Effervescent Granulation PDF

Effervescent Granulation Dr. Masood-ur-Rehman Aarbi INTRODUCTION Effervescence has proved its utility as an oral delivery system in the pharmaceutical and dietary industries for decades. In Europe and the United States of America, effervescent granules and tablets are widespread, and the...

Effervescent Granulation Dr. Masood-ur-Rehman Aarbi INTRODUCTION Effervescence has proved its utility as an oral delivery system in the pharmaceutical and dietary industries for decades. In Europe and the United States of America, effervescent granules and tablets are widespread, and their use is growing in other countries. Effervescent granulation is an important step of “fizzy” dosage forms’ production that most of the time cannot be avoided to achieve the desired characteristics of the effervescent tablets. It is a critical step because it can affect the stability of the final dosage forms. The first effervescent preparations were described over two centuries ago, in the official compendia, in powder forms to use as cathartic salts.  Later, in 1815, a patent describes “a combination of neutral salt or powder which possesses all the properties of the medicinal spring of Seidlitz in Germany, under the name of Seidlitz Powders,” containing sodium potassium tartrate, sodium bicarbonate, and tartaric acid, in the proportions 3:1:1, respectively. Effervescent granules and tablets have become more and more popular as dosage forms because they are promptly soluble, easy to take, and ensure quick therapeutic action. The effervescent forms are defined within Pharmacopeias as “those granules or tablets to be dissolved in water before administration to patients.” They are used to administer water-soluble active ingredients, especially when the large dosage is required.  A typical effervescent drug for oral administration can take more than 2 g of the active ingredient in tablets that can weigh up to 5 g with a diameter of 25 mm or in sachets in case a larger dosage is required. Effervescent tablets or granules are uncoated and generally contain acidic substances and carbonate or bicarbonate that react rapidly to release carbon dioxide once dissolved in water. The disintegration of the tablets usually occurs within two minutes or even less, because of the evolution of bubbles of carbon dioxide. The effervescent form is in fact widely proposed for pain relief and anti- inflammatory therapies. In certain cases, they can shorten significantly drug absorption rate in the body as compared with traditional tablets, resulting in a quicker therapeutic effect.  Effervescent dosage forms also enhance patient compliance. They are easier to administer, particularly helpful to patients, like children, who are not able to swallow capsules or tablets. A pleasant taste, because of carbonation, helps to mask the bad taste of certain drugs. This could also help to avoid the gastric side effect of certain drugs. They are easy to use and appeal to consumers for color and fizzy appearance more than traditional dosage forms. For example, a study shows that patient compliance has increased when the chloroquine phosphate was administered as an effervescent tablet because of the faster response onset than uncoated tablets. Effervescent drugs also have other advantages over conventional pharmaceutical forms. They substitute liquid forms when the active ingredient has a little stability in the water as they are administered only by prior dissolving of the tablet in water. Active ingredients that are not stable in liquid form are most of the time more stable in effervescent form.  Disadvantages of such solid dosage forms are more related to production technology even if processing methods and equipment are the same as the conventional ones. In general, product requirements are similar to conventional granules, namely particle size distribution and shape, along with content uniformity of the active ingredient, to produce satisfactory free-flowing granules capable of tableting using a high-speed rotary tablet press. However, it is also necessary to focus attention on some aspects of the manufacturing procedure, including compression and packaging because effervescent dosage forms are challenging for their stability and consequently critical to make. The pharmaceutical industry faces many issues, especially in the preparation of effervescent tablets, as it is certainly the application for which the choice of the process technology is at least as important as the formulation design. THE EFFERVESCENT REACTION Effervescence is the evolution of gas bubbles from a liquid, as a result of a chemical reaction. The most common reaction for pharmaceutical oral solid dosage forms is the autocatalytic acid–base reaction between sodium bicarbonate and citric acid.  