Oral Rehydration Solutions

The Practical Issues

WHO/UNICEF Standard Formulation

Since 1971, WHO and UNICEF began to promote the use of a standard formulation for the preparation of oral rehydration solutions, widely regarded as the physiologically most appropriate single formulation for world-wide use. It consists of the following active ingredients mixed in dry form for making one litre of solution:

    Glucose, anhydrous 20.0 grammes
    Sodium chloride 3.5 grammes
    Sodium bicarbonate 2.5 grammes
    Potassium chloride 1.5 grammes

    Total weight 27.5 grammes
Aluminium foil packets containing 27.5 grammes of the mixed ingredients for making one litre of solution are distributed internationally by UNICEF under the non-proprietary name of Oral Rehydration Salts (ORS) -- formerly Oralyte. The use of Aerosil (colloidal silicon dioxide) as an excipient in the proportion of 2 grammes per kilogramme of ORS is optional. Aerosil is harmless in this concentration, but renders the ORS solution very slightly turbid. There are a number of alternative preparations that do not comply in composition with the WHO/UNICEF formulation. These have not yet been clinically evaluated.

For reconstitution of the standard formulation when required to be given by mouth, the contents of one ORS packet are to be dissolved in one litre of clean drinking water. UNICEF recommends boiling the water and allowing it to cool before using it for the preparation of the solution as hot water is apt to decompose the sodium bicarbonate. When the content of one ORS packet is dissolved in one litre of water, the following concentrations of the active ingredients are obtained:

    Sodium (Na+)
    Chloride (Cl-)
    Bicarbonate (HCO3)
    Potassium (K+)
    111 m mol/litre
    90 m mol/litre
    80 m mol/litre
    30 m mol/litre
    20 m mol/litre
Solutions complying with the standard formulation, when used correctly, have produced remarkable results in the treatment of dehydration due to a wide variety of diarrhoeal disorders, including cholera, in all age groups. They are also useful to maintain hydration during continuing diarrhoea, provided additional fluids are given to infants to avoid the possible risk of developing hypernatremia. The adoption of such universally applicable solutions simplifies the large-scale production and distribution of premixed ORS.

Production and Distribution

Out of an estimated two billion packets of standard ORS believed to be needed annually for dehydration control throughout the world, only about 80 million are being produced for distribution. Since 1981, UNICEF has been distributing about 20 million packets annually at US $0.08 per one-litre packet, including freight, in an attempt to meet the partial national requirements of 87 nations. Together with WHO, it has continued to encourage national and regional production. By December 1982, 30 developing countries were producing ORS with the assistance of WHO and UNICEF. Brazil alone is now producing some 20 million packets a year, and Pakistan has increased its annual production to 5 million packets. On its part, WHO has recently published a very instructive manual (Guidelines for the Production of Oral Rehydration Salts) which includes specifications, methodology, and quality control.

Some of the countries producing packets of ORS under different brand names include Costa Rica (Sueroral), Tunisia (Orasol), Egypt (Rehydran), Honduras (Litrosol), and Peru (Salvadora). Packets with amounts of ORS smaller than the standard formula are being produced in some countries for practical reasons. In Costa Rica, for instance, Sueroral packets are intended for 240 ml of solution. Such alternative products are more expensive than the UNICEF packets, and can only reach a small minority of users. Besides, the contents may not be uniform in composition or weight. Other shortcomings include the use of packaging materials that are difficult to open, or powders that do not dissolve readily. Some products may have a poor shelf life. These difficulties may discourage some families from using the local products.

The Program for Appropriate Technology in Health (PATH) in Seattle, Washington, USA, has recently developed ORS tablets. These PATH ORS TABLETS, 2.5 cm in diameter and weighing 5 grammes, are currently formulated to make 150 ml of rehydration solution. The tablet formula complies with the WHO standard formulation except that sodium citrate is substituted for sodium bicarbonate to provide the tablets with greater stability and a shelf life of at least one year in polyethylene packages, and even more if foil-laminated packaging material is used.

Modified WHO Formulations

PATH is promoting the local production of these tablets, and is prepared to help in the transfer of the technology for production in developing countries. In fact, by February 1984, PATH was in the process of transferring the production technology to a company in Indonesia and to another in Thailand. Other technology transfer arrangements in Latin America are presently under consideration.

Some ingredients in the standard ORS formulation may be substituted for in-country packet production, or preparation of homemade solutions, without essentially altering the therapeutic effects on rehydration. Selection of substitutes is determined by such additional factors as availability, relative cost, and prolongation of the shelf life.

Some commercial preparations used for oral rehydration contain sodium citrate in place of sodium bicarbonate to achieve a longer shelf life, although the latter is preferred because of lower cost and greater availability.

