Effervescent Dosage Manufacturing

by Dr. Harald Stahl Senior pharmaceutical technologist at GEA Pharma Systems harald.stahl@geagroup.com

Picture 1: Closed Powder Handling using IBC's, Docking Stations and Split Valve Technology by Buck Systems

Oral dosage forms are the most popular way of taking medication even though they have some built-in principle disadvantages. One of these disadvantages is the risk of a slow absorption of the actives. One way to overcome this is to administer the drug in a liquid form, which additionally sometimes allows the use of a lower treatment dosage. The problem that a lot of actives only show a limited level of stability in a liquid form can be overcome by formulating effervescent tablets, which are dissolved in water before administration. Additional advantages of effervescent tablets are:

the chance to improve the taste a more gentle treatment for the patients stomach marketing aspects (fizzy tablets may have more consumer appeal than traditional dosage forms).

The downside of this is the need for quite large tablets, the more complex production process and very often the need for special packaging materials.

FUNDAMENTALS OF EFFERVESCENTS
Effervescents consist of a soluble organic acid and an alkali metal carbonate salt. Quite often the active represents one of these substances. If this combination comes into contact with water carbon dioxide gas is formed. Typical examples of substances used are:

Citric Acid Tartaric Acid Malic Acid Fumaric Acid Adipic Acid Sodium Bicarbonate Sodium Carbonate Sodium Sesquicarbonate Potassium Bicarbonate Potassium Carbonate

For example: the reaction of Citric acid and Sodium bicarbonate

3 NaHCO3(aq) + H3C6H5O7(aq) - 3 H2O(l) + 3 CO2(g) + Na3C6H5O7(aq) 252 g (3 mol) + 192 g (1 mol) - 54 g (1 mol) + 132 g (3 mol) + 258 g (1 mol) From this equation it can also be derived why most effervescent tablets are relatively large. If it is assumed that a placebo tablet consisting of 192 mg H3C6H5O7 and 252 mg NaHCO3comes into contact with 100 ml water it will react to 258 mg C3OH5(COONa)3 + 132 mg CO2 + 54 mg (of extra) H2O. Knowing that 1 mol of CO2 is, under normal conditions, equal to 22,4 litres, which means that 132 mg of CO2 formed by the reaction of the tablet above is equal to 67,2 ml of gas. As the solubility of CO 2 in water at 20 C and 1 bar is already 90 mg of CO2 per 100 ml of water, which means that not much of the gas produced by this tablet will form bubbles, but will go directly into solution. This reaction will start even if only a very small amount of water is added, as water is also one of the reaction products. This means that during manufacturing, but also during storage, all contact with water has to be minimised as much as possible.

PRODUCTION PROCESS The production of effervescent tablets is first of all a conventional solid dosage form manufacturing process, which has to take into consideration, due to the special characteristics of the product, some unusual features. Materials Handling - On the one side the material is quite hygroskopic and on the other side an intake of moisture cannot be tolerated as this will start the effervescent reaction. Principle strategies in overcoming this problem are a completely closed material handling involving IBCs, docking stations, and split valve technology as shown in picture 1(above). In addition this means that all IBCs and also all production machines must allow for proper venting with air of a sufficiently low moisture content. This method is especially attractive if, additionally, potent actives are handled which also require a high level of personal protection for the operators. The alternative is the open handling of the product which allows the use of much simpler types of equipment, but as a downside the ventilation of the production area must be down to the maximum tolerable moisture level required. Granulation and Drying - As most tablets today are compressed by high speed rotary tablet presses, the material to feed these tablet presses has to show some special characteristics not only to avoid segregation, but also to assure a homogeneous filling of the dies to assure a weight homogeneity. The most common approach for achieving materials with these characteristics is to granulate the raw materials. As a straight forward wet granulation will ruin the product by starting the effervescent reaction, several alternatives have been established. A guide for process selection within an industrial scale for a given formulation is shown in (2).