This reaction starts in presence of water, even with a very small amount, as a catalyzing agent, and because water is one of the reaction products, it will accelerate and will be very difficult to stop. For this reason, the whole manufacturing, packaging, and storage of effervescent products have to be planned by minimizing the contact with water. Recently, some effervescent systems have been prepared to act as penetration enhancers for drug absorption, not only in oral forms but also in some topical products, such as skin or vaginal applications.  In these cases, the reaction takes place directly after administration, in the mouth because of saliva, on the wounds because of blood serum, or when formulated in a suppository to treat vaginal infections, the effervescence is provoked by the moisture of the vaginal mucosa to adjust the pH. There are other forms, the effervescence of which is based on a different reaction upon carbon dioxide formation. Effervescence in these cases is due to reactants that evolve hydrogen peroxide and oxygen, which are safe for human use even if they are not suitable for oral administration but can be employed in preparations for external use such as antibacterial for dental plate cleaning. FORMULATION The criteria to choose the raw materials for effervescent products are similar to those for conventional granules and tablets, since in either case, good flowability, compressibility, and compactability are the targets to achieve. The intrinsic characteristics of effervescent forms bring some considerations that will limit the choice of raw materials, including the selection of active ingredients. The moisture content of the raw material is a very significant aspect because it affects the compressibility and stability of the tablets. To avoid premature effervescent reaction during the process or once the granules or tablets are packed, raw materials with very low moisture content have to be used. Since an effervescent form is required to dissolve within two minutes or less in a glass of water (about 100 mL), raw materials’ solubility and rate of solubility are other significant aspects.  The active ingredient must be either soluble, water-dispersible, or at least solubilized by salt formation during the dissolution in the glass of water. The rest of the excipients, such as additives like sweeteners, coloring agents, and flavors, also have to be water-soluble. To design an effervescent formula, it is necessary to consider the stoichiometric ratios in the reaction and the carbon dioxide solubility in water, which is 90 mg/100 mL of water (in Standard Temperature and Pressure conditions, which is defined to be 273 K (0 degrees Celsius) and 1 atm pressure (or 105 Pa)).  The suggested ratio between acid and alkaline components is about 0.6, but sometimes it might be required to increase the acid source to get a pleasant taste. In fact, the alkaline–acid ratio controls both the effervescence capacity and the taste of the solution to administer. When the solubility of the active ingredient is not pH-dependent, the alkaline–acid ratio can be optionally selected. This ratio can also be determined according to the pH that is required for dissolving the active ingredient. In fact, when the active solubility increases at the acid side, the pH of the solution is lowered by adding an excess of the acidic agent.  Conversely, an excess of alkaline sources must be added when the active ingredient is more soluble at higher pH. However, another approach that can be used to increase the active ingredient solubility is to increase the volume of carbon dioxide to be generated by increasing the alkaline component in the formulation. In the latest development in effervescent forms, some formulations have been designed to control the rate of effervescence, to obtain a rapid, intermediate, or slow rate. The rate control is related to the ratio of the acid–alkaline components, but the chemical properties of the effervescent excipients or their combinations can influence it, especially when a slow rate of effervescence is required. RAW MATERIALS The ingredients of effervescent dosage forms require having low moisture content and to be easily soluble. Because of the nature of the effervescence reaction, additional excipients are sparingly used as the alkaline and acid ingredients are also the fillers to get a tablet bulk. They are, indeed, in such a large amount that tablets are much larger than the conventional ones. In case it would be necessary to add a filler, sodium bicarbonate is widely selected because of its lower cost and because it does not influence the final pH of the solution and increases the effervescence effect. Sodium chloride and sodium sulfate are other possible fillers; they are high-density crystalline powders that are very compatible with the other ingredients. Additives are added in small amounts to make the tablets more attractive for users. Flavors, colors, and sweeteners are used as usual in all the formulations. ACID MATERIALS Necessary acidity for effervescence can be provided by three main sources: food acids, acid anhydrides, and acid salts. Food acids, citric acid, tartaric acid, and ascorbic acid are the most commonly used because these have a nice taste and are odorless, not expensive, and easy to handle. Citric Acid Citric acid is the more often used acidic ingredient because of its good solubility and pleasant taste. It is mainly commercially available in powder and is either colorless or in white crystals. The particle size grades are coarse, medium, fine, and powder (only anhydrous). It is very soluble in water and soluble in ethanol.  