WHO is continuing its interest in improving the shelf life of the ORS ingredients by appropriate substitution of ingredients and packaging materials. This has been evoked by evidence from field experience indicating that packaged ORS is subject to deterioration due to the reaction of glucose with sodium bicarbonate leading to the formation of a brownish discolouration and lumping of the ingredients.

Although standard ORS in laminated aluminium foil packets have an estimated shelf life of at least three years, their storage in developing countries with extremely hot and/or damp climates are likely to accelerate deterioration and caking of the ORS mixtures. In an effort to overcome such a problem, WHO has developed three alternative formulations that need to be tested for stability and effectiveness. Sodium bicarbonate is substituted by sodium citrate in two of these alternative formulations, and by potassium citrate in the third.

Deterioration on Storage

At the request of WHO, the Central Laboratory of German Pharmacists in Frankfurt has carried out accelerated stability tests on the four ORS formulations developed by WHO made from ingredients of pharmacopoeial purity, with and without packaging in polyethylene foil or laminated aluminium foil. The results, reported in June 1983 (Pharmazeutische Zeitung), indicate that both humidity and temperature tend to promote deterioration. The percentage absorption of moisture that leads to lumping of the ingredients may reach as high as 10% for anhydrous glucose, 80% for potassium citrate, and 140% for sodium chloride. Sodium bicarbonate starts to decompose at temperatures above 40°C with evolution of carbon dioxide gas which may cause some packets to burst during storage. Significant changes in colour and consistency were observed at storage temperatures exceeding 40°C. Unlike the formulation with sodium bicarbonate, those with sodium or potassium citrate as substitutes proved to be more chemically stable. The conclusion is that glucose and sodium bicarbonate in standard ORS packets, when stored at high temperatures or humidity, would interact and undergo considerable decomposition. By replacing bicarbonate with citrate, a more stable ORS mixture can be obtained.

Laminated aluminium foil proved to be the best packaging material for long-term storage in extremely damp climates, whereas polyethylene foil is preferable for dry and hot climates as its permeability allows drying and stabilization of the ORS mixture during storage. The choice of packaging material, therefore, depends mainly on a country's climatic conditions. Because polyethylene foil is transparent, however, ORS packets can be checked visually for signs of glucose decomposition accompanied by discolouration and lumping. Therefore, the use of polyethylene packets can be a compromise for world-wide distribution.

It is thus concluded from this study that the formulation prescribed below is recommended for large-scale production because of its much slower rate of deterioration, and therefore potentially longer shelf life, in preference to the other three ORS formulations developed by WHO:

    Glucose, anhydrous 20.0 grammes
    Sodium citrate (C6H5Na3O7.2H2O) 2.9 grammes
    Sodium chloride 3.5 grammes
    Potassium chloride 1.5 grammes

    Total weight 27.9 grammes
To help prolong shelf life, an alternative mode of packaging ORS practiced in India essentially involves separation of glucose or sugar from the salt by packaging the latter in a small, sealed packet placed inside a larger packet containing the glucose or sugar, which is then also sealed. These packets, known as kangaroo packets, were shown to be effective for storage for as long as nine months in adverse field conditions without detectable changes in the components. They are useful therefore in areas where the usage rates of ORS solutions are low, provided clear instructions are given for their proper preparation.

Because high temperatures and humidity would accelerate the deterioration process, manufacturers must consider these factors when preparing and packing ORS. The packaged product must be properly stored until distributed for use, preferably at temperatures and humidity not exceeding 30°C and 80 percent, respectively. Batches showing signs of deterioration upon inspection (lumping, turning brown, and difficulty in dissolving) should be discarded. If the ORS packets have only turned yellow, and can still be readily dissolved, they are considered to be still effective and safe to use.

Sucrose as a Substitute

WHO has proposed using 40 grammes of common sugar (sucrose), if justified by availability and cost, in place of the 20 grammes of glucose prescribe in the standard ORS formulation. Although glucose is preferred if it is available at comparable cost, studies have shown common sugar to be almost as effective as glucose for rehydration. In Bangladesh, for instance, substantial savings in cost were achieved by using a crude, locally produced sugar called gur as a substitute for glucose of sucrose. It should be noted, however, that common sugar bought from local markets is sometimes adulterated with water to increase the selling weight, its world priced have fluctuated dramatically in recent years, and shortages are not uncommon in some of the developing countries as is the case in Ghana and Tanzania.

Flavouring Additives

ORS solutions, when properly prepared from UNICEF packets, taste slightly less salty than human tears. Since this is sometimes considered by some to be an unpleasant taste, various flavouring substances have been proposed for addition to ORS to improve the palatability of the solutions. Apart from substantially raising the cost of manufacturing the ORS formulation, solutions with specific artificial flavours do not necessarily appeal to all users.

In a field study carried out in Ankara, Turkey, in 1979, a greater rate of acceptability for the product was observed among children give solutions made from ORS packets supplied by UNICEF compared to those prepared from locally produced packets.