but by which water is also produced as a reaction product, which will then act as a granulation liquid providing more carbon dioxide and also more water. This gives wet granules within 5 -10 min. The rate of effervescent reaction increases rapidly and so it needs to stop at a certain point by starting the drying process and removing the water. For one-step granulation, both fluid-bed granulator-dryer and high shear granulator-dryer are suitable.
In fluid-bed granulator–dryer technology, all the ingredients of effervescent mixture are granulated together in a one step process. In this method, a dry mixture of the powdered form of an acid and carbonate source is suspended in a stream of hot air, forming a constantly agitated fluidized bed. An amount of granulating fluid, usually water, is introduced in a finely dispersed form causing momentary reaction before it is vaporized. The reaction is stopped when water is not sprayed anymore and drying phase is carried out with warm dry air. The granules are then suitable for compression. The main advantage of this method is mixing, drying and granulating in one piece of equipment with minimal loss of carbon dioxide. But this method is difficult to control and reproduce (26,27). Better results in controlling the effervescent reaction is achieved when spraying and drying phase are combined together. It is however, very difficult to reproduce such a process.
Gauthier P. and Aiache J.M have invented the alternative method using a rotor fluid bed spray-granulator to manufacture effervescent granules (28). This method minimizes contact between two components of effervescent system. This is a two-or three continuous step processes for production of effervescent granules. The first step is the granulation of alkaline components in the rotary fluid bed. Then in next step the granulating solution is sprayed in combination with acidic powders, which deposit on the alkaline spheres creating an external acid layer separated by a neutral layer of the binder. Drying is started when agglomeration is completed (27).
In high-shear granulator-dryer technology, it is possible to suddenly switch to drying phase by creating vacuum inside the bowl, just after the granulation phase when wet granules are well massed. Vacuum is created in a few seconds, which immediately provokes the decrease of the water boiling point down to about 20° C. The bowl is heated up at that time to provide more energy for water evaporation. The water released on the granules surface is removed within a few seconds and the effervescent reaction stops. The application of microwave radiation combined with vacuum inside the bowl of high-shear granulator can also be used to stop the effervescent reaction and to dry the effervescent granules (29). Compared to conventional water drying from granules, effervescent granule drying is a short process. However, it is very critical step as removal of small amount of water is difficult from hydrophilic materials. Use of this technology, does not require installation of explosion-proof system as required for fluidized bed systems. Effervescent aspirin produced in high shear granulator-dryer equipped with vacuum and tilting bowl.

2. Dry Granulation Methods
Wet granulation method destroys the product by starting the effervescent reaction. Thus, other alternatives have been established. One of them is dry granulation by slugging (slugs or large tablets that are compressed using heavy-duty tableting equipment) using roller compactors or direct compression techniques. These are most effective alternatives as compared to wet granulation technique.
SLUGGING
The slugs or large tablets are obtained by compression using heavy-duty tabletting equipment Equipments used for roller compaction is known as roller compactor or chilsonator. This equipment compresses premixed powders between two counter-rotating rollers under extreme pressure. The resultant material is in form of a brittle ribbon, sheet or piece. This mainly depends on the configuration of the roller. The slugs obtained from roller compaction are reduced to the required size for tablet granulation purposes. Lubrication may be required during preparation of slugs. The acidic and basic components may be dry granulated separately or together. This method is useful for those materials, which cannot be compressed using conventional wet granulation techniques and require precompression to increase density or exclude entrapped air due to porosity. The advantages of this technique are:
• Simplicity
• Low costs
• Higher product throughput
• Less number of operators and space
• Reduction in air-ventilation
The major drawback of this technique is use of costly excipients. Thus, this technique is acceptable only for small batch size production of effervescent tablets.
DIRECT COMPRESSION
Another alternative process for dry granulation is direct compression. This was successfully used for preparing effervescent tablets of acetyl salicylic acid. This helps in overcoming operational and stability problems during process. This is an ideal process of manufacturing but its use is limited due to the necessity of requirements of sophisticated raw material mixture (Compressible, free flowing and non-segregating).

