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A Review Of Patents On Effervescent Granules

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Effervescence is defined as the evolution of bubbles of gas from a liquid as a result of a chemical reaction

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, they offered the public a unique dosage form that was interesting to prepare. In addition, they provided a pleasant taste due to carbonation which helped to mask the objectionable taste of the drugs. (1)

The choice of ingredients for effervescent granules depends both upon the requirement of the manufacturing process and the necessity of making a preparation which dissolves in water. The required ingredients are at least one acid and at least one base. The base must release carbon dioxide upon reaction with the acid. Examples of such acids include tartaric acid and citric acid. Examples of bases include sodium carbonate, potassium bicarbonate, sodium bicarbonate.

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.

Effervescent salts include the following ingredients, which actually produce the effervescence: sodium bicarbonate, citric acid and tartaric acid. When added to water the acids and base react to liberate carbon dioxide, resulting in effervescence. it should be noted that any acid-base combination which results in the liberation of carbon dioxide could be used in place of this combination as long as the ingredients are suitable for pharmaceutical use.

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 -------à Na3C6H5O7 + 4 H2O + 3 CO2 ------ (i)

Citric acid Sodium bicarbonate Sodium citrate Water Carbon dioxide

H2C4H4O6 + 2 NaHCO3 -------à Na2C4H4O6 + 2 H2O + 2 CO2 ------ (ii)

Tartaric acid Sodium bicarbonate Sodium tartarate Water Carbon dioxide

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)

Methods of preparing effervescent granules:

There are theree 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.

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.

This article reviews the various US patents that are based on the principle of effervescence.

Effervescence in chewable base:

Patent 5,962,022 (1999) assigned to SmithKline Beecham (Brentford, GB) describes an invention that relates to pharmaceutical compositions for oral administration of antibiotics and other medicament with unpleasant taste characteristics and particularly to compositions formulated as tablet. This chewable composition was especially suitable for improving the taste characteristics of range of medicament, particularly for improving the taste of bitter tasting medicament and also provided a pleasant mode of administrating medicament, particularly those with unpleasant mouth feel even in the absence of a bitter taste e.g. antacids. The effervescent couple comprises a basic ingredient and an acidic ingredient. The basic ingredient liberates carbon dioxide when it comes in contact with acidic ingredient and saliva or added to water. The effervescent couple typically comprises of citric acid or sodium hydrogen citrate and sodium bicarbonate. Another aspect of this invention is incorporation of disintegrants that gives the patient an option of dispersing the tablet in small amount of water prior to administration.

Solid, rapidly disintegrating formulation:

Patent 6,245,353 (2001) assigned to Asta Medica AG (DE) describes an invention that provides a novel and therapeutically advantageous solid, rapidly disintegrating, effervescent, rapidly dissolving dosage form for oral administration of cetrizine. The dosage form contains organic edible acid, alkali metal and an alkaline earth metal carbonate and bicarbonate and optionally a pharmaceutically acceptable auxiliary ingredient along with the drug. The formulation of this invention when dissolved in water, yields a solution having a pleasant taste with improvement in patient compliance. This oblivates the need of tedious process of coating the individual crystal of cetrizine for masking the bitter taste. The patent describes the first ever effervescent preparation of cetrizine, which is very effective against allergic disorders.

Another patent 6,242,002 (2001) assigned to Arzneimittelwerk Dresden GmbH (DE) describes rapidly disintegrating oral dosage form. Patients suffering from Parkinsons disease usually have problem due to strong tremors when swallowing a tablet with a liquid. Also, administration of tablet for a patient having swallowing difficulty is not possible. The object of rapid disintegration of Selegiline (an antipakinsonian drug) was achieved by rapidly disintegrating oral dosage form (with or without water) as an effervescent formulation comprising an alkali sensitive drug and an effervescent base of an alkaline earth metal carbonate, an organic edible acid and an alkali metal salt of citric acid and optionally, a pharmaceutically acceptable auxiliary ingredient. This invention discloses an effervescent formulation that can be in the form of granules or tablets. The tablet can also be buccal tablet. By addition of water or contact of such effervescent formulation with saliva, results in a suspension or solution with carbon dioxide evolution and such suspension or solution has a pleasant taste. It also aids in rapid release of ingredients.

