Copyright, CSC Publishing.ablets T & Capsules Robert E. Lee Robert Technologies Amerilab ecause few US companies have experience making B effervescent tablets and , specialty contrac- do most of the tors, such as the company I work for, work. This article describes what you should know about effervescent forms before hiring a manufacturer. and what is should understand what is possible You not. effervescent tablets Effervescence has proved its utility as an oral delivery system in the pharmaceutical and dietary industries for decades. In Europe, effervescent dosage forms are widespread, and their use is growing in the US because they offer pharmaceutical and nutraceutical companies a way to extend their market share. This article summarizes the key facts about effervescent dosage forms, their formulation, and their manufacture. effective dosage effective Key facts about a unique, about Key facts Copyright, CSC Publishing.ablets T & Capsules Figure 1 Effervescent tablets coming off a press. Most steps Effervescent tablets coming tablets are identical to in the manufacture of effervescent those used for making conventional tablets. Binders are normally necessaryBinders are tablets to in effervescent Lubrication of effervescent tablets has historically Depending on the product, formulators can use color clear after tablet disintegration. When sodium disintegration. after tablet solution clear Both is used. bicarbonate potassium are a concern, levels mainly as desiccants. are used types of carbonates is possi- point where handling tablet hardness to a bring the and include dex- water-soluble binders should be ble. These be used A binder should xyitol, and lactose. trose, sorbitol, binders can carry free moisturevery cautiously because into undesirable and can increase disintegra-the tablet, which is in large quantities. The ideal amount tion times when used makes the tablet hard enough to han- of binder is one that to disintegrate (the harder the tablet, dle, but soft enough and dry enough to be stable. the slower the disintegration) been the main stumbling block to an acceptable, mar- lubricants such as magnesium ketable product. Typical stearate are not useful due to their insolubility in water. lubricants Most formulators have to use water-soluble such as sodium benzoate, polyethylene glycol, and adipic acid. These are minimally effective, and depend heavily on the type of granulation they are used in. There are tablet presses that use lubrication spray on the punches so that the formula does not require lubrication. (artificial or natural), sweeteners (acesulfame potassium, sodium saccharin, aspartame, and surcalose), and flavors (artificial or natural) to enhance a product or to mask off-notes derived from the active ingredients. A typical effervescent Formulation Active ingredients Active The low pH in the stomach can cause active The low pH in the stomach can cause A classic example is calcium carbonate, the most is calcium A classic example Many vitamins fall into this category. Typical effer- Typical Many vitamins fall into this category. Typical bases used in the effervescent reaction are used in the effervescent bases Typical However, calcium carbonate releasesdioxide carbon However, Effervescence is the reaction (in water) of acids and Those that are susceptible to light, , or mois- Those that are susceptible to light, Those requiring a large dose. Those that are pH-sensitive, such as amino acids and Those that are pH-sensitive, such as Those that are difficult to digest or disruptive are difficult to digest Those that to the There are several categories of active ingredients: of active categories are several There tablet (1 inch in diameter weighing 5 grams in total tablet (1 inch in diameter weighing milligrams of water- weight) can include more than 2,000 dose. If the requiredsoluble active ingredients in a single ( form)dose is larger than that, the sachet is a common means of delivery. ingredients to become denatured, lose activity, or cause activity, ingredients to become denatured, lose them to remain inactive. Effervescent ingredients, how- solution so that the water-active can buffer the ever, and thus pre- stomach pH increases (becomes less acidic) the active ingredi-vent the degradation or inactivation of induces the ent. This buffering effect (via carbonation) 20 minutes— stomach to empty quickly—usually within maximum absorp- into the small intestine. The result is tion of the active ingredient [1]. vescent formulations have less than 0.5 percent of free vescent formulations have less than maintain that level and prevent other dam- moisture. To age from the ambient environment, the formulation’s package should be 0.001-inch-thick aluminum that com- pletely blocks light, oxygen, and moisture. widely used form of calcium. In a normal tablet or powder, In a normal tablet form of calcium. widely used acid and is in the stomach carbonate dissolves the calcium for absorption. the digestive system carried into the GI, which usually produces gas in when it dissolves in the other hand, as people age, they the stomach. On stomach, and thus a calcium carbon- have less acid in the through the stomach without dissolv- ate tablet may pass if may lead to constipation. However, ing. That, in turn, is taken in an effervescent formula-the calcium carbonate readily available for is in water, tion, the calcium dissolves and there is no risk of excessive gas the body to absorb, constipation. in the stomach or of sodium bicarbonate, potassium bicarbonate, sodium car- bonate, and potassium carbonate. Sodium bicarbonate is very common in effervescent formulas and produces a bases producing . Typical acids used in bases producing carbon dioxide. Typical this reaction are citric, malic, tartaric, adipic, and fumaric. Citric acid is the most commonly used, and it imparts a citrus-like taste to the product. Malic acid can be used in effervescent formulas for a smoother after- taste, but the price of malic acid is higher than that of acids are used adipic, and fumaric citric acid. Tartaric, sparingly because of their low water solubilities. ture. . stomach.