3. Granulation By Heating
This is an alternative technology to wet granulation. It does not require granulating liquid. Agglomeration of the particles of a powder mixer can be achieved by melting hydrated citric acid (approximately 100ºC) so as to release the hydration water, which acts as the granulating liquid. The granules are cooled for obtaining proper hardness and mechanical stability.
The techniques used are:
• Surface hot melt granulation
• Hot melt granulation
Surface Hot Melt Granulation involves mixing all the raw materials together in a blender and the drying the mixture in an oven at 90ºC. Water is then released from citric acid and other ingredients to form granules. However, this method has less reproducibility. This process is sporadic and difficult to control in a static bed dryer.
Hot melt granulation is done in high-shear-granulator-dryer. The bowl is heated up, which helps in release of water of hydration of citric acid. Sometimes this process initiates the effervescent reaction, which produces additional water. This then acts as a binding liquid. The same process has been applied to fluid bed spray-granulator where low melting point polymers like polyethylene glycols (PEG’s) or polyoxyethylene glycols which act as binders are used (30). Yanze and coworkers used fluidized bed dryer melt granulation method to manufacture one-step effervescent granules composed of anhydrous citric acid and sodium carbonate for tabletting and PEG 6000 as a melting binder. This method was found to be an easy process for very rapid production of effervescent granules. It was reported to overcome the problems caused by the manufacturing of effervescent granules with traditional process of granulation (31-32), defective flowability and cohesiveness in dry granulation (33-35) and loss of carbon di oxide, time and energy consumed in the wet granulation methods (36-37). Compressed tablets from these granules were white, smooth and bright tablets with sufficient strength and without processing problems such as sticking, capping and friction (30).
Hot melt extrusion is a recently patented method to produce effervescent granules (38, 39). It requires a hot-melt extrudable binder. The suitable binders are the polyethylene glycols with molecular weight in the range of 1000-8000 Da. It requires extruders, which may be sufficiently equipped with a solid conveying zone, multiple separate temperature controllable heating zones, and an extrusion die. This can be cone by one-step or two step process.


ONE- STEP PROCESS
It involves blending of active ingredients with all other excipients at high temperature in extruder, which softens or melts the binder and the resultant extrudate is then powdered or chopped to form effervescent granules..
TWO-STEP PROCESS
Suitable proportion of acidic agent is mixed with hot-melt binder and the resultant binary mixture is melted. The alkaline agent is added as powder in it and the melted mixture is then extruded, chopped or powdered. The advantage of this method is that it does not require the use of solvents and water and few processes are needed which makes the process simple, continuous and efficient. This method is also very useful for increasing bioavailability of poorly soluble drugs. But this method may use complicated know-how and typically employs high temperatures around and over 100ºC, which may degrade thermolabile active ingredient. Thus, temperature should be controlled throughout the process.
Tabletting Of Effervescent Granules
The effervescent granulations can be tabletted in the same manner as conventional tablet granulations but in an area having low moisture content (0.2%) while conventional tablet manufacturing can be done in the area having moisture content of even 2%. The other issues in tabletting of effervescent granules are poor compressibility of raw materials, large diameter of tablets, and poor content of binder in the formulation and difficulties of lubricating the mixture. The whole process is done carefully and choosing an efficient tablet press. Normally effervescent tablets require tablet presses that can deliver high compression forces. These tablets are quite large, which often leads to insufficient tablet hardness and consequently broken or damaged tablets. This results in a poor yield and also a need to stop the press of packaging line. This problem can be solved by increasing dwell time which can be made possible by modifying the precompression assembly of the tablet press. Packaging effervescent tablets in foil or tube needs careful attention for controlling tablet parameters during compression. Poor content of binder in tablet lead to capping and lamination problem and give inferior quality of tablets. Good quality tablet is obtained by compressing granules when it is still slightly wet, or not dried. This tablet is then dried and stabilized by means of a process step in a static ventilated oven (70-75ºC). They are immediately then packed in aluminum foil lined with polyethylene. To solve lubrication problems, antiadherent materials are sprayed directly onto the dies of the tablet press, during the pause phase of compression. This external lubrication method is however, less compliant to GMP guidelines and thus not very suitable.
Tablet machine manufacturers have applied various adaptations to their existing equipment to avoid problems due to internal lubrication and punch adhesion. Several types of steels are used in the manufacture of compression tooling. Material rich in nickel was found to have the best resistance to rusting induced by hydrochloride salt. However, environmental conditions (humidity and temperature) and contact time were also found to be responsible for rusting. Alternative to use of lubrication is use of constant level powder feed system and punch faces and dies wall lubrication systems. The effervescent granules without lubricant possess poor flowability and sticking of the tablet on die walls or on the punch phases. Problem of poor flowability can be overcome by employing constant level powder feed system which consists of a rotary valve guaranteeing constant powder pressure on the forced filling station which in connection with two independently driven feed wheels will assure an accurate filling of the dies. Sticking of tablets to punch surfaces can be overcome by use of flat faced punches with discs of polytetrafluroethylene. If the problem of tablets sticking to die wall is not remedied, it gives problem in ejection of tablet from die cavity. Common practices to overcome this problem are use of punch face and die wall lubrication systems. These systems allow the addition of a very small proportion of solid or liquid lubricant to the punch faces and the die walls just before they come in contact with the granules. A typical manufacturing facility at New Delhi, India engaged in the manufacturing of effervescent tablets is depicted in Figure.


