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A PROJECT REPORT FOR ELECTIVE SUBJECT ON “EFFERVESCENT FORMULATIONS” SUBMITTED TO THE HEMCHANDRACHARYA NORTH GUJARAT UNIVERSITY, PATAN 2004-2005 IN PARTIAL FULFILLMENT OF THE REQUIREMENT FOR THE DEGREE OF BACHELOR OF PHARMACY SUBMITTED BY YOGI AGRAVAT (FINAL B. PHARM) S.K. PATEL COLLEGE OF PHARMACEUTICAL EDUCATION AND RESEARCH, GANPAT VIDYANAGAR, KHERVA NORTH GUJARAT. CERTIFICATE This is to certify that the project work for elective subject entitled ”EFFERVESCENT FORMULATIONS” represents the bonafide work of AGRAVAT YOGI M. carried out under my guidance and supervision at the Pharmaceutics department of Shree S. K. Patel college of pharmaceutical education and research, GANPAT VIDYANAGAR, (KHERVA) during the academic year 2004-2005. He has collected the literature very sincerely and methodically. This work is up to my satisfaction. Guide: Mr.R.P.Patel (M.Pharm) Department of Pharmaceutics S. k. Patel college of Pharmaceutical Edu. & Res. Ganpat vidyanagar, Kherva. Date: Place: Ganpat vidyanagar,Kherva. Principal I/C: Dr. N. J. Patel (M. Pharm., Ph. D.) S. k. Patel college of Pharmaceutical Edu. & Res Ganpat vidyanagar, Kherva. ACKNOWLEDGEMENT This project report has been prepared to give a brief introduction of “EFFERVESCENT FORMULATIONS” which was under taken for partial fulfillment of degree course in pharmacy. The project work has to be undertaken and completed as per the direction of the syllabus. In this field with very limited acknowledgement need of mine was fulfilled by my able guide Mr.R.P.Patel. He gave me direction on how to work on this project & helped in each & every part of this project work. My special words of thanks to him that he is a “Noble Man” in our department who is ready at all time to guide as well as to teach me and also all the students. My heartly thanks to Mr.B.S.Dave who inspired me to do this work. I am thankful to our principal Dr. N. J. Patel who has been a constant source of inspiration throughout my B. Pharm. My sincere thanks to Asst.Prof.J.K.Patel and Asst.Prof.P.D.Bharadia and Mr.V.M.Patel and Mrs.H.V.Patel for their suggestions and moral support. I also thank entire staff members who helped me a lot to complete this project work. I am thankful to Librarian Mr. P. I. Patel and Computer Lab. Asst. Chaula Ma’m who has also been helpful to me. A special thanks reserved for my college friends and Dharati group for their co-operation and giving constant support. At this stage I thank with deep gratitude to my parents for their moral support, constant encouragement and patience absolutely needed to complete my entire graduation. I also thank to my class mates for finalization of my thesis. Agravat yogi mansukhlal (FINAL B. PHARM) DEDICATED TO MY FAMILY & FRIENDS INDEX Sr.no. 1 2 3 4 5 6 7 8 9 10 11 12 Name of chapter Introduction Composition of formulation Types of effervescent formulation Manufacturing techniques Packaging Market products available Research Analytical parameters Advantages Limitations Summary References Page no. 1 5 15 27 33 36 39 50 53 56 58 60 Effervescent formulations Chapter-1 INTRODUCTION 1 Effervescent formulations 2 INTRODUCTION (a1,b2,b19) Effervescent mixtures have been known and used medicinally for many years. Effervescent powders used as saline cathartics were available in the eighteenth century and were subsequently listed in the official compendia as compound effervescent powders. These were more commonly known as ‘Seidlitz powders’. Effervescent mixtures have been moderately popular over the years since along with the medicinal value of the particular preparation. In addition, they provided a pleasant taste due to carbonation which helped to mask the objectionable taste of the drugs. Effervescent formulations are known in the prior art for various active ingredients and vitamins. These effervescent formulations generally include an agent which is capable of releasing CO2, and an agent which induces the release of CO2. Suitable agents capable of releasing CO2 which are used include alkali metal carbonates or alkali metal bicarbonates, such as sodium carbonate and sodium bicarbonate. Alkaline earth metal carbonate formulations are mainly contained in mineral preparations. Suitable agents for inducing CO2 release include edible organic acids, or their acidic salts, which are present in solid form and which can be formulated with the active ingredient and the other auxiliaries to provide granules or tablets, without premature evolution of CO2. Suitable edible organic acids include, for example, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, ascorbic acid, maleic acid or citric acid. Pharmaceutically acceptable acidic salts include, for example, salts of polybasic acids which are present in solid form and in which at least one acid function is present, such as sodium dihydrogen or disodium hydrogen phosphate or the corresponding citrates. The active ingredients are either present in the effervescent formulation as readily soluble compounds, or they are solubilized by salt formation during the dissolution process. However, it is also possible to disperse poorly soluble active ingredients. Selegiline hydrochloride is extremely sensitive to the customary effervescent bases such as sodium bicarbonate, sodium carbonate or sodium hydrogen citrate in combination with organic edible acids, such as citric acid or tartaric acid. Effervescent formulations 3 In these customary effervescent formulations, the selegiline active ingredient is degraded to amphetamine, methamphetamine and demethylselegiline, and the active ingredient undergoes sublimation. It should be noted that degradation to the above mentioned metabolites occurs only partly. The main part of selegiline sublimes in the presence of alkali metal compounds, particularly alkali metal carbonates, so that surprisingly, loss of active ingredient occurs even in the case of only slight metabolization. The required purity and quantity are no longer met after storage of these effervescent selegiline formulations. Surprisingly, effervescent formulations based on alkaline earth metals in accordance with the present invention are very stable. Most suitably calcium carbonate and citric acid are used as the effervescent base. It can be advantageous to have some of the calcium carbonate react with citric acid to give calcium citrate. Small amounts of sodium citrate do not cause instabilities. However, these amounts may not be more than about 15% of the total weight of the effervescent formulation. At room temperature and even in the stress test at 40 oC. And 75% relative atmospheric humidity, the effervescent selegiline formulations according to the present invention show no relevant loss of quality. This is of particular importance since effervescent formulations have to be well protected against atmospheric humidity during production, filling and storage. Therefore, their preparation is generally carried out only in areas having low atmospheric humidity (Ritschel, Bio Tablette, Echtio Cauher KG 1966, p. 115 f). As discussed by Wells in Pharmaceutical Preformulation (John Wiley publisher, 1988), basic catalysis is in a large number of medicaments a decisive reason for instability. Although calcium carbonate is known to be used in effervescent tablets but only in cases where calcium therapy is required with calcium as an active ingredient, but not as medicinal excipient for other active ingredients where calcium does not contribute to the therapy. Calcium-containing effervescent tablets are generally employed for treating mineral metabolism problems. A ready-to-drink solution or suspension with pleasant taste can be prepared with the effervescent formulations of the present invention, suitably in a volume of from 40 to 80 ml of water, which can be easily drunk even in cases of tremor. This also applies to geriatric patients. Buccal or Effervescent formulations 4 sublingual effervescent preparations are administered directly at the mucosa of the mouth. The dose in the buccal preparation can be considerably lower, for example 1-5 mg of e.g. selegiline. In the case of low-dosed active ingredients, the effervescent formulations according to the present invention can comprise up to about 90%, and in the case of high-dosed active ingredients, from about 30% to about 70% of an effervescent base. The effervescent formulations also permit combined taking together with other active ingredients, as is frequently required in the case of selegiline in Parkinson treatment. Thus, effervescent selegiline formulations can be administered in combination with other soluble tablets, in particular Ldopa/benzerazide combinations or soluble amantadine tablets. Vacuum drying cabinets can be used, for example, to achieve rapid drying. In another method of preparation the acid is partially reacted with the basic components, followed by drying under reduced pressure. A soluble lubricant is admixed to the dry granules before compression. However, tableting can also be carried out by using external lubrication. Effervescent formulations 5 Chapter-2 COMPOSITION OF EFFERVESCENT FORMULATION Effervescent formulations 6 COMPOSITION (A3,A4,A7,A8,B8) Effervescent granules are usually prepared from a combination of citric and tartaric acid rather than from a single acid because the use of either acid alone causes difficulties. When tartaric acid is the sole acid, the resulting granules readily crumble and lack mechanical strength. Citric acid alone results in a sticky mixture which is difficult to granulate during the manufacturing process. The reaction between citric acid and sodium bicarbonate and tartaric acid and sodium bicarbonate, which results in liberation of carbon dioxide, may be shown as follows: H3C6H5O7.H2O + 3 NaHCO3 CO2 ↑------ (i) -------à Citric acid Sodium bicarbonate Carbon dioxide H2C4H4O6 + ↑------ (ii) Tartaric acid dioxide 2 NaHCO3 -------à Sodium bicarbonate Na3C6H5O7 + 4 H2O + Sodium citrate Na2C4H4O6 + 2 H2O + 3 Water 2 CO2 Sodium tartrate Water Carbon It should be noted that it requires 3 molecules of sodium bicarbonate to neutralize 1 molecule of citric acid and 2 molecule of sodium bicarbonate to neutralize 1 molecule of tartaric acid. The proportion of acids may be varied, as long as the total acidity is maintained and the bicarbonate completely neutralized. Usually it is desired that ratio of citric acid to tartaric acid equals 1:2 so that the desired ratio of the ingredients can be calculated as follows: Citric acid: Tartaric acid: Sodium bicarbonate = 1:2:3.44 (by weight) (2) The alkali-sensitive active ingredient, such as selegiline, is suitably bound to neutral auxiliary ingredients to obtain good homogeneity. Suitable neutral carrier substances for the effervescent formulations according to the invention include lactose, sucrose, sorbitol, mannitol, starch, pectins or cellulose. Other auxiliary ingredients, such as colorants, sugars or sweeteners, can improve the appearance and/or the taste of the aqueous Effervescent formulations 7 solutions or suspensions obtainable by disintegration of the effervescent tablet. The criteria for the selection of dissolution media for buffered or effervescent tablets are the same as for conventional tablets.It will be advisable to verify if the buffering capacity and ionic strength of the media are appropriate for the formulation under evaluation. Effervescent tablets generally contain ingredients such as tartaric acid, citric acid, and sodium bicarbonate. These powders would be appropriately mixed and pressed into tablets using the same procedure as chewable tablets. They will not require a disintegrant since they will effervesce when placed in water. Compressed tablet mixtures generally contain the active drug, a diluent (e.g., lactose), a disintegrant (e.g., starch), and a lubricant (e.g., 1% magnesium stearate) When higher melting temperature, higher molecular weight or high softening temperature binders are employed, the hot-melt extrusion may require higher processing temperature, pressure and/or torque than when binders having a lower molecular weight, melting or softening temperature are employed. By including a plasticizer, and, optionally, an antioxidant, in a formulation, processing temperature, pressure and/or torque may be reduced. Plasticizers are not required in order to practice the invention. Their addition to the formulation is contemplated as being within the scope of the invention. Plasticizers are advantageously included in the effervescent granules when hot-melt extrudable binders having a melting or softening point temperature greater than 150oC. are employed. The plasticizer should be able to lower the melting temperature or glass transition temperature (softening point temperature) of