Copyright, CSC Publishing.ablets T & Capsules Figure 2 Figure Packaging materials Packaging must completely protect the effervescent must completely protect Packaging self-destruct. water vapor or they may tablets from Many effervescent product failures occur each year The most common types of packaging are foil packets produce it in an environment where humidity is under moisture bar-strict control and to package it in a suitable All ingredientsbe anhy- in the formulation must rier. should test for free moisture contractor Your drous. before packaging. due to inadequate packaging materials. Many times the choice of packaging material is made based on pricing, rather than considering stability issues. and tubes. Pinholes are a common problem in foil pack- foil (usually more expen- ets. By going to a heavier-gauge sive), you will greatly reduce the number of pinholes. The area within the packet should be large enough to it hold the tablets without creating stress on the foil. Yet, should also be as small as possible to minimize the amount of “room-air” that it can trap inside with the tablets. Given the very low humidity of effervescent tabletting operations, the tablets are so dry that a relative humidity of even 10 percent is fairly high when it’s are made of trapped in close contract with tablets. Tubes plastic, glass, or extruded aluminum with fitted caps con- taining desiccants. Desiccants are used to “bind-up” any free moisture in the tablet or in the air to prevent the Be sure to effervescent reaction from starting prematurely. conduct well-performed stability studies on tubes and any Production The best way to stabilize an effervescent product is to Effervescent tablets and powders are powders tablets and Effervescent in produced base can be per- granulation of the effervescent Wet many years to Fluid-bed dryers have been used for have also been used to make effer- granulators Vacuum Effervescent products normally require tablet presses Strict control of temperature and humidity in all areas much the same manner as conventional tablets and pow- tablets same manner as conventional much the humidity occur in very low production must ders, but areas. Effervescentbe mixed in conven- granulations can twin-cone, such as ribbon, equipment, tional blending should be well All equipment blenders. and V-type allow you to make it completely grounded and should after wash-down. Any traces of mois- and absolutely dry will give erratic granulation resultsture in the equipment in lost batches of product. Figureand most likely result 1 making an effervescentshows a tablet press dosage. adding 0.1 to 1.0 percent water formed by carefully basis) to the chosen blending equip- (weight-to-weight steps must be precisely timed and ment. The granulation thoroughly to distribute the sol- the ingredients mixed blend. The mix is vent or binder solution evenly in the must con- You then quickly discharged to drying ovens. of all equip- stantly monitor the operational parameters variations in drying ment, especially drying equipment, as finished product. times and temperatures can affect the be made, vast While stable granulations will ultimately differences in tablet hardness and disintegration times the granulation. or under-reacting can result from over- and a final mix is After drying, the granulation is sized, performed. the water or make effervescent granulations. Basically, effervescent mixturebinder solution is sprayed onto the The hot, dry air. while it is suspended in a stream of serve to stop the humidity and temperature of the air ensure To reaction quickly and uniformly. effervescent chose the that you produce a free-flowing granulation, particle sizes carefully and monitor all systems closely. gives you a very vescent granulations. This equipment and allows a dust- controlled granulation of the product free environment. The equipment also generally requires less power and less operating space than other types of granulators. In operation, the water or binder solution is sprayed onto the effervescent mixture during blending. Drying occurs by placing the granulation under vacuum and heating it via a thermal jacket. that can deliver high compression forces. If the tablets are to be wrapped in foil or placed into a tube, give care- ful attention to the tablet parameters during compression. Monitor the tablet thickness to ensure the wrapping or packaging equipment can handle the tablets. is a must (65 to 75ºF, relative humidity of 10 percent), or is a must (65 to 75ºF, the formulation will begin a chemical reaction after it’s packaged. In essence, the tablet will self-destruct because the byproducts of an effervescent reaction are water and carbon dioxide.