Manufacturing plant for effervescent tablets
Evaluation
The evaluation parameters mentioned in pharmacopoeias for the effervescent tablets are similar to those mentioned under conventional tablets, however, all of them stress on the disintegration test.
The United States Pharmacopeia(40), British Pharmacopeia(41), European Pharmacopeia(42) and Indian Pharmacopeia(43) mention the following evaluation parameters for effervescent tablets.
•Disintegration Time/Effervescent Time
•Dissolution Time
•Weight Variation
•Content Uniformity
According to the European Pharmacopeia, the effervescent tablets are uncoated tablets generally containing acidic substances and carbonate or bicarbonate which reacts rapidly to release carbon dioxide when dissolved in water. The disintegration of the tablets usually occurs within 2 min or even less, due to the evolution of carbon dioxide.
Other parameters considered by various scientists include
• Crushing Strength/Hardness
• Friability
• Water content & Moisture Uptake Studies
• Carbon dioxide content
• pH of the solution
• Organoleptic properties
The physical and chemical properties of the effervescent tablets need special consideration during the evaluation.
Physical Properties
The physical properties related to the tablet disintegration time are of prime importance.
1. Disintegration Time/Effervescent Time 
The tablet disintegration time is an important criterion as it is the basis and an advantage of this effervescent system. The disintegration time is hindered by the following factors, thus these issues should be specifically given concern during formulation:
Presence and concentration of water insoluble material in the formulation. Since if insoluble materials are left back this gives a bad appearance and the full effect of the materials is not obtained until they are in complete solution.
Use of efficient binders. This tends to make the stronger bridges between the raw materials which retard the disintegration.
Excessive hardness also leads to longer disintegration times, thus tablet harness should be sufficient for strength and stability accompanied by fast disintegration.
It is suggested that the disintegration time should be measured by placing an effervescent tablet in a standard volume of water (approx 120 to 180 ml) at room temperature and recording the time in which the tablet disintegrates. The volume of water and the temperature of water greatly influence the disintegration time. It is therefore recommended to choose the temperature of the water, used actually by the consumers’ i.e. cold tap water. Very often effervescent tablets tend to float on the top of the solution because the density of the mass and the bubbles adhering to the tablet decreases and cause the floating. The tablet should be critically evaluated for disintegration time if they float.
2. Dissolution Study
The criteria for in vitro dissolution studies of effervescent tablets are similar as that of conventional tablets. However, the aspects of pKa or pKb of the active ingredient need to be assessed for this type of systems as they influence the dissolution and absorption. A buffered medium is recommended as dissolution media for effervescent tablets. The ionic strength of the medium should also be assessed.
3. Hardness And Friability
These are interrelated parameters and need to be properly balanced such that the hardness is low enough as not to hinder the disintegration time and concomitantly the friability is not compromised. Effervescent tablets should be strong enough to withstand handling after compression. They are larger in diameter thus, problems of chipping and breaking should be overcome as discussed in the manufacturing section. The choice of proper tools like those with beveled edges minimizes problems of chipping. The ratio recommended for tablet thickness to tablet hardness, for a strong tablet is 1. However, these may pose problems during packaging as they are thicker. The height of the tablets also needs to be considered especially when the tablets are filled in packaging tubes. The looseness or tightness of the pack will be influenced by the tablet height. The standard hardness testers may be used for measuring the hardness, which include the Monsanto’s harness tester, Pfizer’s hardness tester, Strong Cobb or Schleuengir. The friability may be determined using Roche’s Friabilator.
4. Tablet Weight
It depends on the formulation and compression parameters and properly set procedures help to minimize problems of weight variation.
5. Water Content
Determination of water content is an important parameter for the effervescent tablets as it is indicative of the stability of the tablets. The water content is determined by Karl Fischer analysis. This determination is done after extracting with dioxane to prevent reaction of sodium bicarbonate with the Karl Fischer reagent. Sodium bicarbonate is insoluble in dioxane and does not interfere with the estimation. Near Infrared spectroscopy may also be used for determination of water content in the effervescent tablets. This is a quick and non-destructive method for analysis.
6. Carbon dioxide Content
Carbon dioxide content is measured using tests like titrimetric, gravimetric, colorimetric and volumetric. Loss of weight and pressure measurements has also been used for determination of carbon dioxide content (44). Yanze and co-workers have reported that since effervescent pharmaceuticals are more sensitive to ambient humidity during the manufacturing process and storage, the strict control of their carbon dioxide content becomes a prerequisite to guarantee their physicochemical stability. Indirect gravimetry is a simple and precise method that consists in taking the weight before and after the effervescent reaction allowing determination of the released amount of carbon dioxide. However, this method is associated with longer analysis times and poor accuracy of measurements. They have developed a device called the "CARBONDIOXIMETER" that is very easy to set up, and yields quick, accurate, precise and reproducible results which can be taken by a printer or a computer. The "Carbondioximeter" would be a useful tool to the control of physicochemical stability of effervescent pharmaceuticals during the manufacturing process and storage (45).
Chemical Properties
The pH of the solution is an important characterization of the effervescent tablets. The nature of the ingredients of the effervescent tablets leads to formation of a buffer system. Consistency in pH of the solution from various batches is an indicative of the uniform distribution of the raw materials of the batch. A wide variation in the pH of the solution is a sign of a non homogeneous granulation or separation of components during tabletting. It could also indicate errors during weighing of the raw materials. The pH of the solution is also a functionally important parameter for effervescent tablets as it influences the taste of the tablets. The antacids are formulated at slightly acidic pH to augment the taste of the solution and citrus and berry flavors are preferred. Mint flavors are formulated at neutral to slightly alkaline pH. The pH of the solution can be measured by suitable instrumentation at standard volume and temperature. The measurement of the pH should be done at specific time since the effervescent tablets have a tendency to change the pH on standing. The pH change occurs due to constant breakdown of carbonic acid to carbon dioxide and water and due to the presence of slowly soluble materials which require time for complete dissolution.
The content uniformity is another important evaluation parameter which should be performed for effervescent tablets. A limit of ± 10% deviation from the theoretical would be acceptable.
In-Process Quality Control
The in-process quality controls should be routinely performed to assess the operations and confirm the stability. The in-process evaluation parameters for tablets include:
• Tablet weight • Weight variation
• Thickness  • Crushing strength
• Disintegration • Appearance of the tablet
• Friability  • pH of solution
The presence of even trace amounts of water in an effervescent tablet , triggers its decomposition. Thus, measurement of residual amount of water in the formulation is necessary. However, this method is not very accurate since the heat in the apparatus also leads to evolution of the CO2 gas, which gives false results. The Karl-Fischer titration method is also not suitable, because it is not very sensitive for low levels of moisture, which need to be accurately estimated.
The vacuum drying technique, to a great extent gives accurate determinations. However, it is time consuming and has low accuracy. A type of modified Parr calorimeter has been successfully used for detection levels of moisture in effervescent tablets, which gives accurate results.
Stability
Stability problems pose a challenge to the formulator of effervescent dosage form. These problems arise due to loss of reactivity on prematurely exposure of dosage form to moisture. The stability of the active ingredient and drug-excipients compatibility should also be checked. It has been reported that conversion of the sodium bicarbonate partly to sodium carbonate improves the stability of the formulations. Temperature and moisture conditions greatly influence the stability considerations and accelerated stability studies should be performed to assess the stability of the effervescent tablets (46,47).


