Effervescent Tablets

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As per revised definition proposed to US FDA, Effervescent tablet is a

tablet intended to be dissolved or dispersed in water before 03 Current Job Openings a
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 04 FDA Approval Process a
dioxide. They are intended to be dissolved or dispersed in water
before use.
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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
www.pharmatips.in/Articles/Effervescent-Tablets.aspx 1/30
p y g y
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
p g y g
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
d h d d h d A h d f i f d
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
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
h th t i l i t t t ith t d t if th
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
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
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
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
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
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
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
e tab et d s teg at o t e s a po ta t c te o as t s t e
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,
g ,
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
g p y
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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Effervescent Tablets

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Effervescent Tablets

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6/27/2019 EFFERVESCENT TABLETS

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As per revised definition proposed to US FDA, Effervescent tablet is a

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Advantages Of Effervescent Tablets (54,55,56)

The Effervescent Reaction (51,53)

For example: the reaction of Citric acid and Sodium bicarbonate

3 NaHCO3(aq) + H3C6H5O7(aq) - 3 H2O(l) + 3 CO2(g) +

From this equation it can also be derived why most effervescent

This reaction starts in presence of water, even with small amount as

Active Ingredients (54)

there is no risk of excessive gas in the stomach or of constipation.

Preparation of Effervescent tablets

Formulation Ingredients Of Effervescent Tablets

1. Wet Granulation Method

2. Dry Granulation Methods

ONE- STEP PROCESS

Manufacturing plant for effervescent tablets

Aluminum foil provides an excellent packaging material for

Another patent investigation by (50) reports on the use of desiccant

the cap is opened and closed in a "flip-top" arrangement. The vial

Summary of the evaluation parameters to confirm, stability of the

Applications Of Effervescent Tablets

Patents On varied applications of Effervescent Tablets

Monographs Of Effervescent Tablets In Pharmacopeias

Commercial products of effervescent tablets

Commercially available effervescent tablets from brand leaders in

Commercially available effervescent tablets from brand leaders

Aloe Vera effervescent tablets contains 30tablets / carton. Each tablet

1. Swarbrick J. and Boylan J.,

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