 

Disinfectant effervescent tablet formulation:

Patent 6,099,861 (2000) assigned to Chem Link Laboratories, LLC (Kennesaw, GA) describes a water soluble effervescent tablet formulation for preparing a disinfecting solution. The formulation comprises of a first tablet containing bromide releasing agent and a second tablet containing a hypochlorite releasing agent. This invention discloses an effervescent tablet formulation that can be used to prepare a disinfectant solution wherein the formulation avoids the disadvantages and the problems such as difficulty in storage, mixing and handling of concentrated halogens and instability in diluted forms. The formulation described in the patent can be added directly to water to prepare a disinfectant solution.

Effervescent formulation of Amoxicillin:

Patent 6,077,536 (2000) assigned to Beecham Group PLC (Brentford, GB) describes amoxicillin that is not in salt form, can be provided as an effervescent formulation in which it is solubilised upon contact with water providing a clear solution for oral administration. The amoxicillin hydrate is preferred over the trihydrate form and may be present in conjunction with a beta lactamase inhibitor, such as clavulanic acid or its potassium salt. The formulations are typically in form of free flowing powders or granules or tablets.

Another patent 6,051,254 (2000) assigned to SmithKline Beecham PLC (Brentford, GB) claimed a free flowing or granular formulation consisting of amoxicillin hydrate, a beta lactamase inhibitor and an effervescent couple which generates carbon dioxide on contact with water in which the alkaline component of couple is present in excess of the stoichiometric equivalent of the acid component and which is in a sufficient amount both to neutralize the acid component and to soulbilize amoxicillin hydrate along with a sweetener and a flavoring agent.

Multiple unit effervescent dosage form:

Patent 6,132,770 (2000) assigned to Astra Zeneca AB (Sodertaje, SE) describes a new multiple unit effervescent dosage form containing an acid susceptible proton pump inhibitor and also contains a separate second component, at least one effervescent tablet constituent. The core material is in the form of pellets covered with an enteric coating layer having mechanical properties such that the acid resistance of the enteric coated pellet is not significantly affected by compression of the pellets with the other tablet components during tabletting. The patent further describes the method for manufacture of such a formulation and use of such formulation in medicine.

Effervescent Ibuprofen preparation:

Patent 6,171,617 (2001) assigned to Losan Pharma GmbH (Neuenberg, DE) discloses a clearly dissolving ibuprofen effervescent formulation and a process for the preparation of this formulation. The drugs for pain relief should be made available at reasonable prices. But the water soluble salts of ibuprofen such as ibuprofen-lysinate and ibuprofen-sodium lysinate are very expensive as compared to ibuprofen itself and other widely used analgesics such as aspirin and paracetamol. Ibuprofen is an organic acid having poor water solubility. The invention describes an effervescent formulation containing two separately produced granules: 1) ibuprofen granules prepared using ibuprofen and a basic adjuvant I molar ratio of 1:5-10 and 2) ibuprofen free effervescent granules containing an acid component and a carbon dioxide generating component.

Effervescent formulation containing plant extract:

Patent 6,190,697 (2001) assigned to Gergely; Gerhard (AT) describes an effervescent formulation in form of granules and tablets containing effervescent base and at least one water soluble or suspendable plant extract whose particles are coated with oily, fatty or waxy substance. It also contains one emulsifier and antifoaming agent in the coating and/or as a component of mixture. As a result of coating treatment the plant extract becomes sufficiently hydrophobic to prevent the conversion of the effervescent tablet into a paste upon dissolution in water. When in contact with water, the effervescent particles generate carbon dioxide and the plant extract particles are ejected from the tablet owing to the hydrophobic structure and dissolve slowly. In order to obtain appropriate suspension, stabilizer was added.

Another patent issued to Farmo-Nat Ltd (Ashkelon, IL) (patent 5,948,439) reports effervescent granule formulation for the release and efficient dispersion of herbal medicines into bathing water for topical application or into steam for inhalation. These effervescent granules enable both herbal extracts and essential oils to be evenly and efficiently dispersed in water. This is particularly beneficial for the oils that do not disperse well in water.

Sublingual and Buccal effervescent preparation:

Patent 6,200,604 (2001) assigned to Cima Labs Inc (Minneapolis, MN) describes a dosage form adopted to supply medicament to the oral cavity for buccal, sublingual or gingival absorption of the medicament which contains an orally administrable medicament in combination with an effervescent couple for use in promoting absorption of the medicament in the oral cavity. The use of an additional pH adjusting substance in combination with the effervescent couple is also described.