Packaging
Effervescent tablets are recommended to be stored in air tight containers and moisture proof packs. The effervescent packages are also suggested to be hermetically sealed. The reasons for stringent packaging requirements of these products are:
1) The moisture present in the atmosphere may be high which could be sufficient to initiate the effervescent reaction. Thus, effervescent tablets need to be properly protected. The time and the conditions between the production of effervescent tablets and its packaging operation should be minimized to improve the stability of the product.
2) Concern should also be given to the fact that the effervescent tablets may be exposed to the environment when the consumer opens the package for consumption. To improve the long term stability packaging operations are recommended to be carried out at low humidity environments less than 25% RH and 25° C.
Materials
Multiuse containers are recommended for effervescent tablets which include tubes and bottles which have closures that can be resealed after tablets are removed. The tubes may be made of glass, plastic or metal tubes. Alternatively individual foil pouches joined to form a conveniently sized strip of tablets are also used.
Glass provides highest degree of moisture protection to the product. However, certain limitations of glass include
• More breakages
• Heavy weight
• High cost of transportation
• Individual packing not possible
Plastic is also a suitable alternative material as it is low in cost and has a low noise level during packaging. Plastic bottles or tubes may be made up of polyvinyl chloride or polypropylene (Figure). Plastic tubes are however more susceptible to water vapor permeability and are thus recommended to be used for effervescent tablets with low hygroscopicity and accompanied by moisture proof closures.
Metal tubes provided with moisture proof closures are another type of multiple use containers. These tubes should be seamless, thus ensuring elimination of the moisture. Aluminum is most commonly used for the preparation of metal tubes.


