Why Effervescence In Pharmaceuticals?
Effervescence is the method of choice when formulating active ingredients with poor solubility. Sodium glycine carbonates are versatile carriers of carbon dioxide in pharmaceutical effervescent applications.
Stefan Vandenberghe - Group Tessenderlo
Efficiently administering medicine is of the utmost importance in order to obtain good therapeutic results.1a When a patient is admitted to the hospital, drugs are frequently administered intravenously which results in an immediate uptake and prompt release in the bloodstream.1b Active ingredients are transported by the bloodstream to the locations where they have an immediate therapeutic effect.
Unfortunately, this prompt release is more difficult when patients are treated at home. Pharmacists must devise new methods in order to deliver active ingredients as quickly and efficiently as possible. Other very efficient ways to administer the active ingredient include: injectables,1c patches1d and aerosols.1e Injectables often require the assistance of medics or paramedics. Meanwhile, although patches and aerosols are easy to use, not all active ingredients can be administered in this way. Moreover, many patients dislike this administration method, which may cause them to interrupt or discontinue their treatment.
The most common way to give patients their medicine is by oral administration, through pills, tablets, capsules and syrups.1f There are some drawbacks, however, especially concerning pills, tablets and capsules. For example, all three take time to dissolve in the stomach and release the active ingredient. This increases the time that is needed to transport the drug from the intestine into the bloodstream. Dissolving the pill, tablet or contents of the capsule in water prior to ingestion is a common way to avoid this extra step in the stomach. Yet, the obtained solution is seldom clear and contains undissolved material.
One pill alternative is the formulation of active ingredients as effervescent tablets. When dissolved in the water, the basic excipient (a carbonate) and the acid excipient (an organic acid) will react with each other, liberating carbon dioxide. Due to the dynamics of this process, turbulence is created and the active ingredient will dissolve more rapidly1g in the water, leaving little or no undissolved material in the solution. Effervescence is the method of choice in formulating active ingredients with poor solubility.
The effervescence gives a “fresh” and sparkling taste to the solution. This effect, together with added flavorings, will result in a better tasting drink, which makes it more agreeable for the patients to take their medication. Furthermore, sodium glycine carbonate is reported to enhance palatability.2
How is Effervescence Obtained?
 Fig. 1: Sodium Glycine Carbonate |
Effervescence is obtained by adding different solids to a solvent (water), which then undergoes a chemical reaction liberating gas. For therapeutic purposes, carbon dioxide is the gas of choice since it is inert (does not react with the active ingredient) and non-toxic in the applied dosage. Sources of carbon dioxide are mineral carbonates and include sodium bicarbonate, sodium carbonate and calcium carbonate, and are referred to as the basic component. In combination with organic acids, effervescence is created upon reaction in water. The most common organic acids include citric acid, tartaric acid, fumaric acid and sodium salts thereof.
The composition of effervescent tablets further comprises a water-soluble lubricant; e.g., glycine, the active ingredient and some other additives. Production through direct compression does not give satisfactory results, and therefore wet granulation followed by compression is the method of choice. Since in most cases, acidic and basic components must be granulated separately, this adds to the cost of production. However, Ethyfarm recently reported manufacturing of effervescent tablets through hot-melt extrusion.3
Sodium Glycine Carbonate
Sodium glycine carbonate [50610-34-9] is a white powder that is very soluble in water (70g/100ml) and has a molecular weight of 238.11 g/mol. Its chemical structure is shown in Figure 1. The manufacturing process of SGC developed by Tessenderlo uses no organic solvents. Therefore no organic volatiles are present which is a major advantage over SGC obtained by other processes.
Yet, sodium glycine carbonate is scarcely mentioned in patent literature3,9,10,11 and barely mentioned in public literature.4,5,6,8
There are two obvious reasons for this omission:
1. Per gram of sodium bicarbonate, almost 270ml of carbon dioxide are released whereas SGC only releases +/- 95ml carbon dioxide per gram SGC.
2. Price. Of course sodium bicarbonate is a lot cheaper than SGC. That is not surprising as NaHCO3 is one of the raw materials in SGC production.
Therefore, it seems logical for pharmaceutical companies to use NaHCO3 (or other mineral carbonates, for that matter) as the basic component in effervescent tablets. In order to consider the use of SGC, there must be distinct advantages over the use of sodium bicarbonate.