the hot-melt extrudable binder. Plasticizers also generally reduce the viscosity of a polymer melt thereby allowing for lower processing temperature and extruder torque during hot-melt extrusion. It is possible the plasticizer will impart some particularly advantageous physical properties to the effervescent granules. Plasticizers include, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin. Effervescent formulations 8 Such plasticizers can also be ethylene glycol, 1,2-butylene glycol, 2,3butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All such plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co. The amount of plasticizer used in the effervescent granules will depend upon its composition, physical properties, effect upon the effervescent granules, interaction with other components of the granules and other such reasons. Generally, the plasticizer content will not exceed about 40% wt. of the formulation The term "acidic agent" refers to any compound or material that can serve as a proton source and can react with the alkaline agent of the invention to form a gas causing a solution containing them to effervesce. The acidic agent can have more than one acid dissociation constant, i.e. more than one acid functional group. The acidic agent can be any organic or inorganic acid in the free acid, acid anhydride and acid salt form. An acidic agent which is in solid state at room temperatures and shows pH 4.5 or lower when saturated into water at room temperatures or its acid alkali metal salts (e.g. sodium salt, potassium salt, etc.) can be employed. As the acidic agent for the effervescent granule, a compound which is not harmful to animals including man is desirably employed. The acidic agent can be tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha hydroxy acids, ascorbic acid, amino acids and their alkali hydrogen acid salts. And, even in the case of an acid substance such as phosphoric acid or pyrophosphoric acid or other inorganic acids which is liquid or in liquid state at room temperature, when their acid alkali metal salts are solid at room temperature, those acid alkali metal salts can be employed as acidic agents. Among the above-mentioned acidic agents, those having a relatively large acid dissociation constant (103 or more) and a small hygroscopicity (critical humidity at 30 oC. is 40% RH or more) are preferably employed. It is preferred if the acidic agent can form a eutectic mixture with a binder. Because these acids are directly ingested, their overall solubility in Effervescent formulations 9 water is less important than it would be if the effervescent granules of the present invention were intended to be dissolved in a glass of water. The term "alkaline agent" means an alkaline compound that releases a gas, or causes a solution to effervesce, when exposed to a proton source such as an acidic agent or water. The alkaline agent can be a carbon dioxide gas precursor, an oxygen gas precursor or a chlorine dioxide gas precursor. When the alkaline agent is a carbon dioxide precursor, compounds such as carbonate, sesquicarbonate and hydrogencarbonate salts (in this specification, carbonate and hydrogencarbonate, or bicarbonate, are generically referred to as carbonate) of potassium, lithium, sodium, calcium, ammonium, or L-lysine carbonate, arginine carbonate, sodium glycine carbonate, sodium amino acid carbonate can be used. When the alkaline agent is an oxygen gas precursor, compounds such as anhydrous sodium perborate, effervescent perborate, sodium perborate monohydrate, sodium percarbonate and sodium dichloroisocyannurate can be used. When the alkaline agent is a chlorine dioxide (ClO2) precursor, compounds such as sodium hypochlorite and calcium hypochlorite can be used. ClO 2 can be used as a chemical sterilizer in cleansing operations. Where the effervescent agent includes two mutually reactive components, such as an acidic agent and an alkaline agent, it is preferred, although not necessary, that both components react completely. Therefore, a ratio of components which provides for equal amounts of reaction equivalents is preferred. For example, if the acid used is diprotic, then either twice the amount of a mono-reactive carbonate alkaline agent or an equal amount of an all-reactive alkaline agent should be used for complete neutralization to be realized. However, in other embodiments of the present invention, the amount of either the acidic agent or the alkaline agent can exceed the amount of the other component. This can be useful to enhance taste and/or performance of a tablet containing an overage of either component. Having an excess of either the acidic agent or alkaline agent in the effervescent granule will generally result in increased rate of effervescence when compared to an effervescent granule having the same amounts, on an equivalent basis, of both agents. Regardless of whether either agent is in excess, the total amount of gas produced by an effervescent granule will not exceed the theoretical amount of gas produced by the agent serving as the limiting reagent. Effervescent formulations 10 It is possible that including a plasticizer in the present effervescent granules will alter its rate of effervescence. Generally, increasing the amount of plasticizer present will increase or prolong the time of effervescence. The rate of effervescence can also be controlled by varying the hydrophilicity or hydrophobicity of the hot-melt extrudable binder. Generally, the more hydrophobic the binder, the slower the rate of effervescence. The solubility and rate of dissolution of a hydrophobic binder are important factors to consider as the level of binder in the effervescent granule is increased. For example, one can prepare an effervescent granule having a rapid rate of effervescence by a water soluble hot-melt extrudable binder such as an electrolyte or nonelectrolyte such as xylitol, which can form a eutectic mixture with an appropriate acidic agent during hot-melt extrusion. Non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin and tragacanth. Disintegrants can comprise up to about 20 weight percent and preferably between about 2 and about 10 percent of the total weight of the composition. Coloring agents can include titanium dioxide, and dyes suitable for food such as those known as F.D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika, etc. The amount of coloring used can range from about 0.1 to about 3.5 weight percent of the total composition. Flavors incorporated in the composition may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors which have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring may depend on a Effervescent formulations 11 number of factors, including the organoleptic effect desired. Flavors may be present in an amount ranging from about 0.5 to about 3.0 by weight based upon the weight of the composition. Particularly preferred flavors are the grape and cherry flavors and citrus flavors such as orange. Lubricant means a material which can reduce the friction arising at the interface of the tablet and the die wall during compression and ejection thereof. Lubricants may also serve to prevent sticking to the punch and, to a lesser extent, the die wall as well. The term "antiadherents" is sometimes used to refer specifically to substances which function during ejection. As used in the present disclosure, however, the term "lubricant" is used generically and includes "antiadherents". Tablet sticking during formation and/or ejection may pose serious production problems such as reduced efficiency, irregularly formed tablets, and non-uniform distribution of intended agents or ingredients to be delivered thereby. These problems are particularly severe with high speed tableting approaches and methods. Lubricants may be intrinsic or extrinsic. A lubricant which is directly applied to the tableting tool surface in the form of a film, as by spraying onto the die cavity and/or punch surfaces, is known as an extrinsic lubricant. Although extrinsic lubricants can provide effective lubrication, their use requires complex application equipment and methods which add cost and reduce productivity. Intrinsic lubricants are incorporated in the material to be tableted. Magnesium, calcium and zinc salts of stearic acid have long been regarded as the most efficient intrinsic lubricants in common use. Concentrations of two percent or less are usually effective. Lubricants can be used in an amount of up to 1.5 weight percent and preferably between about 0.25 and about 1.0 weight percent of the total composition. Intrinsic lubricants pose certain serious difficulties when used in conventional tablets. Many lubricants materially retard the disintegration of non-effervescent tablets. However, the effervescent granules used in the dosage form of the present invention overcome any such retardation. In dissolution of conventional effervescent tablets, the lubricant may cause "scumming" and/or agglomeration. Stearates, for example leave an objectionable "scum" when an effervescent tablet is placed in a glass of Effervescent formulations 12 water. This "scum" reduces the aesthetic appeal of the solution made from an effervescent dosage form. However, because the tablets of the present invention dissolve in the mouth, the solution is never seen by the user. Therefore, the propensity of a lubricant to "scum" is of less importance. Thus, lubricants which can cause dissolution or scumming problems in other dosage forms can be used in dosage forms according to the present invention without material adverse effect. The coating can also be used in conjunction with an effervescence to cause the effervescence to occur at specific areas of the gastrointestinal tract. Examples or coatings used include: cellulose derivatives including cellulose acetate phthalate (CAP); shellac and certain materials sold under the trademark Eudragit.TM. (various grades may be used in specific combinations). Hydroxypropylmethyl cellulose phthallate in a grade that dissolves at pH 5 is the preferred coating material. Precoating materials may also be used. Examples include cellulose derivatives such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose or combinations and certain materials sold under the trademark Eudragit.TM. (Various grades which may be combined). Hydroxypropylmethyl cellulose phthallate in a grade that dissolves at pH 5 is the preferred coating material. Examples of hot-melt extrudable binders which can be used in the effervescent granules include acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC F68, PLURONIC F127), collagen, albumin, gelatin, cellulosics in nonaqueous solvents, and combinations of the above and the like. Other binders include, for example, polypropylene glycol, polyoxyethylenepolypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide and the like. Binders may be used in an amount of up to about 60 weight percent and preferably about 3 to about 8 weight percent of the total composition. All binders used in this invention are hot-melt extrudable. Binders having melting or softening point greater than about 150 oC can be used. Hot-melt extrudable binders having a melting or softening point temperature greater than about 150oC. Will require use of a plasticizer during hot-melt extrusion Effervescent formulations 13 such that the binder melting or softening point temperature will be lowered below 150oC. The binder can be used in any form such as powder, granules, flakes or heat-molten liquid. While the amount of binder to be added can be modified, it is usually present in an amount less than about 10% by weight and preferably in the range of about 3-8% by weight of the granule. Other materials may be used to aid in site specific delivery, and include, for example, sugars, polysaccharides, starches, polymers, etc. These compounds may be included as coatings or as matrix materials and aid in releasing the drug in specific sections of the gastrointestinal tract, thus promoting site-specific delivery. As the therapeutic compound, use can be of synthetic antibacterial agents of hardly water-soluble pyridone-carboxylic acid type such as benofloxacin, nalidixic acid, enoxacin, ofloxacin, amifloxacin, flumequine, tosfloxacin, piromidic acid, pipemidic acid, miloxacin, oxolinic acid, cinoxacin, norfloxacin, ciprofloxacin, pefloxacin, lomefloxacin, enrofloxacin, danofloxacin, binfloxacin, sarafloxacin, ibafloxacin, difloxacin and salts thereof. Other therapeutic compounds which can be formulated along with the effervescent granules into an effervescent solid dosage form include penicillin, tetracycline, erythromycin, cephalosporins and other antibiotics. Other ingredients or techniques may preferably be used with the present dosage forms