Importance Of Formulation On The Solubility Of Products Containing Sulfonamides And Trimethoprim

Trimethoprim has a low solubility in drinking water (0.4 mg/ml) which leads to sedimentation when veterinary products based on sulfonamides and trimethoprim are used in highly concentrated stock solutions. However, ensuring the availability of both active compounds is crucial to achieving their beneficial synergistic effect. Both active compounds should reach the target tissue at the optimal ratio and concentration. If only the sulfonamide part is dissolved, animals don't benefit from the synergism, leading to a lack of clinical efficacy. Furthermore, sedimentation in the water delivery systems creates extra work for the farmer and increases the risk of blockages in the pipelines.

A field trial was carried out to compare the recovery of sulfadiazine and trimethoprim from two veterinary products used in drinking water, both containing 500 mg sulfadiazine and 100 mg trimethoprim/g. Both products were administered at the registered dose of 25 mg sulfadiazine and 5 mg trimethoprim/kg body weight/day (pigs and chickens) and medicated water was consumed within 12 hours after the start of administration. Therefore, a highly concentrated stock solution with a proportioner set at 1% dilution (1:100) was used.

Two products, two different formulations

The first product tested was HydroTrim®, a unique formulation based on the nanonisation of trimethoprim. Using this technology, poorly soluble trimethoprim crystals are ground into many small nanoparticles. The subsequent increased surface area results in the fast and complete dissolution of trimethoprim.

Figure 1. Nanonisation of trimethoprim in HydroTrim®

The second product tested was a simple powder mixture. 

Visual appearance

The visual appearance of the stock solutions after product administration was evaluated. 

HydroTrim® - Excellent homogeneity throughout the administration period.

Other formulation - substantial and increasing sedimentation beginning 0.5 hours after administration.

Concentrations of sulfadiazine and trimethoprim

Water samples were taken from the stock containers and the drinking nipples in 10 pens to determine the concentrations of both active compounds. Samples were collected 2, 6 and 10 hours after the product was added to the water.

The concentration of sulfadiazine and trimethoprim in the stock container (samples collected from the middle of the remaining volume) can be seen in Figures 2 and 3, respectively.

Figure 2. Sulfadiazine concentration in the stock containers

Figure 3. Trimethoprim concentration in the stock containers

The concentration of sulfadiazine and trimethoprim at the nipples can be seen in Figures 4 and 5, respectively.

Figure 4. Sulfadiazine concentration at the drinking nipples

Figure 5. Trimethoprim concentration at the drinking nipples

After 12 hours of HydroTrim® administration via a proportioner, the filter in the water system was still clean (Figure 6). 

Figure 6. Clean water system filter after 12 hours of HydroTrim® administration via a proportioner 

Conclusion

HydroTrim® administration through proportioners achieved perfect homogeneity due to its unique formulation technology. In contrast, the simple powder mixture showed immediate sedimentation of trimethoprim after administration. With HydroTrim®, trimethoprim concentrations were significantly higher both in the stock container and at the nipples, leading to superior synergistic activity between sulfadiazine and trimethoprim.