Advantages of SGC over NaHCO3
Effervescent tablets made with SGC will of course react with acid when moist. The big advantage of SGC is that this reaction with acid4 does not release water (Figure 2). Effervescent tablets made with other mineral carbonates will rapidly decompose upon exposure to moisture since the decomposition leads to the formation of carbonic acid and thus carbon dioxide and water, therefore accelerating the decomposition.
 Fig. 2: Sodium Glycine Carbonate Does Not Release Water When Reacted with Acid |
SGC is much more soluble7 in water (70g per 100ml) than sodium bicarbonate (approximately 10g per 100ml). This is a distinct advantage while the SGC effervescent tablet will more rapidly dissolve in water, thus ensuring that the active ingredient is rapidly and effectively in solution. Some authors have made the comparison between standard effervescent tablets and the SGC ones for piroxicam. After five minutes, only 65% of piroxicam was in solution with the classic tablets, whereas the SGC formulation made 100% of the piroxicam available after five minutes.
SGC is also very stable when heat is applied.7,8 When heated during 16 hours at 60°C, no thermodynamic changes occurred. When heating SGC at a rate of 1°C/minute from room temperature to 180°C, thermodynamic changes occurred starting at 140°C. Storing SGC in an oven at 80°C during four days showed no loss of weight whatsoever. Under the same conditions, NaHCO3 lost 35% of is weight due to decomposition into sodium carbonate, carbon dioxide and water.
The presence of glycine will buffer the obtained solution. Therefore pH sensitive active ingredients will not decompose when brought into solution using SGC-based effervescent tablets. For sensitive applications; e.g., antibiotics, this can be a major advantage.9
When compressing effervescent tablets with SGC, a water-soluble binder is not necessary in the formulation, because glycine itself has been documented as a very good binder.10
In several publications, authors describe SGC effervescent technology in the following applications: 3,11 acetylsalicylic acid, vitamin B12, butobarbital, tetracycline, mepacrine, piroxicam and amoxicillin.
Conclusion
Although SGC-based effervescent technology is more expensive than classical effervescent tablets based on mineral carbonates, it is far superior. The SGC tablet has a longer shelf life, has a faster dissolving power and buffers the solution. Especially when the active ingredients are very sensitive, formulators should consider SGC as the effervescent agent of choice.
About the Author
Dr. Stefan Vandenberghe is co-responsible within Group Tessenderlo for process development and development of new products and applications within the fine chemicals division. Free samples of SGC and other glycine specialties are available upon request. More info: S. Vandenberghe, pilot plant, Group Tessenderlo, Stationsstraat, 3980 Tessenderlo, Belgium. Tel: (32) (0) 13612240; Fax: (32) (0) 13672343. E-mail: stefan.vandenberghe@tessenderlo.com.
References
1a. L.V.Allen Jr, N.G.Popovich and H.C. Ansel, Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, 8 the edition, p. 92 and onward.
1b. ibid, p. 170.
1c. ibid, p. 168.
1d . ibid, p. 302.
1e . ibid, p. 171.
1f . ibid, p. 162-171.
1g . ibid, p. 149.
2. J.M. Aiache, Pharm. Acta Helv, 49, 169 (1974).
3. A.Galat, U.S. Patent 3,392,195 (1968), Losan Pharma, DE 19606151 (1997), Ethypharm, US Patent 6,649,186 (2003).
4. C. Boymond, Labo-Pharma, Problèmes et techniques (271), 987-995 (1979).
5. J. Amela, R Salazar, J. Cemeli, Drug Development and Industrial Pharmacy, 22(5), 407-416 (1996).
6. J.P. Faguet, F. Puisieux, D. Duchène, Labo-Pharma, Problèmes et Techniques, (274), 207-210 (1978).
7. Tessenderlo Chemie, unpublished results.
8. N. Anderson, G .Banker, G. Peck, J. Pharm. Sci, 71(1), 7 (1982).
9. Chiesi Farmaceutici S.p.A., US Patent 6,667,056 (2003), Beecham Group Plc, WO 91/15197 (1991).
10. Synthélabo, Fr. Demande 9300008 (1993).
11. B. Cazals, Fr. Demande 2,096,949 (1972).