The use of aluminum foil strips, blisters and Alu-Alu blisters for packaging of effervescent tablets provide a hermetically sealed package (Figure). A unique type of foil package developed specially for effervescent tablets is such that all the tablets are connected to a desiccant through channels. The effervescent tablets packed in foils and blisters should be tested for effect of moisture on the stability of the tablets.
Some manufacturers in Europe use thermoformed plastic blisters with a foil backing. The effervescent tablets need to have a higher hardness when this packaging technique is adopted so that they do not break on removal. An alternative approach is the use of Aclar, a transparent film which has a very low moisture vapour transmission rate, thus giving good protection to the product. However, it is expensive so should be used as and when required.
Aluminum foil provides an excellent packaging material for effervescent tablets because it is
• Flexible 
• Good barrier towards gases, water-vapour and light 
• Non-toxic and Immune to microbiological attack 
• Excellent heat conductivity, suitable for heat sealing strip packing technique 
Filling
The filling of effervescent tablets in bottles should be accompanied with a silica gel bag, which would absorb the moisture and improve the stability of the product. Random filling of the tablets is not suggested in glass bottles as the effervescent tablets are large in diameter (approx 1”). It is recommended that the tablets be stacked one over another in the tubes. The diameter of the tubes used for packaging of the effervescent tablets is very important. A diameter just larger than the size of the tablets, which provides proper stacking of tablets and which ensures minimum air space in the tube is recommended. Every time the containers are opened, the environmental air enters the tubes. Thus minimum air space will ensure minimum exposure of these tablets to the moisture. Moisture can also enter through the closure, for which the top most tablet acts as a desiccant and protects the tablets. However, on regular usage the amount of air space progressively increases which would lead to entry of the moisture. The tablets at the end of the stack may be checked for stability as they have a greater chance of becoming non-reactive. Multiuse containers like the bottles or tubes require moisture proof closures. Metal caps with waxed, aluminum foil, pulp backed cap liner provide good protection. Caps with a chamber of silica gel or a desiccant that absorbs the moisture through the closure has also been used.
Effervescent tablets, when packed inside heat-sealed foil pouches, inserted into cartons pose certain drawbacks. First, it doesn’t provide protection against tablet breakage the way a rigid container does. Secondly, because each tablet is wrapped individually, the small size often prohibits bright, attractive graphics from being printed on the packaging. Effervescent tablets are extremely susceptible to moisture, so use of a desiccant-packing closure is very useful. United Dessicants have developed a typical pack that consists of an injection-molded polypropylene tube that holds the tablets straightforward. It also consists of a breakaway band on the injection-molded tube and a snap-fit cap. The cap incorporates a silica gel adsorbent to trap moisture that makes its way inside the tube after the cap is removed by the consumer and snapped back on (48).
Another type of the tube (PAK®) provided by Knight-McDowell for effervescent-tablets consists of an injection-molded polypropylene container and a polyethylene closure with a silica gel adsorbent to trap moisture. They claim that this type of package provides good protection against tablet breakage and has a surface that accepts full-color graphics, to improve marketing and make the package attractive from the consumer’s view point. Its cap design is also unique and the snap-on-polyethylene cap is tamper-evident. The effervescent-PAK is designed with a small well around its edges, so that when the cap is pushed on during the capping process, it locks behind the edges, thus forming a breakaway band that prevents tampering. Molded into the underside of the injection molded PE cap is a flexible spiral spring. Not only does it house the moisture-adsorbing desiccant, but it also holds the tablets securely in place, thus preventing breakage (49).

