The Effervescent Reaction

Effervescence is the evolution of gas bubbles from a liquid, as the result of a chemical reaction. The most common reaction for pharmaceutical purpose is the add-base reaction between sodium bicarbonate and citric acid  

Recently, some effervescent systems have been prepared that act as penetration enhancers for drug absorption, not only in oral forms but also in some topical forms, such as skin or vaginal applications. In these cases the reaction takes place directly after administration, in the mouth due to saliva (4), upon the wounds due to blood serum (5), or when formulated in a suppository. The effervescence can be provoked by the moisture of the vaginal mucosa to treat vaginal infections or by simply adjusting the pH. 

There are other forms in which effervescence is based on a reaction different from carbon dioxide formation. Effervescence is due to reactants that evolve oxygen or other gases, which are safe for human consumption 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. 

The criteria to choose the raw materials for effervescent products are not very different from those for conventional tablets, since in both cases good compressibility and compactability are the targets to be achieved. 

The intrinsic characteristics of effervescent forms bring some considerations that limit the choice of the raw material, including the selection of the active ingredient. Moisture content of the raw material is a very significant aspect, because it affects compressibility and stability of the tablets. To avoid premature effervescent reaction during the process or once the tablets are formed, raw materials with very low moisture content have to be used. 

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The acidity for the effervescent reaction can be obtained from three main sources acids, acid anhydrides, and acid salts. Traditional sources of acid materials are the organic acids, citric and tartaric acid however, some acid salts also are used. 

When granulating either with solvents containing water or pure water, the effervescent reaction will start. Care must be taken to maintain adequate control of the process. Vacuum processing is often beneficial due to the ability to control the effervescent reaction and the drying process. 

Even the moisture in the air may be enough to initiate the effervescent reaction of an effervescent product if it is not properly protected. When the consumer opens the container, the effervescent product will again be exposed to the moisture in the air. Consequently, the packaging of all effervescent products is very important. The time between tablet production and start of packaging operation should be kept as short as possible. 

When water is used as granulation liquid for effervescents, the effervescent reaction will start and cause a chain reaction. The critical point in such a process is to stop this reaction at the correct time by evaporating the water created by this reaction. In a single-pot processor, this can be very easily and accurately achieved by switching on the vacuum-drying system (possibly supplemented with gas-assisted drying or microwave drying) (24). 

Because of the nature of the effervescence reaction, additional excipients are sparingly used as the alkaline and acid ingredients also act as fillers to get a tablet bulk. 

It is very soluble in water and very hygroscopic compared to 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, because it is a diprotic acid, while citric acid is a triprotic one. In terms of compressibility it is comparable to citric acid (8). 

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 (9). If exposed to light, it gradually darkens. Its behavior in the effervescent reaction with sodium bicarbonate is comparable to the other acids (citric and tartaric) in terms of release rate of carbon dioxide. 

Sodium carbonate is commercially available in three different forms, all very soluble in water anhydrous, monohydrate, or decahydrate (13). It is more resistant to the effervescent reaction and in some formulations can be used as a stabilizing agent in amounts not exceeding the 10% of the batch size. It is used as a stabilizing agent in certain effervescent formulas because it absorbs moisture preferentially, preventing the effervescent reaction from starting. Of course the anhydrous form is the... 

Manufacturing conditions are crucially important even with regards to stability of the products after they have been packed. Almost all the raw materials used for effervescent tablet manufacturing are hygroscopic, and hence moisture absorption from the air must be prevented to avoid the effervescent reaction prior to use of the tablets. 

For this technique, it is necessary to use a granulating liquid that might interact with the powders initiating the effervescent reaction. Hence it is essential to handle the process with great care. 

The peculiar process that distinguishes effervescent granulation consists in a single-step granulation of all the components of the formulation, which can be performed either with nonreactive or reactive liquids with reference to the effervescence reaction. 

The application of microwave radiation, combined with vacuum inside the bowl of the high-shear granulator (27), can also be used to stop the effervescent reaction and to dry the effervescent granules (28). 

I.3.2. Process with Alcohol or Hydroalcoholic Solution. As reported in the previous example, it is sometimes preferable to granulate with a hydroalcoholic solution to initiate a lighter effervescence so as to keep the reaction under better control during the process. Use of alcohols is indispensable in case a binder like PVP is included in the formulation. In fact, the amount of water required to dissolve PVP to obtain the binding action will be too high, and it will not be possible to keep the effervescent reaction under control. 

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