Dry methods - Dry methods like slugging, direct compression or roller compaction are used quite regularly in the production of solid dosage forms. A detailed review of the different dry methods can be found in (1). Especially for the production of effervescents the use of these methods is attractive as no liquid is involved, which means that no additional drying step is needed. Another advantage is the reduced need for equipment due to the limited number of unit operations required. As a consequence of this, the ventilation of the machines or of the building can be simplified. Especially roller compaction as a continuous methods allows, if properly automated, the realization of a very high throughput. The major argument against the use of dry methods is the need for expensive excipients which is only acceptable for small production volumes. Two granulates method - One possibility for making wet granulation is to run two separate granulation steps for the alkaline and the acid components with a subsequent dry blending step. This can be done in a high shear granulator, with subsequent drying, a single-pot or in a fluid bed spray granulator. Detailed reviews of all these technologies can be found in (1). Advantage of this method is that only conventional equipment is needed which can also be used for the granulation and drying of other materials. Major disadvantages are the running time required for this complex process, cleaning aspects if two parallel lines are not used for the two granulations. A critical step can be the blending process and as a consequence the homogeneity of the tablets as not all materials are bonded into one granule as in a conventional wet granulation process.

Pictue 2: One-Pot Processor ULTIMAPro 75 by Collette One granulate method using organic solvents - As the effervescent reaction is only started if the materials come into contact with water and not if they come into contact with organic solvents, one possibility is the use of organic solvents as a granulation fluid. This can be executed in a high shear granulator and subsequent drying, a single-pot or in a fluid bed spray granulator. The only disadvantage of this method is the need for more complex equipment to handle these fluids. Especially if a fluid bed is used, then a quite complex system for the exhaust gas treatment is required as a mixture of organic vapor and a large amount of non-condensable process gas has to be treated. This system can be applied much more easily in a tray dryer or a single pot as only the organic vapor has to be handled. An example of a Single-Pot is shown in picture 2. Other than that the method offers a lot of advantages which originate from the lower heat of evaporation in comparison with water: a high throughput; the possibility for drying at lower temperatures and the freedom to use a lot of different excipients to achieve the desired product characteristics.

One granulate method using water - Although this chapter seems to be a contradiction in terms to the statements made above, it is possible to use water as a granulation fluid. Only a very small amount of water is added which will start the pre-effervescent reaction by which some of the carbondioxide is already released during the granulation phase, but by which water is also produced as a reaction product, which will then act as a granulation fluid producing more carbondioxide and also more water. This avalanche needs to be stopped at a certain point by starting the drying process and removing the water. This can be done using a high shear granulator with subsequent fluid dryer by discharging at the end of the granulation process the material into a pre heated fluid bed dryer. As the most critical step is the discharge and transfer operation this works fine for small and medium batch sizes, but might lead to problems for larger batch sizes as the long time needed for this operation is unacceptable. A second possibility is the use of a single-pot, where the granulation process can be aborted by switching to the drying mode, which can either be effected by the use of a double jacket and a vacuum system only or also gas or microwave technology assisted. While the first two possibilities work pretty well for the small and medium scale, they might be due to the poor surface/volume ratio- too slow for the larger scale. In any case, the heat energy stored in the warm granules at the end of the granulation process will be sufficient to start the drying process the moment the vacuum exhaust system is switched on. A detailed review of drying in single-pots is given in (3). Fluid bed spray granulation is a unique process where granulation and drying take place at the same time. This assures at all times a low moisture level limiting the pre-effervescent reaction to a minimum. In addition, when using a fluid bed for drying, it is very easy to reach the very low final moisture level required for storage. Downside is that more granulation fluid is needed than in a high shear process. Addition Of Lubricant - It is common practice in tablet production to add a lubricant after granulation. The most commonly used substance is magnesium stearate. Its function is to improve the flow of the material, which is extremely important as the dies of a tablet press are filled by volume. A second function is to prevent the tablet sticking to the punch faces or to the walls of the dies. In effervescent production substances like magnesium stearate should not be used as they are insoluble in water and a film will consequently form on top of the water after the tablet has dissolved. Strategies to overcome this problem are the use of other lubricants which are soluble in water, for example a mixture of spray dried L-leucine and polyethylene glycol which is described in (4), (5). The other possibility is to work without any addition of a lubricant, this has the advantage of saving the blending step, but as a downside has special requirements for the tablet press which will be discussed later in that chapter.