It can be used as a monohydrate or anhydrate, depending on the selected equipment technology and process conditions. Anhydrous citric acid is less hygroscopic than the monohydrate. However, caking of the anhydrous ingredient may occur upon prolonged storage at humidity greater than 70%. Citric acid monohydrate is used in the preparation of effervescent granules, while the anhydrous form is widely used in the preparation of effervescent tablets. Tartaric Acid It is very soluble in water and very hygroscopic, more than citric acid. In the effervescence reaction with sodium bicarbonate, it behaves like citric acid in producing an evident effervescence. It must be used in a higher amount to get the proper stoichiometric proportions, being a diprotic acid, while citric is a triprotic acid. In terms of compressibility, it is also comparable to citric acid. Ascorbic Acid It is white in crystalline form and light yellow in fine powder. It is not hygroscopic, and this may be helpful in production because it is easier to handle. It is freely soluble in water (1 g in about 3 mL) and absolute ethanol. If exposed to light, it gradually gets dark. Its behavior in the effervescent reaction with sodium bicarbonate is comparable to the other acids (citric and tartaric) in terms of the release rate of carbon dioxide. Acid Anhydrides Anhydrides of food acids are a potential acid source as they are precursors of the corresponding acid by hydrolyzation in water. The effervescent effect is strong and sustained by the continuous production of acid in the solution. Water has to be avoided for the whole process when anhydrides are part of a formulation; otherwise, they would be hydrolyzed into the corresponding acid before its use. Acid Salts Sodium dihydrogen phosphate, amino acid hydrochlorides, acid citrate salts, etc. are acid salts that are used in effervescent formulation since they are water-soluble and react quickly with alkaline sources. In combination with another of the above- mentioned acids, they work as a pH buffering agent during drug administration, thus promoting active ingredient absorption while mitigating possible undesired side effects for the stomach. Other Less Frequent Sources of Acid Fumaric and nicotinic acid, which are not hygroscopic, have lower water solubility than that of the others. Malic acid is highly hygroscopic and soluble but has less acid strength than the tartaric or citric acids. It is sometimes preferred for its smooth and light taste. Acetylsalicylic acid, though active ingredient, which is very commonly administered in effervescent preparations, is used in combination with other acid sources for its low water solubility. Adipic acid is not used as an acid source because of its low water solubility but can be found in effervescent formulas as a lubricant. It has given good results as a lubricant for effervescent calcium carbonate tablets. SOURCES OF CARBON DIOXIDE Carbonate salts are the most popular source for effervescence; bicarbonate forms are more reactive than carbonates, providing a stronger effervescence effect. Sodium Bicarbonate It is the major source of carbon dioxide in effervescent forms, which is able to provide a yield of 52% of carbon dioxide. It is commercially available in many different grades according to particle size, from free-flowing uniform granule to fine powder, which is odorless and slightly alkaline in taste. When heated to about 50°C, sodium bicarbonate begins to dissociate into carbon dioxide, sodium carbonate, and water.  On heating to 250–300°C, for a short time, sodium bicarbonate is completely converted into anhydrous sodium carbonate. However, the process is both time- and temperature-dependent, with 90% conversion completed within 75 minutes at 93°C. Being a nonelastic material, it has very low compressibility, but this issue is overcome when produced by spray-drying technique. Sodium Carbonate It is commercially available in three different forms, all very soluble in water: anhydrous, monohydrate, and decahydrate. It is more resistant to the effervescent reaction, and in some formulations, it can be used as a stabilizing agent in an amount not exceeding 10% of the batch size since it absorbs moisture preferentially, preventing the effervescent reaction to start. Of course, the