to enhance the absorption of the pharmaceutical ingredient, to improve the disintegration profile, and/or to improve the organoleptic properties of the material and the like. These include, but are not limited to, the use of additional chemical penetration enhancers, which are referred to herein as noneffervescent penetration enhancers; absorption of the drug onto fine particles to promote absorption by specialized cells within the gastrointestinal tract (such as the M cells of Peyer's patches); ion pairing or complexation; and the use of lipid and/or surfactant drug carriers. The selected enhancement technique is preferably related to the route of drug absorption, i.e., paracellular or transcellular. A bioadhesive polymer may preferably be included in the drug delivery device to increase the contact time between the dosage form and the mucosa of the most efficiently absorbing section of the gastrointestinal tract. Examples of known bioadhesives used include: carbopol (various grades), sodium carboxy methylcellulose, methylcellulose, polycarbophil (Noveon Effervescent formulations 14 AA-1), hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, and sodium hyaluronate. Disintegration agents may also be employed to aid in ispersion of the drug in the gastrointestinal tract. Disintegration agents include any pharmaceutically acceptable effervescent agent. In addition to the effervescence-producing disintegration agents, a dosage form according to the present invention may include suitable noneffervescent disintegration agents. Nonlimiting examples of disintegration agents include: microcrystalline cellulose, croscarmelose sodium, crospovidone, starches and modified starches. Propylglycol or glycerin as a binder is only needed in small amounts to achieve the wanted mechanical characteristics of the effervescent tablets and to keep the wanted dissolving attitude. Handling the binder propylglycol or glycerin is also very simple. It can be mixed with the active substance or with the combination of active substances and possibly with the carrier without destroying their tipping ability and thus their simple ability to be mixed with the sherbets. At the same time there is no danger that the binder could cause a loss of carbon dioxide of the sherbets. Effervescent formulations 15 Chapter-3 TYPES OF EFFERVESCENT FORMULATIONS Effervescent formulations 16 (1)Effervescent drug delivery system for oral administration(A5) The pharmaceutical compositions of the orally administerable medicaments in combination with an effervescent as a penetration enhancer for influencing absorption of a drug in the gastrointestinal tract. Effervescence leads to an increase in the rate and/or the extent of absorption of the drugs that are known or suspected of having poor bioavailability. It is believed that such increase can rise from one or all of the following mechanisms: 1. reducing the thickness and/or the viscosity of the mucus layer which is present adjacent to the gastrointestinal mucosa; 2. alteration of the tight junctions between cells, thus promoting absorption through the paracellular route; 3. inducing a change in the cell membrane structure, thus promoting transcellular absorption; 4. increasing the hydrophobic environment within the cellular membrane. The present dosage forms include an amount of effervescent agent effective to aid in penetration of the drug in the gastrointestinal tract, aid in penetration of the drug across the gastrointestinal mucosa. The formulations may be distinguished from other effervescent formulation that are enteric coated on the basis of the amount of effervescent material that they contain. Prior formulations contain approximately half to a quarter as much bicarbonate as drug on a weight basis (together with a proportionate amount of acid). In these cases, the small amount of effervescent couple serves only to rapidly disintegrate the tablet. Preferably, the effervescent is provided in an amount of between about 5% and about 95% by weight, based on the weight of the finished tablet, and more preferably in an amount of between about 30 to about 60%. However, the amount of effervescent agent must be optimized for each specific drug. For drugs that are weekly acidic or weakly basic, the pH of the aqueous environment can influence the relative concentrations of the ionized and the unionized forms of the drug present in solution, according to the Henderson- Effervescent formulations 17 Hasselbach equation. The pH of solutions in which an effervescent couple with equimolar amounts of base and acid has dissolved is slightly acidic due to the evolution of CO2. While it is impractical and may not be desirable to change the pH of the contents of the small intestine. Thus, the relative proportions of the ionized and unionized forms of the drug may be controlled. The materials used to promote site-specific absorption may preferably be included as coatings and/or as matrix materials. If a coating is used, it may be applied to the entire dosage form or to the individual particles of which it consists. Coating materials may be used to prevent the release of the active agent before the dosage form reaches the site of more efficient absorption. (2) Multi-Sensory Technologies for Today’s Effervescent Bath and Shower Products (A9) The fizzing sound of the effervescent reaction, the burst of fragrance delivered directly under the bather’s nose, the dispersion of color throughout the bath water, and the tactile sensations of emollients both in the water and on the skin after the bath helps create high levels of consumer satisfaction. a. Multi-Sensory Stimulation One of the beauties of effervescent products is that they are able to stimulate up to four senses — smell, sight, touch and sound — at one time. Taste can certainly also be stimulated, but that sense is usually beyond the scope of our industry. b. Olfactory Stimuli All product developers and marketers have learned that fragrance selection can make or break a product. In the case of bath products, it can make the bath water smell nice; it can scent the entire room; it can leave a lingering scent on the skin; and, in the case of aromatherapy fragrances, it can provide specific effects such as calming or invigorating benefits. Granules act a lot like tablets in that they are dense and sink while they are effervescing. At most, they will last on the bottom for 30 or 40 seconds. This means that the fragrance release from granules will be very quick. Another important point about fragrance release from granules is that this form allows consumers to easily measure out the amount of product being used. Effervescent formulations 18 As you see, the molded product has a density less than 1, so it will float. It also has a high dissolution rate, greater than a gram per second. c. Visual Stimuli A solution to this is water-soluble glitter. This material is available in many colors. The colored flecks tend to float on the foam’s surface, giving it a speckled appearance. As they dissolve, their color spreads out a bit giving a “melting” look. It imparts a sparkly look to the product and does not cause a mess in the tub. d. Tactile Stimuli When it comes to bath products, the sense of touch focuses on two areas: the feel of the water and the feel of the skin, both during and after product use. As one can imagine, emollients, humectants and polymers are frequently added to effervescent bathing products. Emollients include vegetable oils such as sunflower oil, jojoba oil and almond oil and esters such as IPM and the various benzoate esters. Humectant polymers such as PEG and polyquaternium-10 have been used successfully. Materials that cause skin tingling sensations are also interesting. Menthol is the most common of these materials. (3) Effervescent granules with delayed effervescent effect (A2) The effervescent granules with delayed effervescent effect consist of at least one acid component and one component evolving gas under the action of acid, as well as of active substances, fragrances, plant extracts, vitamins, minerals etc. admixed as needed, the particles of the acid component being coated with--preferably 1 to 30% by weight of--at least one carbonate compound--possibly including a partial reaction--and/or a hydrocolloid. The gas-evolving component consists of alkali hydrogen carbonate, alkali carbonate, and/or alkaline-earth carbonate particles which are coated with at least one further substance, particularly with a melt of polyethylene glycol 6000. The particles preferably have a grain size above 0.2 mm. It is described in a few examples that for the purposes of improved stability, not only the acid component but also the carbonate component of the effervescent mix be coated with very slight amounts of polyethylene glycol and HPMC (hydroxypropylmethylcellulose). This again would lead to a delay that is highly insufficient for the purposes of the present invention. Effervescent formulations 19 For active substances such as paracetamol, lactulose, N-Acetylcysteine, ranitidine, plant extracts, multivitamins and/or trace elements, for instance, an organic acid treated with 1 to 10% by weight of calcium carbonate can serve as the acid component to which the alkali hydrogen carbonates, alkali carbonates, and/or alkaline-earth carbonates that have been delayed in their effervescent effect are then added as described above. This yields, on one hand the desired, delayed effervescent effect and on the other hand the intended stability. The sachets are preferably made in a width of 10 to 30 mm and a length of 7 to 20 cm. The amount of effervescent granules that is required depends on the active substances that should be incorporated. The weight of a sachet may for instance be 1 g if only small amounts of active substances are to be dissolved. In the case of effervescent mineral mix sachets which should contain a given amount, for instance, of calcium or magnesium, it will be necessary to use the appropriate amount of citric acid in order to set the desired pH value, so that the effervescent mineral mix sachets may weigh as much as 4-5 g. (4) EFFERVESCENT PLANT EXTRACT (B11) FORMULATION CONTAINING The effervescent formulation elation in the form of granules or of a tablet contains, in addition to the effervescent base, at least one watersoluble or at least suspendable plant extract whose particles are coated with at least one oily, fatty or waxy substance. At least one emulsifier and/or at least one antifoam may be present in the coating and/or as a further component of the mixture, in particular applied as a further component of the mixture to a pharmaceutically permissible filler as carrier. The individual phases are prepared by a procedure in which the plant extract or the filler is heated--preferably in a granulator, in particular in a vacuum granulator--and wet or mixed with a melt or solution of the oily, fatty or waxy substance or at least one emulsifier and/or at least one antifoam and then dried-preferably in a vacuum--and sieved to the desired particle size. By means of conventional measures, such as, for example, by the addition of antifoams, such as, for example, simethicone or dimethicone, or by the application of the antifoam to the dry plant extract itself it was possible to achieve only a slight improvement by reducing the foaming and-- Effervescent formulations 20 associated with this--also only a slight reduction in the dissolution time of the effervescent tablet. Granulation of the plant extracts with the object of increasing the size of the particles and reducing their number within the effervescent tablet in order thus to prevent the formation of a concentrated solution around the plant extract particles and effervescent particles during dissolution of the tablet in water also did not achieve the object since precisely these granulated particles then agglomerated to an extreme extent and exhibited undesired and by no means rapid dissolution properties. In order, if required, to impart better flowability to the extracts treated with fatty, oily or waxy substances, it is possible to add a fine filler which adheres to the fatty surface and thus prevents the agglomeration of the active ingredient phase. All conventional pharmaceutical tablet fillers suitable for this purpose, such as sugar alcohols, mannitol, sorbitol and furthermore maltodextrin, pulverized sucrose, pulverized lactose, fructose, glucose, etc. These fillers can be introduced directly into the plant extract phase (cf. Example 1), or the plant extract phase is homogeneously mixed with a filler after the preparation and then mixed with the effervescent granules containing the remaining ingredients, flavors, etc. For example, mannitol or sorbitol takes up a part of the oily, fatty