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Wednesday, December 21, 2011

Preparation of Effervescent tablets -Free Pharmacy Material from

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.

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. 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.

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.

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.

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.

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.

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.

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.

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. 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. 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:
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.

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.

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.

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).

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

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.
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.

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.

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.

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.

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.

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.

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.

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.

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.


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