anhydrous form is preferred for this purpose. A particular grade of modified sodium bicarbonate is available whose surface is coated with a carbonate layer to increase bicarbonate stability so as to be suitable for direct compression Potassium Bicarbonate and Potassium Carbonate They are lesser soluble than the corresponding sodium salts and are more expensive. They can partially substitute the sodium salts when a reduced amount of sodium ion is required. Calcium Carbonate Precipitated calcium carbonate occurs as fine, white odorless, and tasteless powder or crystals. Its water solubility is very poor and is not soluble in ethanol or isopropanol. It is a high-density powder that is not suitable for direct compression. It is normally used as a drug in effervescent tablets for patients who suffer from calcium shortage. It can also be used as an alkaline source because it provides stability to the effervescent system. Sodium Glycine Carbonate Sodium glycine carbonate provides a light effervescence reaction but brings rapid disintegration of the tablets, so it is often applied in the preparation of fast dissolving sublingual tablets. It is much more compressible than the other alkaline compounds, and it has been found suitable for direct compression. BINDERS In general the use of a binder is usually necessary to provide the tablet the proper hardness to handle them. In effervescent formulations use of binder is limited by the fact that any binder, even if water-soluble, tends to retard the tablet disintegration and take some moisture into the tablets. Therefore, the amount of binder in a given formula will be a compromise between desired granule strength and desired disintegration time. A small amount of water, finely distributed on the powder bed, acts as a binder by partially dissolving the raw materials and preparing them for agglomeration. Other solvents, for example, ethanol and isopropanol, can be used as a granulating liquid to dissolve dry binders.  In fact, when both the alkaline and acidic components are granulated together with water, it would not make sense to put a binder in the formulation because the small amount of water will never activate it due to being not enough for dissolving it. The most popular binder for effervescent tablets is polyvinylpyrrolidone (PVP) due to its strong binding power at low concentration in the formula, effective from 2%. PVP K25 and K30 are preferred for their good water solubility and do not retard the drug dissolution rate, thus matching the final purpose of effervescent tablets. They are used in water, alcohol, and hydroalcoholic solutions and can also be used for dry granulation. LUBRICANTS Tableting is a critical step of effervescent production, and selecting the lubricant is one of the most important issues because of the chemical–physical nature of the lubricants. As most of the lubricants have low water solubility, they tend to inhibit the tablet disintegration, which, as already said, must be very rapid in case of effervescent tablets.  The effervescent tablets – mainly for marketing reasons – are often required to provide a clear transparent solution, that is, without any insoluble “film” formation on the water surface or any residue left. When selecting a lubricant, proper attention must be given to its solubility in water, along with its compatibility with the active ingredient therapeutic action. Lubricant substances, known as suitable for effervescent manufacturing, are sodium benzoate, sodium acetate, L-leucine, and carbowax 4000. Combinations of lubricants have also become a possibility. Literature reports calcium and potassium sorbates and micronized polyethylene glycol (PEG) with calcium ascorbate or trisodium citrate.  Spray-dried L-leucine and PEG 6000 are also considered as a successful mix. Other lesser soluble lubricants are still however used in formulating effervescent tablets. In any case for good lubrication, a balance should be found between compression efficiency and water solubility. Magnesium stearate is commercially available in combination with sodium lauryl sulfate, a surfactant agent that helps in dispersion. ADDITIVES In order to improve the taste and appearance of effervescent preparations, some additives are also put in little quantity in the formulas. Water-soluble flavors like lemon, orange, and other fruit essences are particularly suitable to achieve the organoleptic requirements. They are usually about 0.5%–3.0% of the final dose. Most of the time flavors are combined with sweeteners like sorbitol, sucrose, aspartame, stevia, and saccharin sodium.  Coloring agents can include all the dies soluble and suitable for food such as the FD&C ones, and all the natural coloring substances amount to about 0.1%–3.5% of the dose. In addition, surfactants or antifoaming agents can be used to improve the performance of the effervescent preparation at the time of use. THANKS