Another patent investigation by (50) reports on the use of desiccant in the packaging of effervescent tablets. The invention consists of a one-piece vial assembly, having a container and cap for moisture-free environment. In one type, the container and cap are joined together by a hinge; hence the vial assembly is a one-piece assembly in which the cap is opened and closed in a "flip-top" arrangement. The vial assembly includes a desiccant entrained plastic. In another type, the desiccant entrained plastic is located in a desiccant sleeve, which surrounds at least a portion of the product within the vial assembly sleeve. In yet another type, the sleeve surrounds the vial assembly interior with a thin-walled plastic so that the product contained within the vial assembly is completely surrounded by the desiccant entrained plastic sleeve. They have reported that in this type of a pack the product is subjected to about fifty times less moisture when compared to a conventional stoppered vial.
Packaging Problems
Packaging operation should be conducted at low RH and low temperature conditions. The common problems encountered when effervescent tablets are packaged in tubes or foil are as following: 
Pinholes: They are common when the tablets are foil packed. Use of a heavier gauge of the foil reduces the number of pinholes. However, the cost should be taken into consideration.
Area of the packet: The area within the packet should be large enough to easily hold the tablets without stress on the foil and it should also not be too large, because it holds air, which could lead to problems of stability. Entrapment of even 10% moisture within the tablet packet is considered to initiate the effervescent reaction prematurely.
Stability: The stability of the tablet depends on the integrity of the package, and thus packed tablets should be subjected to accelerated stability studies at 40°C and 75% RH for atleast 3 months. All the test parameters mentioned in Table 2 need to be assessed to confirm the effect of various RH and temperature conditions on the integrity of the pack and thus on the stability of the tablets in the pack. High humidity conditions cause an increase in the physical deterioration of the product. A simple Penetration Dye Test has also been recommended to determine whether the package allows transmission of moisture
The common reasons for degradation of effervescent products due to an unsuitable package could be that the material does not have a water vapor transmission rate of 0, thus moisture enters the package. The seal of the foil is not of good quality, then this may also allow entry of the moisture