Novel method for producing effervescent tablet:

The instability of effervescent tablets, their tendency to absorb moisture and lose reactivity is generally known problems. This rules out the possibility of using wet granulation method for preparing such formulations. Paten 6,284,272 (2001) assigned to Chiesi Farmaceutici S.P.A. discloses a technique that enables preparation of effervescent tablet and can have direct industrial application. It is based on the use of a particular effervescent blend of acids and sodium glycine carbonate, present in sufficient amount to rapidly disperse and assist dissolution of the formulation. According to another aspect of the invention, it was found that the use of blend of certain acid with sodium glycine carbonate allows preparing effervescent tablets by direct compression in normal thermo-hygrometric condition and with standard tabletting equipment. This technology is also applicable to active ingredients or excipients that can not be wet granulated or which contain a residual percentage of hardly eliminable water of crystallization.

Another patent 6,066,335 (2000) assigned to Machoczer; Horst (Gkeichen, DE) describes a method of producing effervescent tablet which consists of at least one active ingredient, one binder and sherbets wherein propylene glycol or glycerin is used as binder. The sherbets are added to this mixture in an air conditioned atmosphere and the mixture is formed into tablets. This method produces mechanically stable effervescent tablets with a high dissolving velocity. An important advantage of this method is the requirement of small apparatus and short processing time. The method is applicable to prepare pharmaceutical tablets as well as effervescent tablets for washing and bathing.

Method for improving delivery of Tyrosine supplement by effervescence:

Patent 6,294,579 (2001) assigned to Joseph W. Carnazzo, describes a method of promoting a delivery of Tyrosine supplement to human body. Tyrosine is an amino acid precursor for the synthesis of the neurotransmitters norepinephrine and dopamine. Tyrosine appears to have a positive impact on stress induced performance in humans. The problem with tyrosine supplements is that accurate dosage is difficult to achieve. This is so because tyrosine does not dissolve well in water or other neutral pH liquids and is very acid labile. This results in erratic absorption and inconsistent results. This invention describes the method of promoting tyrosine availability to the body in effervescent form that allows tyrosine to dissolve and disperse in to solution upon activation with water. The increase in solubility and dispersal gives a more uniform absorption of the product after ingestion. The effervescent form of tyrosine buffers stomach acid thereby inhibiting destruction of tyrosine.

Effervescent granules with delayed effervescent effect:

Patent 6,432,450 (2002) describes effervescent granules with delayed effervescence. Unlike the known effervescent tablets, the granules packed in sachets are often difficult to handle. When in contact with water, the components of the effervescent system such as citric acid and sodium hydrogen carbonate, which are very finely subdivided, start to react producing effervescence. The adjuvant or other substance that is retained on the surface or drop to bottom and display poor solubility. This effect is amplified when the granules are poured from a commercial sachet, which in most of the cases close to square shape and for this reason has a relatively wide tear opening. The components of the effervescent mix then hit a correspondingly large part of the liquid surface forming a relatively thin layer. This patent states that the effervescent granules with delayed effervescence consist of at least one acid component and one component evolving gas under the action of acid as well as of active substance, fragrances, plant extracts, vitamins, minerals etc. admixed as needed. The gas evolving components include alkali hydrogen carbonate, alkali carbonate and/or alkali earth carbonates particles which are coated with melt of polyethylene glycol 6000. The particle size is above 0.2 mm.

Effervescent granules prepared by hot melt extrusion method:

Patent 6,071,539 (2000) assigned to Ethypharm Inc (FR) describes the effervescent granules having a controllable rate of effervescence prepared by hot melt extrusion of acidic agent , alkaline agent and a hot melt extrudable binder having melting or softening point below 150o C and capacity to form eutectic mixture with the acidic agent. A formulation according to this invention can provide a rate of release of an active ingredient that ranges from immediate to a delayed or controlled release over a prolonged period of many hours. According to one of the aspect of this invention, it has been found that combination of the effervescent granules with the other ingredient can provide effective taste masking of particularly poor tasting compounds. This aspect of the invention provides a dosage form which offers both immediate or extended release and effective taste masking.