Copyright, CSC Publishing.ablets T & Capsules T&C . 1992: 1987: 37: Some active Arzneim. Forsch. Acta Psychiatr. Scand. Suppl Scand. Acta Psychiatr. In a tablet form, disintegration can In a tablet form, disintegration References Conclusion 1998: 15(6): 925-930. Possible drawbacks . 1989: 10: 377-387. 3. Nuernberg, B. and Brune, K. Buffering the stomach 6. Eichman, J.D. Mechanistic studies on effervescent- 5. Eichman, J.D. and Robinson, J.R. Mechanistic stud- Robert E. Lee, M.S., is the research and development senior sci- 1. Yassin, A.E.B. Optimization of the biological avail- A.E.B. Yassin, 1. Lack of bioequivalence between 2. Anderson, M.P. Off-notes of some active ingredients. Off-notes Disintegration time. Effervescent technology provides a novel dosage form 4. Hespe, W., Vershoor, J.S.C., and Olthoff, M. Vershoor, 4. Hespe, W., 86: 31-35.W. 86: 31-35.W. diflunisal in man. content enhances the absorption of ingredients have off-notes that cannot be masked by flavors ingredients have off-notes will lead to an unacceptable product. and sweeteners. This entist at Amerilab Technologies, 3101 Louisiana Ave. N., New N., 3101 Louisiana Ave. entist at Amerilab Technologies, 763 525 1262, fax 763 525 1285. Hope, MN 55427 Tel. is a lead- Amerilab Technologies www.amerilabtech.com. Website: ing contract manufacturer of effervescent products. The company is certified NSF/GMP and is FDA inspected. Successful efferves- cent products include those containing amino acids, vitamins, min- erals, herbal extracts, plant growth hormones, and a host of active pharmaceutical ingredients. take up to 5 minutes. This depends mainly on the tempera- take up to 5 minutes. the active ingredients present. ture of the water and Biopharm. Drug Disp Pharmaceutical Research. solutes diffuse into the intercellular space between space intercellular into the diffuse solutes carbon dioxide that the It is theorized cells. epithelial cells, space between the intercellular alters (widens) of active ingredients to greater absorption which leads increased [6]. The and hydrophilic) (both hydrophobic could be active ingredients of hydrophobic absorption parti- dioxide gas molecules non-polar carbon due to the membrane, thus creating an increased tion into the cell which would allow the hydrophobic environment, ingredients to be absorbed [6]. hydrophobic active induced permeability enhancement. 1997: Ph.D disserta- tion. University of Wisconsin-Madison. 372-375. ies on effervescent-induced permeability enhancement. ability of certain medicament. 1996: Ph.D. dissertation. ability of certain medicament. 1996: Al-Azhar University. disulfiram formulations. for nutritional supplements and pharmaceuticals. The for nutritional supplements and pharmaceuticals. of a wide variety of ability to incorporate large dosages , plus active ingredients in an easy-to-swallow ingredient, offers increased absorption of the active advantages over conventional tablets. Bioavailability of new formulations of amoxicillin in rela- tion to its absorption kinetics. This Here, the Moisture vapor can The number of people Many studies have demonstrated that Advantages of effervescent formulations enter the package. There are ingredients in the formula that are not the efferves-compatible with each other or with cent components chosen for the product. The packaging material does not have a moisture The packaging material rate of 0. vapor transmission The seal of the foil pouch is compromised. can happen when there is too much dust in the can happen when there is too much dur- packaging area or when a machine malfunctions ing wrapping of the product. pharmaceutical or nutraceutical company should pharmaceutical or nutraceutical company closely ensure that its R&D department collaborates Each staff member with the contract manufacturer. for a suc-must learn which raw materials are suitable cessful effervescent product and which are not. After packaging, effervescent products effervescent After packaging, should be for degradation of an efferves- The common reasons • • Better dosing. The product is typically self-mixing and flavorful. No need to swallow tablets. Incorporation of large amounts of active ingredients. Incorporation of large amounts of active • effervescent tablets and powders enhance absorption of a number of active ingredients (e.g. disulfiram and caf- feine), compared to conventional formulations [2, 3, 4]. because the carbon dioxide created by the effer- That’s vescent reaction can induce enhanced active-ingredient permeability due to an alteration of the paracellular path- way [5]. The paracellular pathway is the primary route of absorption for hydrophilic active ingredients in which who cannot swallow tablets or who dislike swallowing who cannot swallow tablets or who tablets and capsules is growing. And many products require the patient or customer to swallow several tablets have difficulty swal- in particular, at a time. The elderly, an effervescent dosage form, one lowing tablets. With dose can usually be delivered in just 3 or 4 ounces of someone swal- about the amount used when That’s water. lows a conventional tablet or . Many times effervescent tablets can include flavorings so they taste much better than a mixture of a non-efferves- cent powder in water. In many cases, one effervescent tablet will equal threeIn many cases, one effervescent tablet to amounts. ten conventional tablets in active dose other packaging you are considering. Figure 2 shows a 2 shows Figure considering. you are packaging other tablets. effervescent wrapping machine packaging rela- at 40ºC and 75 percent a test chamber set placed in whether to determine for at least 3 months tive humidity you end of the third month, be stable. At the they will test, tablet (package leak physical tests should perform time, tablet hardness, and sen- appearance, disintegration product) to determinesory evaluation of the any whether should also per- during testing. You off-notes developed (HPLC/MS) to test the actives in form chemical assays been any product degradation? If so, the tablet. Has there why? cent product are