or waxy substance and also the emulsifier and prevents the agglomeration of the coated particles of the plant extract phase. The preparation of the plant extract phase can be carried out as follows: the freely soluble plant extracts are preheated to 45 to 60 oC; a solution or melt of the fatty, oily or waxy substances--preferably with one or more emulsifiers--is applied. This solution is uniformly distributed while stirring, and the solvent is then evaporated, preferably by means of a vacuum before drying, it is also possible to add fillers to it. All conventional effervescent components may be used for the preparation of the effervescent base or of the effervescent granules, the acid component preferably consisting of citric acid, tartaric acid, malic acid or of the salts thereof, such as, for example, monosodium citrate or monosodium tartrate. The base fraction of the effervescent base expediently consists of CO2 -eliminating alkali metal bicarbonates or carbonates, such as sodium and/or potassium bicarbonate or carbonate, and partly, but not exclusively, Effervescent formulations 21 of alkaline earth metal carbonates, such as calcium carbonate and/or magnesium carbonate. In particular, sweeteners, such as sugar, sodium cyclamate, saccharin sodium, aspartame and acesulfame, and flavors or other galenical fillers, such as sugar alcohols, e.g. mannitol and sorbitol, and also maltodextrin, optionally sucrose, fructose, lactose, etc., may be used as additives and excipients. (5) Multiple unit effervescent dosage forms comprising proton pump inhibitor (B9,B12,B16) A new tableted multiple unit effervescent dosage form containing an acid susceptible proton pump inhibitor in the form of the racemate, an alkaline salt thereof or one of its single enantiomers or an alkaline salt thereof, and effervescent tablet constituents. The proton pump inhibitor is preferably omeprazole or an alkaline salt thereof, or S-omeprazole or an alkaline salt thereof. The Applicant has now surprisingly found that effervescent tablets according to the present invention comprising enteric coated units of an acidic susceptible proton pump inhibitor can be manufactured by compressing said units into tablets without significantly affecting the properties of the enteric coating. One object is to provide a tableted multiple unit effervescent dosage form comprising an acid susceptible proton pump inhibitor, or an alkaline salt thereof or one of its single enantiomers or an alkaline salt thereof, in which the active substance is in the form of enteric coating layered units compressed together with effervescent tablet excipients into such an effervescent tablet. The enteric coating layer(s) covering the individual units of active substance has properties such that the compression of the units into a tablet does not significantly affect the acid resistance of the enteric coated units. The tabletted multiple unit effervescent dosage form is especially suitable for patients with swallowing disorders and in pediatrics. Effervescent formulations 22 (6) Pharmaceutical compositions containing an effervescent acid-base couple (B2,B14,B19) A pharmaceutical composition in the form of effervescent tablets comprising an active ingredient and an effervescent blend, wherein the effervescent blend comprises an acidic component and sodium glycine carbonate as alkaline components. Preferred acid components are fumaric acid, maleic acid, and their salts. Tablets are prepared in normal thermohygrometric conditions and with standard tabletting equipment. The acid and the alkali are the essential components which provide the effervescence and the disintegration of the tablet when is contacted with water. Sodium bicarbonate is one of the most used carbonate because it is very soluble and of low cost. Alternatively, modified sodium bicarbonate can be used, obtained by heating common sodium bicarbonate in order to convert the surface of its particles to sodium carbonate so increasing its stability. 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. Conventional excipients such as diluents, ligands, bufferings, sweeteners, flavourings, colourings, solubilizers, disintegrants, wetting agents and other excipients of common use may be added to the formulation. The instability of effervescent tablets, their tendency to absorb moisture and lose reactivity is generally known. Due to this instability in the presence of water, conventional wet granulation and the subsequent granulate compression are very hardly applicable. Alternatively, techniques of anhydrous granulation, in the absence of aqueous phases, have been applied using volatile organic solvents like ethanol. However such techniques requires special manufacturing environments with strictly controlled relative humidity conditions (normally lower than 20%) and with explosion proof equipments. The use of sodium glycine carbonate in effervescent formulations is described in patent applications and scientific literature regarding Effervescent formulations 23 formulations containing hydrated amoxycillin (PCT WO 9115197), isosorbide-5-mononitrate (DE 4416769) and enzymes (FR 2305194). The acidic component in these formulations is constituted of citric, tartaric, malic or adipic acid and the manufacturing process foresees steps of slugging, milling slugs, blending and compressing or the use of anhydrous excipients or, also, an external lubrication of the machine is performed. One of the preferred acids is fumaric acid which may be present in the form of salt such as mono sodium or potassium fumarate. Another preferred acid is maleic acid eventually present as a salt. The choice of the acid is made according to the characteristics of the active ingredient. The formulation may comprise other excipients like: a lubricant selected from PEG higher than 4000 and preferably PEG 6000 sodium benzoate, sodium and potassium fumarate, leucine, alanine; Other advantages of the composition are the low content of sodium ions, due to the employ of sodium glycine carbonate, with respect to other sodium carbonates and the less fizzy effervescence, more pleasant to the patient. Moreover the composition of the invention, because of its small size, light effervescence and rapid disintegration, can also be prepared as fast dissolving or sucking in the mouth. Infact, as introduced in the mouth, when in contact with saliva, the tablet disintegrates and rapidly forms a solution or an aqueous dispersion easily swallowable (7) A solid pharmaceutical dosage form adapted for direct oral administration. (A2) Formulations incorporating the effervescent granules according to one aspect of the present invention can further include one or more additional adjuvants and/or active ingredients which can be chosen from those known in the art including flavors, diluents, colors, binders, filler, surfactant, disintegrant, stabilizer, compaction vehicles, and non-effervescent disintegrants. The effervescent granules themselves do not generally include therapeutic compounds or other active ingredients. The formulation provides a thermal heat process for preparing an effervescent granule comprising a pharmacologically active agent. In some embodiments, the method comprises combining an acidic agent, a Effervescent formulations 24 pharmacologically active agent, a hot-melt extrudable binder which can combine with said acidic agent, a pharmacologically active agent, and a plasticizer. The inclusion of a plasticizer in the formulation is optional. The acidic agent, alkaline agent, hot-melt extrudable binder and the optional plasticizer may then be dry blended to form a mixture. The mixture may then be hot-melt extruded to form a eutectic mixture. The effervescent mixture is then hot-melt extruded to form effervescent granules having a controllable rate of effervescence. The mixture is then screened and blended after which said mixture is subjected to compression until tablet form is achieved. The effervescent granules of this formulation can be in the state of powder or fine particles to increase the dissolution rate, and preferably a particle size such that 90% or more passes a 16 mesh (1,000 mu.) screen, and more preferably a particle size such that more than 90% passes a 18 mesh (850 mu m) screen. Generally, the larger the effervescent granule, the longer it will take to completely disintegrate. This is particularly true when there are low levels of effervescent couple present in the granules. By controlling the relative ratio of acidic agent: alkaline agent, the effervescent granules can be used to regulate the pH of their environment. Thus, the present granules can be used to regulate the pH of body cavities such as the mouth, rectum or vagina. When the solubility of the active ingredient increases at the acid side, the pH of the solution is lowered by adding the acidic agent in an amount more than equivalent to the alkaline agent. When the solubility of the active ingredient increases at the basic side, the pH of the solution is raised by adding the alkaline agent in an amount more than equivalent to the acidic agent. In either case, the pH near the acidic agent immediately after the dissolution is low, while the pH near an alkaline agent is high. In a case where the solubility of an active ingredient does not depend on pH, the ratio of an acidic agent and an alkaline agent can be optionally selected. An acidic agent and a carbon dioxide precursor are used respectively in a powdery or granular state, usually 90% or more of them being capable of passing through a 100 mesh (150 .mu.) screen. The particle size of the binder used will usually be about 100 mesh (150 .mu.). In any case, it is generally acceptable that the additional amount of either component can remain unreacted. Effervescent formulations 25 Rate of effervescence of the effervescent granule can be controlled by: (1) varying the relative amounts of the components; (2) optionally forming a eutectic mixture between the acidic agent and hot-melt extrudable binder; (3) varying acidic agent: alkaline agent ratio; (4) hydrophilicity vs. hydrophobicity of hot-melt extrudable binder; (5) varying the effervescent couple: hot-melt extrudable binder ratio; and (6) varying the amount of plasticizer present. It should also be noted that when the effervescent granules are included in a tablet form, The hardness of the tablet can be controlled by the pressure used on the punches to compress the effervescent granule-containing formulation and by the amount of effervescent granules, concentration of effervescent couple, and amounts of drug and other excipients present in the tablet composition. The effervescent granules of the formulation can be included in formulations containing active ingredients and particularly pharmacologically active agents. When the effervescent granules are formulated into tablets, such tablets can also contain coloring agents, noneffervescent disintegrants, lubricants and the like. The effervescent granules of the invention can be formulated in a variety of forms such as a tablet, capsule, suspension, reconstitutable powder and suppository. The mass of each such pharmaceutical tablet generally should be less than about 2.0 g and preferably less than about 0.5 g. The tablet may include surface markings, cuttings, grooves, letters and or numerals for the purpose of decoration and/or identification. Preferably, the tablet is a compressed tablet. It includes effervescent granules, together with a therapeutic compound and other components. The size of the tablet is also dependent upon the amount of material used. Circular, disk-like tablets desirably have diameters of about 11/16 inch or less, whereas elongated tablets desirably have a long dimension of about 7/8 inch or less. The therapeutic compounds which can be formulated in suitable dosage forms along with the effervescent granules of the invention also include antibacterial substances, antihistamines and decongestants, antiinflammatories, antiparasitics, antivirals, anxiolytic agents, morphine derivatives, serotonin agonists, levorotatory isomers of thyroxine, cholesterol lowering agents, alpha adrenergic blocking agents, local anesthetics, antifungal, amoebicidal, or trichomonocidal agents, analgesics, Effervescent formulations 26 antiarthritics, antiasthmatics, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antineoplastics, antipsychotics, antihypertensives, phenanthrene derivatives, antidiarrheal agents, diuretics, and muscle relaxants. Effervescent formulations 27 Chapter-4 MANUFACTURING TECHNIQUES Effervescent formulations 28 General methods of preparing effervescent granules(A3,A5,B5,B6,B18) There are three methods of preparation for the effervescent granules viz. wet granulation, dry granulation and fusion. The fusion method is the preferred method of preparation of effervescent granules although other two methods can also be used. 1)Wet granulation This is the oldest method of granule preparation, although it suffers from problems of reproducibility. The individual steps in the wet granulation process of tablet preparation include milling and sieving of the ingredients, dry powder mixing, wet massing, granulation, drying and final grinding. Wet massing is the most important step in the wet granulation process. In this step, the granulating agent is added to the powder mixture. At the end of wet massing, the damp powder will pack to the consistency of a dry snow ball and crumble into fragments, not into powder, under the finger pressure. The granulating agent can be water added to solvents such as alcohol, propylene glycol or glycerin which act as moistening agents. In the granulation step, the granules themselves are formed by forcing the moistened powder through a screen in an oscillating granulator, hammer mill or multi mill. The resulting granulated material is dried on trays in hot air circulation oven or preferably in fluidized bed dryer. Particles may agglomerate and form a lump during oven drying. Therefore, dry screening is necessary. The screen used for sizing should have slightly larger opening than that used to prepare the original granules if excessive powder is not to be formed and granulation lost during sizing. 