Patent 6,488,961 (2002) also, assigned to Ethypharm Inc (FR) disclosed effervescent granules having a controllable rate of effervescence i.e. a rapid, intermediate or slow. The 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 to alkaline agents ratio, 4) hydrophilicity vs hydrophobicity of the binder, 5) varying the effervescent couple to hot melt extrudable binder ratio and 6) varying the amount of plasticizer present.

Hot melt extrudable binder which can be used in effervescent granules include acacia, tragacanth, gelatin, starch, cellulose, polyethylene glycol, guar gum etc.

Effervescent granules as penetration enhancer for oral administration:

Patents 6,350,470 (2002) and 6,509,306 (2003) assigned to Cima Labs Inc (MN) describes the use of effervescence as a penetration enhancer for drugs known or suspected of having poor bioavailability. Effervescence can occur in the stomach, once the tablet or any other dosage form is ingested. In addition to effervescence in the stomach, the effervescence can occur in any other part of gastrointestinal tract such as esophagus, duodenum and colon, by use of appropriate coatings. The site of effervescence and drug release is chosen to correspond with the segment of the gastrointestinal tract displaying maximal absorption of the formulated drug, or to gain some other therapeutic advantage.

It is believed that such increase can rise from 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 cell, thus promoting absorption through the paracellular route

3) inducing a change in the cell membrane, thus promoting transcellular absorption;

4) increasing the hydrophobic environment within cellular membrane.

Formulations of these inventions contain high concentration of effervescent component to generate effervescence in sufficient amounts to promote permeability and absorption of the drug. The effervescent penetration enhancers of this invention are not limited to those which are based on evolution of carbon dioxide. Reactants that evolve oxygen or other gases and which are safe for human consumption can also be used.

Conclusion:

The effervescent dosage forms have come a long way since the time of their development and with the evolution of modern techniques and modern excipients it is now possible to control the rate of effervescence and hence that of drug release. Such systems, which were once considered for treatment of gastric acidity, are now applicable to treatment of different diseases as well. Such systems definitely hold promise for the future by improving patient compliance at a reasonably lower cost.

References:

  1. Lieberman H. A., Lachman L., Schwartz J. B. (Eds.), Pharmaceutical Dosage Forms: Tablets, Vol.1, 2, 285, Marcel Dekker, Inc. NY, 1993.
  2. Ansel H. C., Popovich N. G., Allen L. V. Jr., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6, 469-471, B. I. Waverly Pvt. Ltd., New Delhi, 1999.

About  authors

A. V. Gothoskar1 , Sanjay J Kshirsagar 2

 

1 Area Technical Manager, MR Technologies, Colorcon Asia Pvt Ltd.,Verna Industrial Estate, Verna, Goa, India.

2 Senior Lecturer in Pharmaceutics, Singhad College of Pharmacy,Lonavala, Mumbai-Pune Highway, India

Dr Abhijit V Gothoskar has completed his graduation, post-graduation and doctorate from Pune University, India. He is the gold medalist at graduate and post graduate levels for his outstanding performance. His research areas include Oral Controlled Drug Delivery Systems and applications of polymers in the field of pharmaceuticals. He has worked as a Senior Lecturer in Pharmaceutics in Maharashtra Institute of Pharmacy, Pune for five years and is currently working as Modified Release Area Technical Manager at Colorcon Asia Pvt Ltd. His current job responsibilities include generation of applications data, development of platform technologies for OCRS and trouble shooting.

Contact information:

Phone: +91-832-2883434 Fax: +91-832-2883440 e-mail: abhijit_gothoskar@yahoo.com

Sanjay J Kshirsagar 2 Senior Lecturer in Pharmaceutics, Singhad College of Pharmacy

Lonavala, Mumbai-Pune Highway, India.

Email: sanjayjk@rediffmail.com

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1 Comment

PALAK_MOTAN's picture
PALAK_MOTAN says:
hello sir, you have very nicely explained the effervescent granules and reviewed the patents also, i am a PG student and am interested in doing a project on effervescent granules in my second year dissertation work, can you tell me which drugs can i you for my project work as most have been patented as seen in your article and can you tell me the various evaluation tests that would be done on the effervescent granules or any references?
PALAK J MOTAN M.S PHARMACEUTICS NIPER AHMEDABAD @motanenterprise_111@yahoo.co.in
Submitted by PALAK_MOTAN on Mon, 02/07/2011 - 07:07