Summary of the evaluation parameters to confirm, stability of the effervescent tablets.
Tablet parameters Package Seal Parameters
Tablet appearance Package leak/ integrity test
Tablet hardness Vacuum underwater test
Content Uniformity Detection of tracer materials
Sensory evaluation Purging with detectable gases 
Disintegration Time IR seal inspection
Electronic air-tightness tester

Applications Of Effervescent Tablets
1.Effervescence induces penetration enhancement of broad range of compounds ranging in size structure and other physiological properties across rat and rabbit small intestinal epithelium.
Eichman and Robinson demonstrated that effervescence could be used as a penetration enhancer. These researchers passed a large volume of CO2 through the donor compartment of a modified using diffusion apparatus and were able to demonstrate enhanced permeation of drugs through rabbit epithelium placed between the cells. The effervescence-induced enhancement is mediated via the following effects: •A solvent drag effect due to increased fluid flow
•Opening of tight junctions
•Increasing the hydrophobic nature of the cell membrane
The suggested reason for penetration enhancement is the co2 bubbling directly onto epithelium and induces enhanced drug permeability due to an alteration of the paracellular pathway (57,58).
2. Effervescent blend can be used to obtain programmed drug delivery from hard gelatin capsules containing a hydrophilic plug (59).
3. A controlled release effervescent osmotic pump tablets have also been used since long time for traditional Chinese medicine (60).
4. Floating drug delivery systems based on a reservoir system consisting of a drug containing effervescent core and polymeric coating. The concentration of effervescent agents significantly affects the floating time (61).
5. It is helpful in pulsatile system; a quick releasing core was formulated in order to obtain rapid drug release after the rupture of the polymer coating (62).
6. In design of simple zero order release system by incorporation of low levels of effervescent mixtures within the tablet matrix can be done (63).
7. In remote areas, especially where parenteral forms are not available due to prohibitive cost, lack of qualified staff, effervescent tablets could become an alternative. The use of Chloroquine phosphate effervescent tablet for epidemic disease like malaria and viral fever is an example of this type (64).
8. To solve the problems of physicochemical stability and high cost of transporting syrups, effervescent tablets provide a realistic solution.
9. A new dosage form of levodopa, which has the characteristic of loading high concentration at the upper part of the intestine, has been developed to improve bioavailability. Effervescent tablet formulation, coated with HPMC phthalate, as the enteric material is suitable for the purpose of dissolution (65).