2) Dry granulation: Typically, the process involves compressing a powder mixture into a rough tablet or ‘slug’ on a heavy duty rotary tablet press. The slugs are then broken up into granular particles by a grinding operation, usually by passage through an oscillating granulator the individual steps include mixing of the powders, compression (slugging) and grinding. Effervescent formulations 29 3) Fusion method: The most important method for preparing the effervescent granules is the fusion method. In this method, the compressing step of dry granulation process is eliminated. Instead, the powders are heated in an oven or using other suitable source of heat. The particular advantage of this method is that it uses the water of crystallization present in citric acid as binding agent. Just before mixing the powders, the citric acid crystals are powdered and then mixed with the other powders (previously passed through sieve #60) to ensure uniformity of the mixture. The sieves and the mixing equipment should be made of stainless steel or other material resistant to the effects of acids. The mixing of the powders is carried out as rapidly as possible, in an environment of low humidity to avoid the absorption of moisture from the air by the chemicals and a premature chemical reaction. After mixing, the blend is placed on a plate of glass or suitable dish in an oven previously heated to 93-104o C. The blend is turned during the process. The heat causes the release of the water of crystallization form the citric acid. The released water then dissolves a portion of the powder mixture and causes the chemical reaction to start, with the consequent release of some carbon dioxide. This caused the softened mass of powder to become somewhat spongy, and when of the proper consistency, similar to bread dough, the mass is removed from the oven and rubbed through an acid resistant sieve to produce granules of desired size. When all the mass has passed through the sieve, the granules are immediately dried at a temperature not exceeding 54o C and immediately transferred to containers which are tightly sealed. According to a method of producing effervescent tablets which consist of at least one active substance or a combination of active substances, of at least one binder, possibly of carriers as sweeteners, flavours, colourings, scents, softeners and bleaches, and of sherbets, wherein propylglycol or glycerin is used as a binder, wherein the active substance or the combination of active substances and possibly the carriers are mixed with the binder, wherein the sherbets are added to this mixture in an air-conditioned room and wherein the mixture including the sherbets is formed into tablets. Further, there is provided an effervescent tablet consisting of at least one active substance or one combination of active substances, of at least one binder, possibly of carriers as sweeteners, flavours, colourings, scents, Effervescent formulations 30 softeners and bleaches, and of sherbets, which comprise propylglycol or glycerin as a binder. The active substances to be used in the method and for the effervescent tablet according to the invention are not limited at all. They include, for example, calcium, magnesium, potassium, iron-II-gluconate, vitamin E, vitamin C, paracetamol, cimetidine, piracetam, acetylsalicyl acid, ambroxol, indomethacin and acetylcysteine or any other active substance. The combination of substances to be used includes for example multi vitamins, multi vitamins with minerals, beta carotin with vitamin E and/or vitamin C, vitamin C with minerals, anionic and/or not-ionic tensides or other washing active substances. Also all combinations of active substances which can be orally taken in solving form can be used. Those skilled in the art also know possible compositions of sherbets for the effervescent tablets. These sherbets consist of a base component and an acid component wherein especially the acid component also can be used as an active substance. One known example thereof is ascorbic acid (vitamin C). Usually, as base component sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and calcium carbonate are used. As an acid component besides ascorbic acid mono sodium citrate, wine acid and/or citric acid can be considered. Advantageously, the method according to the invention includes intensely mixing the active substance or the combination of active substances and possibly carriers with the binder before adding the sherbets, and directly forming a mixture including the sherbets into tablets. Advantageously, in case of both the method and the effervescent tablet according to the invention the amount of binder is in the range of 0.004 to 2.5% per weight of the whole effervescent tablets, especially in the range of 0.004 to 1.5% per weight of the whole effervescent tablets, and more especially in the range of 0.01 to 1.0% per weight of the whole effervescent tablets. Further, the amount of sherbets advantageously is in the range of 58 to 93% per weight of the whole effervescent tablets, and especially in the range of 70 to 90% per weight of the whole effervescent tablets. Processing, manufacturing, mixing and packaging of effervescent product should be carried out under humidity controlled conditions. It is Effervescent formulations 31 important to note that complete segregation of a humidity-controlled area is important. Moisture will move against air currents and temperature gradients to achieve equilibrium with surrounding areas. The use of access rooms to enter and exit main environmental areas is important to minimize transfer of moisture from uncontrolled areas to controlled areas. Another area of concern during the production of effervescent powders is the processing or blending of the raw materials. Conventional blending equipment can be utilized for effervescent powders provided the equipment could be operated in very low humidity areas. All equipment should be well grounded, and capable of being dried absolutely after washdown operations. Any traces of moisture in the equipment will give erratic product results and most likely result in lost batches of product. With the blending of an effervescent product mixture comes the issue of the product stability. Controls must be established to insure that the effervescent powder is consistent in regards to particle size and moisture level. Once the effervescent powder is consistent, storage studies should be done on the effervescent powder product prior to placing it in its final protective package to ascertain the handling and storage conditions, which are acceptable. 4) Hot Melt Extrusion In one aspect of this hot-melt extrusion method is described herein. An acidic agent and an alkaline agent, preferably a carbon dioxide precursor, and a hot-melt extrudable binder, all in a dry state, are placed into a mixer or hopper and agitated (blended) until thoroughly mixed to form an effervescent mixture. The effervescent mixture is then hot-melt extruded at a rate and temperature sufficient to melt or soften the binder, to minimize degradation of the components and to form an extrudant which is subsequently ground or chopped into effervescent granules. An acidic agent and a hot-melt extrudable binder, capable of forming a eutectic mixture with the acidic agent, are placed into a mixer and agitated until thoroughly mixed to form a mixture which is hot-melt extruded and ground to form a granular eutectic mixture. An alkaline agent, such as a carbon dioxide precursor, is added to the granular eutectic mixture and thoroughly blended to form an effervescent mixture. The effervescent mixture is then hot-melt extruded at a rate and temperature sufficient to melt or soften the eutectic mixture, to minimize degradation of the components, e.g. degradation of NaHCO3 to Na2 CO3, and to form an extrudant which is subsequently ground or chopped into effervescent granules. Effervescent formulations 32 The hot-melt extrusion process preferably employed is conducted at an elevated temperature, i.e. the heating zone(s) of the extruder is above room temperature (about 20oC.). It is important to select an operating temperature range that will minimize the degradation or decomposition of the effervescent composition during processing. The operating temperature range is generally in the range of from about 50oC. to about 150oC. as determined by the setting for the extruder heating zone(s). The temperature of the mixture being hot-melt extruded will not exceed 150oC. and preferably will not exceed 120oC. The hot-melt extrusion is conducted employing a dry granular or powdered feed. Conversely, one can prepare an effervescent granule having a slow rate of effervescence by employing a poorly water soluble hot-melt extrudable binder such as hydrogenated castor oil, lipids, wax, cholesterol, fatty acids or mono-, di- or triglycerides. Additionally, an effervescent granule having an intermediate rate of effervescence can be prepared by employing a binder, or combination of binders, such as those just discussed and optionally a surface active agent or cosolvent that improves wetting or disintegration of the effervescent granule. Effervescent formulations 33 Chapter-5 PACKAGING OF EFFERVESCENT FORMULATION Effervescent formulations 34 PACKAGING (A6,B7) Processing and environmental conditions all having to do with the stability of effervescent products. Finally the most critical factor that has to do with the stability of an effervescent product is the packaging. In the U.S., effervescent powders are most frequently strip wrapped in individual pouches arranged in conveniently sized strips and stacked in a paperboard box. Each dose of effervescent is hermetically sealed in its own container and is not exposed to the atmosphere until the time of use. The most commonly used materials for pouches are heat-sealable, aluminum foil laminates. Aluminum foil laminates are comprised of three layers, a paper outer layer, middle foil layer and a heat sealable inner polyethylene layer the laminates create a flexible, absolute barrier to gases, water vapor, and light. It is nontoxic and immune to microbiological attack. It has excellent heat conductivity, thereby making it an excellent choice for heat-sealing, strippackaging operations. Protection of an effervescent tablet: NSI wanted new effervescent tablets to stand out from the crowd. A PP tube with a metallized label and desiccant cap are just the ticket. Effervescent tablets carry an active ingredient that is released when the tablet is dissolved in water. The allure of this delivery system is two-fold. First, some people don't like to or are physically unable to swallow a pill; if the pill's contents can be incorporated in a dissolvable tablet, swallowing is no more difficult than quaffing a glass of water. Second, active ingredients dissolved in water enter the bloodstream almost immediately. NSI will market its effervescent products under two labels: Vita Fizz(TM) and Effer Power(TM). Each label comprises the same five items: children's vitamin, multi-vitamin, calcium, vitamin C and Hangover Relief(TM). While the Vita Fizz label is for distribution to U.S. health food stores, Effer Power(TM) is aimed at mass merchandisers. Hangover Relief is packaged in a 10-count and the other four products in 20-count tubes. Advances in packaging