As per revised definition proposed to US FDA, Effervescent tablet is a tablet intended to be dissolved or dispersed in water before administration.
It generally contains in addition to active ingredients, mixture of acids/acid salts (citric, tartaric, malic acid or any other suitable acid or acid anhydride) and carbonate and hydrogen carbonates (sodium, potassium or any other suitable alkali metal carbonate or hydrogen carbonate) which release carbon dioxide when mixed with water. Occasionally, active ingredient itself could act as the acid or alkali metal compound necessary for effervescent reaction.
Effervescent tablets are uncoated tablets that generally contain acid substances and carbonates or bicarbonates and which react rapidly in the presence of water by releasing carbon dioxide. They are intended to be dissolved or dispersed in water before use.
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INTRODUCTION
Background
Effervescent mixtures have been known for over 250 years. The famous Rochelle salt (potassium sodium tartrate) dates back to 1731 in conjunction with such a mixture. In the 18th century, effervescent powders as saline cathartics were listed as “Seidlitz powders” in the official compendia.
In the 1930s, the effervescent products gained much importance with the technology of Alka Seltzer. These mixtures have been moderately popular over the years since along with medicinal activity they are attractive dosage form for the patients. Effervescent reactions have been used alternatively preparation of other dosage forms, such as suppositories (for laxative effect), vaginal suppositories (for contraceptive effect) and drug delivery system (floating system and orally disintegrating tablets) (1).
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.
Soluble effervescent tablets are prepared by compression. In addition to active ingredients, they contain mixtures of acids (like citric, tartaric, malic and fumaric acid) and carbonates like sodium, potassium bicarbonate that release carbon dioxide when dissolved in water.
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. Desiccants are usually added to the containers.
Labeling: It should be labeled that these products are not to be swallowed directly (2). 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. The label also states that the tablets are to be dissolved in water before being taken.
Directions for use may be mentioned on the label as follows:
The Effervescent Reaction (1,3)
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.
3NaHCO3(aq) + H3C6H5O7(aq) 3H2O+CO2 + 3Na3C6H5O7(aq)
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 (4)
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 and gastrointestinal
• 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.
• Activated charcoal preparations used in the management of theophylline poisoning
Advantages Of Effervescent Tablets (4,5,6)
1.Fast onset of action
Effervescent tablets have major advantage that the drug product is already in solution at the time it is consumed. Thus, the absorption is faster and more complete than with conventional tablet. This is particularly helpful in treating acute symptoms of pain. Faster absorption means faster onset of action, critical in treating acute symptoms such as pain. Buffered preparations with adjustable stomach pH optimize formula performance characteristics.
Effervescent drugs are delivered to the stomach at a pH that is just right for absorption. Many medications travel slowly through the gastrointestinal tract or have absorption that is hampered by food or other drugs. To achieve desired absorption levels, such drugs have to be often administered as injections or with increased dosages.
2.No need to swallow tablets
Effervescent medications are administered in liquid form so they are easy to take as compared to tablets or capsules. The number of people who cannot swallow tablets or who dislike swallowing tablets and capsules is growing. Many diseased conditions require the patient or customer to swallow several tablets at a time. The elderly, in particular, have difficulty in swallowing tablets. With an effervescent dosage form, one dose can usually be delivered in just 3 or 4 ounces of water. The amount used when someone swallows a conventional tablet or capsule.
3.Good stomach and intestinal tolerance
Effervescent tablets dissolve fully in a buffered solution. Reduced localized contact in the upper gastrointestinal tract leads to less irritation and greater tolerability. Buffering also prevents gastric acids from interacting with the drugs themselves, which can be a major cause of stomach and esophageal upsets.
4.More portability
Effervescent tablets are more easily transported than liquid medication because no water is added until it's ready to use. .
5.Improved palatability
Drugs delivered with the effervescent base, taste better than most liquids, mixtures and suspensions. Superior taste masking is achieved by limiting objectionable characteristics and complementing formulations with flavors and fragrances. Effervescent pharmaceuticals retain their flavor after lengthy storage. The effervescent tablets essentially include flavorings so they taste much better than a mixture of a non-effervescent powder in water. Moreover, they produce fizzy tablets, which may have better consumer appeal than the traditional dosage forms.
6. Superior stability
Excellent stability is inherent with effervescent formulations, particularly surpassing liquid forms.
7. More consistent response
Drugs delivered using effervescent technology have predictable and reproducible pharmacokinetic profiles that are much more consistent than tablets or capsules.
8. Incorporation of large amounts of active ingredients
In many cases, one effervescent tablet will equal to three conventional tablets in active dose amounts.
9. Accurate dosing
Researchers have shown that effervescent tablets enhance the absorption of a number of active ingredients (e.g. disulfiram and caffeine), compared to conventional formulations. This is because the carbon dioxide created by the effervescent reaction can induce enhanced active-ingredient permeability due to an alteration of the paracellular pathway. The paracellular pathway is the primary route of absorption for hydrophilic active ingredients in which the solutes diffuse into the intercellular space between epithelial cells. It is postulated that the carbon dioxide widens the intercellular space between cells, which leads to greater absorption of active ingredients (both hydrophobic and hydrophilic). The increased absorption of hydrophobic active ingredients could be due to the non-polar carbon dioxide gas molecules partition into the cell membrane, thus creating an increased hydrophobic environment, which would allow the hydrophobic active ingredients to be absorbed.