Patents On varied applications of Effervescent Tablets
•Levamisole effervescent tablets which comprise a composition characterized by excellent solubility yielding crystal clear solutions in water, good storage stability, and ease of use. There are also methods for the oral administration of levamisole to swine in predetermined dosages via the drinking water offered to animals utilizing the aforesaid levamisole effervescent tablets. It gives detailed information related to levamisole effervescent tablet containing levamisole hydrochloride, alkali metal bicarbonate, adipic or fumaric acid, lubricant and dye (66).
•A pharmaceutical dosage form incorporates microparticles which are susceptible to rupture upon chewing or which are adapted to provide substantially immediate release of the pharmaceutical ingredient contained in the microparticles. These microparticles are provided in a tablet with an effervescent disintegration agent. When the tablet is taken orally, the effervescent disintegration agent aids in rapid dissolution of the tablet and hence permits release of the microparticles, and swallowing of the microparticles, before the pharmaceutical ingredient is released from the microparticles. The system therefore provides particularly effective taste masking (67).
• An oral pediatric vitamin supplement comprising: a mixture of at least one effervescent disintegration agent, and a pediatrically effective amount of at least one intended ingredient selected from the group consisting of vitamins and minerals and mixtures thereof, wherein said mixture is present in the form of a compressed tablet of a size and shape adapted for direct oral administration to children and which will rapidly and completely disintegrate when administered; and wherein said effervescent disintegration agent is present in a amount which is effective to both aid in rapid disintegration of said tablet and to provide a positive organoleptic sensation to children (68).
• The invention relates to effervescent tablets and granules comprising a shell material, a basic sparkling component, an acidic sparkling component, and a sweetening agent, macro and microelements and vitamins as active agents. The effervescent tablets and granules comprise 20-50% by mass of mannitol as shell material, 8-25% by mass of potassium hydrogen carbonate as basic sparkling component, 9-27% by mass of malic acid as acidic sparkling component, and 0.4-2.2% by mass of aspartame as sweetening agent. Furthermore, the invention relates to a process for preparing the above-described effervescent tablets and granules (69).
• An effervescent composition and tablet made from acidic effervescent component for direct tabletting of effervescent tablet and process for its preparation are described in the patent (70).
• A pharmaceutical composition containing effervescent acid-base couple comprising active ingredient and sodium glycine carbonate and acid capable of reacting with sodium glycine carbonate to release carbon dioxide (71).

Monographs Of Effervescent Tablets In Pharmacopeias
USP29 NF24 Aspirin effervescent tablet for oral solution Potassium bicarbonate effervescent tablets for oral solutions Potassium chloride, potassium bicarbonate and potassium citrate effervescent tablets for oral solutions.
BP 2005 Effervescent Soluble Aspirin Tablets Effervescent Co-codamol Tablets Soluble Paracetamol tablets

Commercial products of effervescent tablets

Commercially available effervescent tablets from brand leaders in different countries

Commercially available effervescent tablets from brand leaders in INDIA.
Name of product Active ingredient Manufacturer
Vitalmag Magnesium citrate, Folic acid ,Vitamin B6 ICN Hungary
Calcium sandoz Calcium ICN Hungary
Ca-C 1000 Calcium,Ascorbic acid ICN Hungary
Cacit CaCO3 Procter and Gamble
Tagamet Cimetidine Glaxo smithkline
Zantac Ranitidine Glaxo smithkline
Solpado Paracetamol ,Codeine phosphate Sanofi-aventis
Histac Ranitidine HCl Ranbaxy
Pepfiz-O&L Papain ,Fungal diastase ,Simeticone Ranbaxy
Effcal CaCO3 , Vitamin D3 Ranbaxy
Hangoverz Aspirin, Caffeine
Pious Pharma. Ltd
Prolyte fizz Glucose + Potassium Chloride + Sodium Bicarbonate + Sodium Chloride + Anhydrous Citric Acid
Cipla


Example
Aloe Vera Effervescent Tablets

Aloe Vera effervescent tablets contains 30tablets / carton. Each tablet contains 250 mg of IASC certified Aloe Vera Freeze Dried Powder 200X and 60 mg vitamin C.
One carton eaquals 1, 5 liters of 99% Aloe Vera Juice.
The tablet increases the intake of vitmin C and vitmin E.
Aloe Vera contains enzymes, polysaccharides (f. Ex. Acemannan) , essential amino acids, vitamins and minerals.
Aloe Vera has long been used because its fine qualities concerning stomach and bowels. A daily partake of Aloe Vera contributes to:
* Improved digestion
* The pH value in the stomach is stabilized
* The bowels are cleansed and their status improved.
* Irritations in the mucous membrane are relieved
* The immune defence is improved
* Improved ability of the body to absorb C-and E-vitamin
Take one tablet / day with a fresh taste of Lemon.


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aya  |  09-Apr-2012 02:16:37 IST
very goood
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