For the sake of improving safety in handling and use, special package types have been designed for some formulations which have been used for many years. These new package types include water-soluble bags and Effervescent formulations 35 squeeze bottles. Some of the new packaging, e.g. water-soluble films, are somewhat more expensive than conventional packaging materials, but the end users are encouraged to value their health. Squeeze bottle: These are calibrated plastic packages which are used to store liquid formulations. When the bottle is squeezed, a known volume of the formulation is released. This technique improves the accuracy of dosing the liquid and reduces the danger of accidental spillage, and hence reduces the risk of environmental pollution. The technique also improves safety in handling, particularly during measurements, since direct contact is avoided as much as possible. Water-soluble bags: This involves the packaging of wettable powders in special bags made of polyvinyl alcohol and polyesters. Before application, the bag together with the component powder are dissolved in water during preparation of the spray solution. Advantages: - Since the bag dissolves completely and the remaining packaging material is not a hazardous waste, this technique is environmentally acceptable. - The technique maintains precise dosage without spills - Since there is no direct contact with the pesticide, user exposure hazards are minimized. Conclusion: As was pointed out, improved technology in the development of new formulations makes it possible to avoid environmental contamination and to improve safety in the handling and use of pesticides. Since some of these formulations are still new, they have not fully penetrated the market in developing countries. However, regulatory pressure from environmental authorities and consumers, including stringent registration requirements, are expected to play a major role in the adoption and registration of safer, more revolutionary types of pesticide formulations. It is therefore advised that conventional formulations be replaced by the newer and safer types of formulations discussed above. This switch would have significant safety advantages both for the user and for the environment. Effervescent formulations 36 Chapter-6 MARKET PRODUCTS AVAILABLE Effervescent formulations 37 Sr. No. Name of product Active ingredient Manufacturer Ref. 1 Aspro (GB-A-1287475) Aspirin Nicholus B13 2 Biompi(GB-A-1300998) Ampicilin Biochemie B14 3 Amorcent(EP-0281200-A1) Amoxicillin Gist-brocades B13 4 Citracal liqitab Ca-Citrate Revital B3 5 Suprum forte Vit-B (complex) Revital B3 6 Ferrotine Vit-C,Iron Revital B3 7 Citrapar Paracetamol Revital B3 8 Effervit Glucosamine Wampole’s B4 9 Gluceffer tab Glucosamine Bajamar chem.. B18 co. 10 Glucosamine effervescent Glucosamine tablets 11 Sulphate Potassium Airborn B18 labs,Essex Chloride Pottasium Effervescent 12 Tower Airborn B4 Airborn B4 Airborn B4 Chloride effervescent Vit-B(complex) Dietory supplement tablets 13 Aliborange Vit-C Vit-C, Effervescent tablets 14 Revitalvit Calcium Tablet Vit-D&K Airborn B4 15 Osteomax tablet Mg&Vit-D Airborn B4 16 Solpadol Paracetamol & Sanofi- B3 Effervescent formulations 17 Redoxone 38 Codeine Synthelabo Vit-C&Zinc Sanofi- B3 Synthelabo 18 LiFizz Multivitamin tab Multivitamins Sipharm B4 19 Remedeine Paracetamol&Di Sanofi- B3 hydrocodeine Synthelabo tartrate 20 Thymes blossom Efferbath - - - - - - Auravita B21 Yerbamate& Auravita B21 tablets 21 Zotrime tab Guarana 22 jan-e-vries powder Yerbamate Auravita B21 23 ZanFSI Clear Creatine Creatine ZanFSI B1 24 ProEndorphin tab Phenylalanine Alka-seltzer B1 25 Celltech Creatinine Creatinine Qfac.Comac B2 26 Chlorpheniramine Chlorphenirami Alka-seltzer B1 effervescent tablets ne 27 Nardil® Penelzine Vitar B20 28 Parnate Isocarboxide Vitar B20 29 Carbex Selegiline Vitar B20 30 Instachlor Chlorine Vitar B20 Effervescent formulations 39 Chapter-7 RESEARCH Effervescent formulations 40 (A)Floating or pulsatile drug delivery systems based on coated effervescent cores (A8) The objective of this study was to develop and evaluate floating and pulsatile drug delivery systems based on a reservoir system consisting of a drug-containing effervescent core and a polymeric coating. Preliminary studies identified important core and coating properties for the two systems. The mechanical properties (puncture strength and elongation) of acrylic (Eudragit® RS, RL or NE) and cellulosic (cellulose acetate, ethyl cellulose) polymers, which primarily determined the type of delivery system, were characterized with a puncture test in the dry and wet state. For the floating system, a polymer coating with a high elongation value and high water- and low CO2 permeabilities was selected in order to initiate the effervescent reaction and the floating process rapidly, while for the pulsatile DDS, a weak, semipermeable film, which ruptured after a certain lag time was best (ethyl cellulose/dibutyl sebacate 20%, w/w). With the floating system, the polymeric coating did not retard the drug release. A polymer (cellulose acetate or hydroxypropylmethylcellulose) was added to the core to control the drug release. The time to flotation could be controlled by the composition (type of filler, concentration of effervescent agents) and hardness of the tablet core and the composition (type of polymer and plasticizer) and thickness of the coating. For the pulsatile system, a quick releasing core was formulated in order to obtain a rapid drug release after the rupture of the polymer coating. Pulsatile drug delivery systems are characterized by two release phases, a The cores for the pulsatile system were coated with an ethanolic ethyl cellulose (10%, w/v) solution, 20% (w/w) dibutyl sebacate based on the polymer weight) in a Glatt lab-coater. The coating conditions were: air inlet temperature, 40– 45°C; outlet temperature, 26–30°C; air flow, 110 m3/h; pan speed, 10 rpm; nozzle diameter, 1.2 mm; atomising air pressure, 1.1 bar; spray rate, 40 g/min). Polymer films were prepared by casting the organic polymer solution onto Teflon frames mounted on levelled glass plates (area of casting, 12.0×12.0 cm2; standard formulation, polymer, 6 g; plasticizer, 1.2 g (20%, w/w, based on the polymer); solvent, 40 ml (ethanol for Eudragit® RS and RL and ethyl cellulose and acetone for cellulose acetate and lyophilised Eudragit® NE). The films were dried for 48 h at room temperature, then peeled from the Teflon plate and stored at room temperature at 52% RH for Effervescent formulations 41 48 h and cut into pieces of 4×4 cm2. The exact film thickness was measured at five points with a thickness gauge Minitest 600 (Erichsen, Hemer, Germany). For the preparation of wet films, the dry films were put into bags (7×7 cm2, made from a 40-mesh plastic screen with three sides sewn closed) to avoid sticking and folding of the films in the medium. The bags with the films were then placed in 0.1 N HCl and shaken in a horizontal shaker (GFL® 3033, Gesellschaft für Labortechnik, Burgwedel, Germany; 37°C, 70 rpm, 24 h). In another modification, HPMC was incorporated within the effervescent drug core (single-layer system). The generated CO2 was not separated from the HPMC layer as with the two-layer system, but was entrapped in the HPMC matrix and could therefore not escape from the gelled matrix. The time to flotation of these tablets was slightly higher than with the two-layer system, which could be explained by a slower CO2 formation because of the presence of the effervescent agents within the HPMC matrix. Without HPMC, the drug was released completely within 30 min, while the inclusion of 10 or 20% (w/w) HPMC significantly retarded the drug release. At a 10% HPMC content in the one-layer tablet, the release was slightly faster without effervescent agents in the formulation. The generated gas within the gelled HPMC matrix probably formed an additional diffusion barrier for the drug. As expected, even rupturing of the coating had no influence on the drug release, because the polymeric coating was not a release-controlling barrier. The polymeric film prevented the disintegration of the HPMC tablet in the beginning and ensured gel formation, which was a prerequisite for the retarding effect and for the entrapment of the generated gas. Uncoated tablets rapidly disintegrated prior to gel formation because of the disintegrating effect of the effervescent agents. With increasing coating level, the floating started later due to the delayed water penetration through the thicker coating. (B) Disinfectant effervescent tablet formulation (A5) A water soluble effervescent tablet formulation for preparing a disinfecting solution comprising a first tablet containing a bromide releasing agent and a second tablet containing a hypochlorite releasing agent. It is an object of the present invention to provide an effervescent tablet formulation that can be used to prepare a disinfecting solution wherein the formulation avoids the disadvantages and problems of prior art disinfectant Effervescent formulations 42 concentrates. It is an object of the present invention to provide a product to be used for preparing a solution for disinfecting dental and medical instruments and equipment that dissolves fully and results in a solution which has disinfecting power for a useful period of time over a wide pH range. The present invention comprises a water soluble effervescent tablet formulation that can be added directly to water to prepare a disinfecting solution. The preferred disinfecting agent is a combination of a bromide releasing agent and a hypochlorite releasing agent. Further, the formulation includes a stabilizer for increasing the stability of the effective disinfecting species in solution. In particular, a two tablet system has been developed wherein the bromide releasing agent is in one effervescent tablet and the hypochlorite releasing agent is in a second effervescent tablet. Sodium bromide is useful as the bromide releasing agent. Sodium dichloroisocyanurate is useful to provide both hypochlorite and to act as a stabilizing agent to maintain desired levels of the active ingredients. Both tablets contain effervescent agents such as are used in the art; for example, sodium bicarbonate in combination with citric acid. Other ingredients may optionally be included such as surfactants, deodorants, lubricants, and fillers. The tablets prepared from the active agents and the effervescent agents are of such a size and concentration to allow using whole tablets or multiple tablets in a one quart volume or other typically used volume. The use of tablets eliminates having to dilute and mix concentrates, and store diluted liquids. The use of tablets further eliminates having to pour powder concentrates which may produce undesirable and harmful dust. The effervescence provides rapid solubility and mixing of the active ingredients. The use of the two tablet system allows for formation of the preferred hypobromous acid species . An effervescent tablet formulation for preparing a disinfecting solution, comprising: A first tablet comprising an effervescing agent and a bromide releasing agent; and A second tablet comprising an effervescing agent and a hypochlorite releasing agent Effervescent formulations 43 (C) Effervescent microspheres and Manufacturing (A6,B19) The invention concerns multilayer microspheres containing an acid substance, a basic substance, and a water-soluble isolating agent which, when it dissolves in water, after almost instant effervescence, brings about a homogeneous dispersion of active principal(s) which is present in the acid and basic substances. The invention also concerns a method for preparing such microspheres by rotational granulation on a fluid air bed associated with a system of tangential spraying of the wetting liquid. The present invention relates to multilayer effervescent microspheres and to a process for preparing such microspheres. The term "microsphere" will be intended to refer to microgranules formed of a support material consisting of a matrix in which the active principle(s), to which auxiliary substances are optionally added, is (are) dispersed. In accordance with the European Pharmacopea monograph on spheres, microspheres have an average diameter of less than 1.0 mm and greater than or equal to 1.0 .mu.m. They are generally intended for oral or parenteral administration and are used either as constituents of pharmaceutical form, such as tablets, or in their natural form combined or otherwise with other excipients, and distributed or otherwise in unit doses, such as sachets, gel-capsules or powder for injectable preparation. These effervescent forms are intended to be dispersed in water before absorption. Their