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Water medication: Stability of different molecules in medications in drinking water
A commercial product is formed by a combination of the active ingredients and excipients. The active ingredient is the compound with therapeutic properties and the excipient is what is added to transform the active ingredients into a combination suitable for administration.
Commercial products used to medicate drinking water must meet quality, safety, and efficiency conditions throughout their life span, both in storage and in use, where stability is critical. Stability tests play a key role in the eventual development of a product. These tests are done with EMEA (European Medicines Agency) and CVMP (Committee for Medicinal Products for Veterinary Use) quality standards based on simulating the actual conditions at the farm.
A commercial product is formed by a combination of active ingredients and excipients.
The active ingredient is a compound with therapeutic properties.
The excipient is what is added to transform the active ingredients into a combination suitable for administration.
Its stability will depend firstly on the compatibility between the excipient and active ingredient: The excipients and some impurities may destabilize the medication. The degradation causes instability and leads to loss of the medication’s potency, undesirable changes in performance (dissolution, bioavailability, etc..) and products that have broken down can cause toxicity.
In a "solid" state chemical reactions are due to the low substance to excipient ratio, changes in the particles (shape, size, impurities, and defects), and the effect of temperature (temperature, pH, light, and oxygen). When we are dealing with a "solution", the temperature, pH, solvent-diluent ratio, light, oxygen, and co-solutes (buffer salts, antioxidants, chelating agents, etc.) are responsible for the degradation.
Table 1. Examples of degradation. Source: Crowley and Martini 2001.
Examples of degradation
Hydrolysis
Oxidation
Isomerization
Photolysis
Polymerization
Penicillins
Ascorbic acid
Tetracycline
Folic acid
Ampicillin
The stability of different products is checked by applying various stability tests.
1. Proven stability of the commercial product
The goal of "stability tests" is to evaluate the quality of the substances added to form the commercial product and recommended storage conditions and use.
A product is considered stable if the active ingredient maintains its specified potency from the date of manufacture to final administration to the animal.
The "stress test" helps determine the intrinsic stability of the molecule by identifying products’ degradation through analytical procedures. We speak of "evidence of long-term stability" to monitor the physical, chemical, and microbiological properties during the life of the product in the same package that is proposed to circulate in the market and "accelerated stability tests" designed to achieve an increased rate of chemical or physical degradation of a product in extreme or exaggerated circumstances and in their original packaging.
Type of test
Storage Conditions
Minimum time
Long term stability
25ºC ±2ºC / 60% RH ±5%
6-12 months
Accelerated stability
40ºC ±2ºC / 75% RH ±5%
6 months
Systems have been developed for laboratory degradation studies simulating different pharmaceutical field conditions.
Figure 1. System for laboratory degradation studies simulating different pharmaceutical field conditions.
2. Stability tests in storage and transportation
The aim is to identify environmental conditions that give stability to the product from manufacture to administration to the animal, taking into account the expiration date based on: analysis, storage temperature recommended, exposure to environmental factors (temp extremes, light, humidity, etc.) and other special restrictions that should be reflected in the label.
Figure 2. Environmental conditions. Source: Cha, Vadim Solomakin, and Alex Bickov from the Noun Project. https://creativecommons.org/licenses/by/3.0/
3. Stability tests in sealed container of the product
The goal is to keep the commercial product with a low % of impurities and with constant physicochemical and microbiological properties. The packaging must protect the product to prevent adverse reactions due to external factors.
4. Stability tests in use of the product
The aim is to check how long the product remains stable after opening the package.
Figure 3. Open package (left) and precipitation (right).
5. Stability tests in drinking water
The different water qualities that can be found on farms make such tests really important. With water there can be physicochemical, microbiological, and pH variations. You should check the stability and solubility of the product in all water conditions and temperatures, simulating real situations (see this article). Test samples of medicated water at different intervals of time checking the concentration of the active ingredient in hard water (pH 8-9) and soft (pH 5-7), and at different temperatures. The maximum solubility of the product when the concentration is several times higher than that used at the field level should be noted. Turbidity as reduced transparency due to the presence of suspended particles is measured and expressed in units NTU (Nephelometric Turbidity Units). The insoluble fraction can be measured by filtering the solution, drying, and final weight of the residue. Also, it should be assured that the presence of chlorine in the water does not involve phenomena that will act adversely on the stability of the molecule.
Figure 4. A stability test sample of a commercial product in hard water and soft during 24 hours. Source: Av. Tecnol. Porc. VI(3): 110-113.
Figure 5. A stability test sample of a commercial product in hard water and soft depending on time. Source: Av. Tecnol. Porc. VI(3):110-113.
6. Biofilm stability tests
Biofilms are complex communities of microorganisms resistant to antibiotics, coated with an extracellular polymer that helps retain food and protect themselves from toxic agents. The presence of biofilm in water pipes, often due to poor application of sanitizing methods, may affect the stability of the medications. Stability testing can be performed by an antibiogram of these organisms along with a sample of the product to use and looking at the result: if there is massive microbial growth, there is no inhibition, while if it has an effect its stability is compromised.
Figure 6. Three phases of biofilm formation: attachment, colonization, and growth of complex structures of the biofilm. Source: Figure adapted with permission from the Center for Biofilm Engineering, Montana State University.
Figure 7. Biofilm bacteria can move in many ways: either collectively in waves, rolling on the surface, shedding in groups, or individually dispersed in the stream. Source: Center for Biofilm Engineering, Montana State University.
7. Stability tests in maximum storage of medicated water
Prolonged storage may affect the quality of medication (palatability and pollution). This period should correspond to the maximum time during which the concentrate is still effective and safe (expiration date). Factors associated with water-unstable products are poor bioavailability, inability to optimize the active components on the basis of efficacy and safety, lack of proportional response to dose, suboptimal doses, and uncontrollable precipitation after dosing, among others. Interactions between products dissolved in water should also be considered. The graph shows how to modify the pH of water to mix florfenicol with other substances.
Figure 8. Average pH in solutions and in water pipes of various components in the presence of florfenicol.
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We must assure correct management, primarily in the following points: Number of animals / drinker, placement, flow, control of water consumption, design and height of the drinker.
Upon medicating water, the doses should be repeated with a time interval that prevents plasma levels from dropping below the minimum effective concentration and exceeding the toxic concentration.
Medicating water using a tank is an easy and flexible method used to administer drugs, but it can be imprecise if the products we use aren’t totally soluble.
Biofilm, “the dirt in water pipes”, the causative agent of problems in the conditions and the quality of the water supply, is the subject of this article.
Both "vehicles" for oral medication may be valid and often complementary, but as when making any decision we must consider several factors along with their advantages and disadvantages: cost, speed, flexibility, efectiveness...
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