10. Improved therapeutic effect
The effervescent components aid in improving the therapeutic profiles of the active ingredients. They also help in solubilization of poorly soluble drugs.
Other Considerations:
• Convenient and easy administration than other liquid medicines to administer
• Less chance of misuse
• Ability to combine multiple active ingredients, if therapeutically appropriate
• Innovative, yet less risky than unproven technology
Possible Drawbacks
1. Unpleasant taste of some active ingredients Some active ingredients have unpleasant taste that cannot be masked by flavors and sweeteners. This will lead to an unacceptable product.
2. Disintegration time In a tablet form, disintegration can take up to 5 min. This depends mainly on the temperature of the water and the active ingredients present.
3. Relatively expensive to produce due to large amount of more or less expensive excipients and special production facilities.
4. Larger tablets requiring special packaging materials.
5. Clear solution is preferred for administration, although a fine dispersion is now universally acceptable
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 carbon dioxide bubbling directly onto epithelium and induces enhanced drug permeability due to an alteration of the paracellular pathway (7,8).
2. Effervescent blend can be used to obtain programmed drug delivery from hard gelatin capsules containing a hydrophilic plug (9).
3. A controlled release effervescent osmotic pump tablets have also been used since long time for traditional Chinese medicine (10).
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 (11).
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 (12).
6. In design of simple zero order release system by incorporation of low levels of effervescent mixtures within the tablet matrix can be done (13).
7. In remote areas, especially where parenteral forms are not available due to prohibitive cost, lack of qualified medical 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 (14).
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 (15).
10. Cosmetic effervescent tablets have different applications like bath as an existing perfumed line extension, bath including essential oils and hydrating agents, foot care including essential oils and/or hydrating agents, hand care with hydrating agents and nail care products (14).
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 (16).
•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 (17).
• 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 (18).
• 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 (19).
• 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 (20).
• 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 (21).
• An effervescent rapidly disintegrating oral dosage form of alkali sensitive agents includes active ingredient Selegiline HCl which is sensitive to effervescent base like sodium bicarbonate, sodium carbonate and sodium hydrogen citrate (22).
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
See also
Manufacuring of Effervescent tablets
Commercial Products Of Effervescent Tablets
REFERENCES
1. Swarbrick J. and Boylan J., Encyclopedia of Pharmaceutical Technology; Volume -1,1037-1049 (2002), Marcel dekker Inc., New York.
2. Mohrle R., Effervescent tablets in Liberman H., Lachman L. and Schwartz, J., Pharmaceutical dosage forms: Tablets, Volume - 1:285-292, First Indian Reprint (2005) Marcel dekker Inc., New York.
3. Parikh D M, Handbook of Pharmaceutical granulation technology; 2nd Edition, 154:365-383 (2005), Taylor & Francis, New York.
4. Robert, L. E., Amerilab technologies, Effervescent tablets.
6. Effervescent tablets, .
7. Enhanced buccal delivery of fentanyl using Oravescent drug delivery system, 1(1), 2001.
8. Jonathan, E., Joseph, R., Pharm. Res., Mechanistic studies on effervescent induced permeability enhancement, 15(6),925-930 (1998).
9. Gohel, M., Manhapra, S., Modulation of active pharmaceutical material release from novel tablet in capsule system containing effervescent blend, J. Cont. Rel., 79(1-3),157-164 (2002).
10. Xian L., Wei-San P., Studies on controlled release effervescent osmotic pump tablets from traditional Chinese medicine compound recipe, J. of Control. Rel., 96(3), 359-367 (2004). 11. Ina, K., Bodmeier, R., Floating or pulsatile drug delivery systems based on coated effervescent cores, Int. J. Pharm., 187, 175-184, (1999).
12. Hashim H., Li, P., Improving the release characteristics of water soluble drugs from hydrophilic sustained release matrices by in situ gas generation, Int. J. Pharm., 35(3), 201-209 (1987).
13. Yanze F., Duru, C., Rapid therapeutic response onset of a new pharmaceutical form of chloroquine phosphate 300 mg effervescent tablet, Tropical Medicine and International Health, 6(3),196-201 (2001).
14. Nishimura K., Sasahara K., J. Pharm. Sci., Dosage form design for improvement of bioavailability of levo-dopa: Formulation of effervescent enteric coated tablets, 13(7), 942-946 (1984).
16. U.S. Patent 4,153,678, (1979)
17. U.S. Patent 5,178,878, (1993)
18. U.S. Patent 5,223,264, (1993)
19. U.S. Patent 5,707,654, (1998)
20. U.S. Patent 5,762,951, (1998)
21. U.S. Patent 6,667,056, (2003)
22. U.S. Patent 6,242,002, (2001)
Authors
Dr.Avani , Tejal Shah, Reena Dua and Renuka
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