breakdown is ensured by a release of carbon dioxide resulting from the action of an acid--generally an organic acid, citric acid being the one most commonly used--on a base--generally a carbonate such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, calcium carbonate, magnesium carbonate or lysine carbonate to avoid the introduction of sodium. The known effervescent forms also comprise diluent adjuvants (generally sugars), binders, sweeteners and flavorings. Most of the standard processes for preparing effervescent forms comprise a step of granulating powder, either via a wet route or via a dry route. The effervescent mixture contains at least one crystalline solid organic Effervescent formulations 44 acid and at least one carbonate releasing CO2 in the reaction with the organic acid and is characterized in that the acid crystals bear a coating containing calcium carbonate which adheres to the surface of the acid crystals by means of the bonding layer formed by partial react-on of the calcium carbonate of the coating with a surface layer of each acid crystal. The mixture is prepared by heating the organic acid in ethanol and water to about 60 oC. in a mixer at a pressure of about 0.1 bar or less and by introducing the calcium carbonate which is left to react until the pressure has risen to about 0.9 bar. The present invention relates to multilayer effervescent microspheres containing an acidic substance, a basic substance and a water-soluble isolating agent whose dissolution in water leads, after almost immediate effervescence, to a solution or a homogeneous dispersion of active principle. According to a first variant, the water-soluble isolating agent is dispersed in the entire bulk of each microsphere, the latter having a two-layer structure: a layer of acidic substance in which is dispersed the water-soluble isolating agent and a layer of alkaline substance in which is dispersed the water-soluble isolating agent. According to a second variant, the water-soluble isolating agent is in the form of a thin film separating the acidic and alkaline substances. In this case, each microsphere has a three-layer structure: a layer of acidic substance and a layer of alkaline substance separated by a layer of water-soluble isolating agent. Whether the microspheres have a two-layer or three-layer structure, the water-soluble isolating agent serves two purposes; it acts as a binder and as an isolating barrier intended to avoid an effervescence reaction between the alkaline substance and the acidic substance during the preparation process but also during storage of the microspheres, irrespective of the storage conditions. The water-soluble isolating agent is chosen from polyvinylpyrrolidone, hydroxypropyl cellulose, methyl cellulose, lactose and sucrose. The present invention also relates to a process for preparing the effervescent microspheres described above using the method of rotary granulation in a fluidized air bed. Effervescent formulations 45 The advantage of rotary granulation applied to these effervescent compositions is the continuous linking of the operations in one and the same chamber which, as a result of the components used and certain precautions taken, induces no effervescence. Furthermore, this rotary granulation technique allows the relative proportions of the various compounds to be modified, in particular the relative molar proportions of the acidic and basic fractions. Specifically, the process according to the invention makes it possible advantageously to obtain effervescent forms whose relative proportion of alkaline and acidic fractions is less than the stoichiometric proportion implemented in the prior art for effervescent tablets manufactured by the granulation method, without the quality of the effervescence being adversely affected. In particular, the relative proportion of the alkaline and acidic fractions implemented in the context of the process according to the invention is less than 0.6, in particular less than 0.25. All the steps of the process according to the invention are carried out under atmospheric pressure, without any specific dehydration system or any specific precautions. The apparatus used to carry out the process for preparing the effervescent microspheres is, for example, apparatus constructed by the company Glatt, onto which a rotor tank is fitted. Said process is performed by rotary granulation in a fluidized air bed combined with a system for spraying powder and a system for the tangential spraying of wetting liquid. The process comprises two continuous steps, a first step of spheronization of microspheres using a powder A and a second step of spheronization of a powder B on the microspheres of powder A, one of the powders A and B being acidic and the other alkaline and it being possible for each of them to contain or consist of one or more active principles. During the first spheronization, the powder A is placed in the moving rotary granulation tank and suspended in the air bed. The components of the powder A are mixed together for five minutes and the air inlet temperature is stabilized to a temperature To. Effervescent formulations 46 The powder A thus blended is sprayed with a wetting liquid containing the water-soluble isolating agent. The microspheres of powder an obtained are dried by bringing the air inlet temperature to Ts and are then optionally screened using a 1000 .mu.m screen. During the second spheronization, the air inlet temperature is brought to. The powder B and the wetting liquid containing the water-soluble isolating agent are then simultaneously sprayed onto the dried powder A microspheres obtained previously. The powder B is sprayed by means of the powder spraying system installed on the Glatt apparatus. The two-layer microspheres obtained are dried by bringing the air inlet temperature to Ts. After drying, the microspheres must be packaged quickly, but a small amount of moisture uptake does not harm the storage. During the two spheronizations, the wetting liquid containing the watersoluble isolating agent is the same, for example polyvinylpyrrolidone (PVP) dissolved in an alcohol or an aqueous-alcoholic mixture, in particular PVP dissolved to 4% by weight in ethanol at 60% by volume. The two-layer microspheres obtained according to the process of the invention have an average particle size of between 20 and 500 .mu.m. A subject of the present invention is also a process for preparing effervescent microspheres which have a three-layer structure according to the second variant described above. Said process is performed according to the method of rotary granulation in a fluidized air bed combined with a system for the tangential spraying of wetting liquid. The process comprises three continuous steps, a first step of spheronization of microspheres using a powder A, a second step of spheronization of a water-soluble isolating agent on the microspheres of powder A, and then a third step of spheronization of a powder B on the microspheres A protected with a film of water-soluble isolating agent, one of the powders A and B being acidic and the other alkaline and it being possible for each of them to contain or consist of one or more active principles. During the first spheronization, the powder A containing an added binder, for example PVP, is placed in the moving tank and suspended in the air bed. The components of the powder A are mixed together for five Effervescent formulations 47 minutes and the air inlet temperature is stabilized to to. The powder A thus blended is sprayed with a wetting liquid. The microspheres of powder A obtained are dried by bringing the air inlet temperature to Ts. During the second spheronization, the air inlet temperature is brought to To. The watersoluble isolating agent is added directly to the tank and the wetting liquid sprayed until microspheres of powder A which are coated with a film of water-soluble isolating agent are obtained, and are dried by bringing the air inlet temperature to Ts. After drying, the coated microspheres are screened and the powder B is then added directly to the rotary granulation tank when the air inlet temperature has stabilized at To. The three-layer microspheres are obtained by spraying the preceding microspheres with a wetting liquid. The three-layer microspheres obtained are dried by bringing the air inlet temperature to Ts. After drying, the microspheres must be packaged quickly, but a small amount of moisture uptake does not harm the storage. During the first two steps, the wetting liquid is, for example, an aqueous-alcoholic solution, in particular ethanol at 60% by volume. During the final step, the water-soluble isolating agent can be introduced by means of the powder B, in which case the wetting liquid used will be the same as during the first two steps, or alternatively the isolating agent is introduced by means of the wetting liquid, which will be an alcoholic or aqueous-alcoholic solution containing the isolating agent, for example PVP dissolved to 4% by weight in ethanol at 60% by volume. The three-layer microspheres obtained according to the process of the invention have an average particle size of between 200 and 1000 .mu.m. According to the process for manufacturing microspheres, whether they are two-layer or three-layer microspheres, the powder of alkaline nature contains a sodium bicarbonate or any other carbonate usually used in the preparation of effervescent forms, such as lithium hydrogen carbonate, monosodium carbonate, lithium glycine carbonate, monopotassium carbonate, calcium carbonate, magnesium carbonate; one or more active principles if the latter have alkaline properties; whereas the powder of acidic nature contains an organic acid, for example citric acid or a compound used as active principle, for example ascorbic acid, acetylleucine and/or one or more active principles if the latter have acidic properties. The acidic and alkaline powders can also contain a diluent, for example lactose or Glucidex; flavorings and sweeteners, for example orange Effervescent formulations 48 flavoring, citric acid, sodium saccharinate; various excipients. According to one embodiment of the invention, the powder A is of alkaline nature and the powder B is of acidic nature. According to another embodiment of the invention, the powder B is of alkaline nature and the powder A of acidic nature. The wetting liquid is sprayed by means of a nozzle 1.2 mm in diameter, at an average flow rate of between 10 and 30 g/min. The air inlet temperature of the fluidized bed is between 55 and 650C during the spheronization steps (To) and between 75 and 85 oC. during the drying phases (Ts). The microspheres obtained according to the process of the invention contain 5 to 75% of alkaline substance, 10 to 75% of acidic substance, 3 to 15% of water-soluble isolating agent, 5 to 50% of diluent and 1 to 30% of flavorings and sweeteners. The relative humidity of the microspheres obtained according to the process of the invention, measured for fifteen minutes by the infrared balance method at 90oC., is between 1 and 2% at the rotary granulation tank outlet. The overall yield for the process is calculated from the fraction of particles smaller than 2500 .mu.m in size, the working yield of the spheres corresponds to the fraction of particles between 200 and 1000 .mu.m, for the process for preparing three-layer microspheres, between 20 and 500 .mu.m for the process for preparing two-layer microspheres. The feasibility of the process according to the invention is evaluated according to the ease with which the microspheres are obtained, the speed of production of a batch and the yield for each step. Analysis of the batches includes particle size analysis of a sample of 100 g of spheres by the superimposed screens method (sample obtained from the total fraction of a batch), after which a morphological study of the microspheres obtained, relating to the overall appearance, sphericity, cohesion and uniformity of the particles, is carried out by examination with a binocular magnifying glass. Effervescent formulations 49 According to one variant of the invention, the two-layer or three-layer effervescent microspheres are manufactured by the mounting technique combined with a system for the tangential spraying of wetting liquid. The powder A and the powder B can be mounted successively on spheres of active principle coated with water-soluble isolating agent, or on neutral spheres (D) Novel formula of an effervescent vaginal tablet (A2) The use of a vaginal tablet containing progesterone has been reported in dogs but has not been pharmacologically evaluated in humans. In the present study we examined the pharmacokinetics of natural progesterone administered in the form of vaginal tablets to