Picture 3: Punch face and die lubrication system by Courtoy

Tablet Compression - The compression of effervescent tablets is different from the compression of normal pharmaceutical tablets. The first aspect is that for storage over a longer time a very low moisture content such as typically less than 0,3% of water is required, while it is common for other tablets to work in the area of about 2%. In addition, effervescent tablets have a tendency to be quite large. This very often leads to the problem that the tablet hardness is not sufficient, which not only results in a significant number of broken or at least damaged tablets resulting in a poor yield, but also in a need to stop the press or the packaging line. One possibility of overcoming this problem is to increase Dwell Time by modifying the pre-compression assembly of a tablet press. The most commonly used system on the market to do this is the Courtoy Air Compensator System which is described in detail in (6). If one decides to work without a lubricant, the first problem is the poorer flow characteristics of the material. This can be addressed by using a constant level powder feed system, which consists of a rotary valve guaranteeing constant powder pressure on the forced filling station which in connection with two independently driven feed wheels will assure an accurate filling of the dies. Details can be found in (6). The second problem, when working without a lubricant, is that the tablets tend to stick on the die walls or on the punch faces. At the least this is a cosmetic problem, because of the scratches on the tablet surface, but it can also be real production stopper if the press has to be stopped in order to remove manually the tablets which have not properly ejected. A common practice used to overcome this is the use of a punch face and die wall lubrication system. These systems allow the addition of a very small proportion of solid or liquid lubricant to the punch faces and the die walls just before they come in contact with the granules. An excellent description of these systems can be found in (6). In picture 3 such a system is shown. Lastly, it should be mentioned that tablet presses, due to their design easily allow the processing of effervescent materials while only purging the compression zone with dry air, removing the need to vent the complete room. Packaging - After the material has been pressed into tablets then the surface area of the material has been significantly reduced, which means that the rate moisture is absorbed from the air has also been reduced. Consequently, this means that the dehumidification of the environmental air is now less critical. Blisters and tube arrangements are used for packaging. For example, standard packaging materials are used in the packaging of food products or some nutraceuticals where shelf life is not critical. In most cases, this is not acceptable for pharmaceutical products. Aluminum, which has a lesser water permeability, is used instead of standard polymer blister materials. If ten or even more individual tablets are packed into one tube very dry air can be added, but as the user opens the tube to take out the first tablet, then ambient moist air will enter which will destroy the effervescent tablets. To overcome this silica gel or other drying agents are incorporated into most tube lids. CONCLUSION Effervescents are an interesting pharmaceutical dosage form offering some unique advantages when compared to simple tablets. The manufacturing process involves some critical steps which need to be addressed carefully during formulation and factory design. 1. 2. 3. 4. 5. Parikh, D.M., Handbook of Pharmaceutical Granulation, Marcel Dekker Inc., New York, 1997 Pearlswig, D. M., Simulation Modeling Applied To The Single Pot Processing Of Effervescent Tablets. Master's Thesis, North Carolina State University, 1995 Stahl, H., Drying of pharmaceutical granules in single pot systems. Pharm. Ind. 1999, 61 (7) ,656-661 Rscheisena, G.; Schmidt, P.C., Preparation and optimisation of leucine as lubricant for effervescent tablet formulations. Pharmaceutica Acta Helvetiae 1995, 70 (2), 133-139 Rotthuser, B.; Kraus, G.; Schmidt, P.C., Optimization of an effervescent tablet formulation containing spray dried L-leucine and polyethylene glycol 6000 as lubricants using a central composite design. Eur. J. Pharm. Biopharm. 1998, 46 (6), 85-94 Van der Goten, W.; Special requirements for tablet presses to be used in effervescent production. Technical Paper; Courtoy, Halle 2001

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This technical article was first publish in the journal Pharmaceutical Technology Europe in April 2003, if you like to download in pdf format follow link to our library.