non-oestrogen-primed postmenopausal women. Dosages of 50 and 100 mg were used to determine single-dose pharmacokinetics. The effect of continuous use on hormonal, chemical, and lipid profiles were evaluated Our study was conducted to assess the pharmacokinetics of natural progesterone administered in the novel formula of an effervescent vaginal tablet. Our study was conducted to assess the pharmacokinetics of natural progesterone administered in the novel formula of an effervescent vaginal tablet advantages are related mostly to patient compliance. Vaginal tablets are easily administered by the woman herself. There is no messy discharge as is sometimes seen with vaginal suppositories or creams. Only three women (6%) experienced minimal vaginitis during the treatment, and none withdrew from the study due to local vulvovaginal irritation. The vaginal tablet should be inserted only twice daily. This is a convenient schedule also for working women who can insert the tablet in the morning before going to work and in the evening when they return, compared to the vaginally used oral progesterone gelatin capsule that needs to be inserted 3 or 4 times per day. Advantages are related mostly to patient compliance. Vaginal tablets are easily administered by the woman herself. There is no messy discharge as is sometimes seen with vaginal suppositories or creams. Only three women (6%) experienced minimal vaginitis during the treatment, and none withdrew from the study due to local vulvovaginal irritation. The vaginal tablet should be inserted only twice daily. This is a convenient schedule also for working women who can insert the tablet in the morning before going to work and in the evening when they return, compared to the vaginally used oral progesterone gelatin capsule that needs to be inserted 3 or 4 times per day Effervescent formulations Chapter-8 ANALYTICAL PARAMETERS 50 Effervescent formulations 51 Evaluation parameters: Both physical &chemical properties should be considered when evaluating effervescent formulation. Here only physical properties will be discussed because chemical properties will be affected by it’s effervescent base. Many tests for example titrimetric, gravimetric, colorimetric, volumetric tests as well as loss of weight measurements have been proposed to determine the carbon dioxide content. Method based on carbon dioxide pressure generation and weight loss has been recently applied. The determination of water content by Karl fisher titration in effervescent preparation was possible after extraction with dioxanes. Sodium bicarbonate which reacts with Karl fisher reagent is insoluble in dioxanes and does not interfere with determination. For tablets: The disintegration and dissolution time is very important characteristics for effervescent products. It is expected that a well formulated effervescent tablets will disintegrate and dissolve within 1 to 2 min to form a clear solution. Consequently the residue of undissolved drug must be minimal. The temperature of the water also influence the dissolution time. It is therefore important to choose the temperature of water that is actually used by the consumer. Such factors such as the crushing strength and friability will influence the possibility of packaging the tablets on packaging lines as effervescent tablets chip easily at the edges during handling. When the tablets are filled in the tubes, the tablet height is of utmost importance since the looseness or tightness of the packaging depends on the tablet height. When small or fairly small amounts of drug form part of the formulation it is essential that the content uniformity be carefully supervised. For powder and granules: Disintegration and dissolution time are as much important as powder weight variation. As the mass of the powder is many times larger than that of the tablet, larger amount of raw material will have to be handled when packaging the same number of tablets. Therefore the production area will be larger. Effervescent formulations 52 All the steps during production of effervescent formulation should be in dehumidified conditions. (less than 20 %RH &20°c) or mixing, drying , granulating , milling can be performed in the normal humidity conditions and store the final mixture in dehumidified areas provided that packaging should also be in dehumidified area. In direct compression method, the mixing can be done at normal humilities but in that case the mixture is dried to prevent a premature effervescent reaction. By means of causing dehumidified air to flow through the bed in a suitable container. Tabletting and packaging are also done in dehumidified conditions. Thus the number of manufacturing stages in the low humidity zones is reduced. Effervescent formulations 53 Chapter-9 ADVANTAGES Effervescent formulations 54 (1)ADVANTAGES (A1) Effervescent products offer many advantages but only when manufactured and packaged correctly. Advantages of effervescence include: good tasting, sparkling drinks containing ingredients which do not normally taste good in liquid form high dose products where large conventional tablets would have to be swallowed better delivery for those persons who dislike or cannot swallow tablets and capsules quicker and more complete absorption of dosages compounds normally not stable or soluble in liquid form A properly prepared effervescent tablet or powder can allow a large dose of ingredients to be taken in a single serving. The organic food acid combines with the carbonate source to form potassium, sodium, calcium or magnesium salts of the acid and buffers the solution to a normal pH, so it is easy on the stomach. Clinical studies performed on a variety of effervescent products demonstrate that the ingredients penetrate the blood stream within as little as 15 minutes. 1. Better and quicker absorption In water, soda and fruit juices, effervescent tablets produce a pleasant tasting, slightly sour solution. This is due to organic fruit acids contained in the tablets. In conventional solid tablets, the compounds often dissolve slowly in the stomach, which frequently delays or reduces absorption. With effervescent tablets dissolved in a liquid, the ingredients are absorbed quickly, completely and uniformly. 2. Optimal compatibility After swallowing, conventional solid tablets or capsules are transported to the stomach where they dissolve gradually. The passage takes variably long in different people, depending on anatomical and physiological factors. In case of a longer passage time, solid dosage forms can dissolve partially and this can cause irritation of mucous membranes. With a dissolved effervescent tablet, the ingredients are evenly distributed in the solution, so that high, localized concentrations cannot occur. The solution of the effervescent tablet Effervescent formulations 55 contains a balanced ratio of acids and carbonates. This balance is called a buffer. 3. Increase in liquid intake Daily liquid consumption should be 1.5 - 2 liters in adults. With increased intake required during excessive fluid loss caused by events such as intensive physical activity, diarrhea, or high temperatures in summer. The intake of dissolved effervescent tablets supports the daily liquid supply. 4. Advantages in case of swallowing problems Many people have problems swallowing solid tablets or capsules. For these people, effervescent tablets are a good alternative. 5. Simple handling and measuring into exact doses Effervescent tablets are simply dissolved in a glass of water, soda, or fruit juice - and after a short period of time a palatable solution is ready for drinking. This is a great advantage over having to dissolve granules or powders. Granules and instant powders must be measured first and then stirred in the glass several times to obtain a uniform solution. With effervescent tablets, the dose is standardized and the liquid quantity is variable allowing for the taste to be adjusted according to individual preference. Effervescent formulations 56 Chapter-10 LIMITATIONS Effervescent formulations Limitations of effervescent formulations 57 (A1) 1. It cannot be given to the children because of possibility of gas (CO2) toxicity. 2. If packaging is not done properly then there are chances of degradation by environmental moisture. 3. It has shorter shelf life as compared to other solid dosage forms. 4. It requires special machinery requirements for manufacturing. 5. This dosage form is costly then tablets. Effervescent formulations 58 Chapter-11 SUMMARY Effervescent formulations 59 Summary Effervescent formulations are those which are capable of producing CO2 on contact with water. When these agents are added in the glassful of water they give effervescence. This technique is generally employed for antacid preparations. In this preparation alkali metal bicarbonates & alkali metal carbonates like Sodium carbonate &Sodium bicarbonates are added which reacts with citric acid or tartaric acid to give effervescence. Other ingredients of this formulation are coloring agents, flavoring agents, lubricants, binders etc.. Different types of effervescent formulation are effervescent formulation for oral use, effervescent bath products, effervescent formulation for delayed effect, effervescent formulations containing plant extract, effervescent proton pump inhibitors etc.. Effervescent formulations can be prepared by one of the following methods: wet granulation, dry granulation, fusion method, hot melt extrusion etc.. The packaging of effervescent formulation should be such that it can maintain stability of the product especially protect the product against moisture. For this purpose squeezed bottles or water soluble bags are used. The future of effervescent preparation is very bright. There are many advance in this technology that are: floating or pulsatile drug delivery system based on coated effervescent cores, effervescent micro spheres, effervescent vaginal preparation etc.. There ate many advantages of this dosage form which are patient compliance, increased rate of absorption, large dose can be given etc.. There are certain limitations too. That are it can not be given to the children because of risk of carbon dioxide toxicity; it’s shorter shelf life; chance of product deterioration if packaging is not done properly and the cost of manufacturing is high, as compared to other tablets. Anyway, the future of effervescent formulation is very bright. Effervescent formulations 60 Chapter-12 REFERENCE Effervescent formulations 61 (a)from books: (a1). Mohrle,R.,Effervescent tablets,In.,Pharmaceutical dosage forms,Vol;1,(H. A. Lieberman &L. Lachman,eds.),Marcel Dekker,Inc.,New York,1980,pp.225-258. (a2) Reviews of patents on effervescent granules by A.V. Gothoskar&S.J. Kshirsagar (a3). Saleh, A.I., Aboutaleb, A., Boymond, C., Stamm, A. An approach to the direct compression of effervescent tablets: mechanical properties of the ingredients. Expo. Congr. Int. Technol. Pharm. 3, 38-48 (1985) (a4). scheisen, G., Schmidt, P.C. Preparation and optimazation of lubricants for effervescent tablets. Eur. J. Pharm. Biopharm. 41 (a5). International Journal of Volume 187, Issue 2 , 5 October 1999, Pages 175-184 Pharmaceutics (a6). Anderson, H.R., Banker, G.S. and Peck, G.E., 1982. Quantitative evaluation of pharmaceutical effervescent systems I: Design of testing apparatus. J. Pharm. Sci. 71, pp. 3–13. (a7). Krögel, I. and Bodmeier, R., 1996. Evaluation of the floating properties of coated drug delivery systems containing effervescent excipients. Eur. J. Pharm. Biopharm. 42, p. 21. (a8). Krögel, I. and Bodmeier, R., 1997. Development of floating or pulsatile DDS based on effervescent cores. Proc. Int. Symp. Control. Release Bioact. Mater. 24, pp. 237–238. (a9). AH Rau and H Yorozu, Effervescent bath tablet formulation technology, Cosmet Toil 107(12) 55-62 (1992) Effervescent formulations 62 (b)from internet: (b1)http://www.alka-seltzer.com/as/facts.htm (b2)http://www.drugdeliverytechnology-articleindex.htm (b3)www.effervescent-vitamins.com (b4) http://www.myvitanet.com/ (b5) www.pharmaceutical-technology.com (b6)URL: http://www.bmp-production.de/ (b7) http://www.pharmaquality.com/Cover%20Story8.htm (b8) http://www.recip.se/faq.asp (b9) http://www.ibismedical.com/ (b10)http://www.uni-pharma.gr/company1.htm (b11) http://www.phcog.org/positions.html (b12) http://www.blackwellpublishing.com/. (b13) http://www.medshopexpress.com/ (b14) http://www.drugstore.com/ (b15) http://www.healthtouch.com/ (b16) http://www.blueprintforhealthmn.com/ (b17) http://www.healthsentinel.com/ (b18)http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682878.ht ml (b19)http//www.mypharmacy.co.uk Effervescent formulations (B20) http://www.vitar.cz/eng/calcm.phtml (b21) www.allnaturalvitamins.net/ (b22)www.qfac.comac 63