Using crystal engineering, a team of researchers from the Indian Institute of Science (IISc) Bangalore has successfully produced a highly efficacious binary salt of two commonly used drugs — norfloxacin (antibacterial) and sulfathiazole (antimicrobial). The salt is more effective than a physical mixture of the two drugs. The results were published in the journal Molecular Pharmaceutics.
The two drugs were ground for nearly 30 minutes and made into a solution from which the salt was produced. It has enhanced pharmaceutical effects compared to the physical mixture of the two drugs.
The underlying reason for the salt’s improved efficacy is the better solubility and diffusion of the drugs, particularly norfloxacin and, therefore, enhanced bioavailability and pharmaceutical activity.
“Norfloxacin in a pure form or in a physical mixture has low solubility and permeability, so the amount of the drug that goes through the membrane and gets into tissues is less. To compensate for this, higher dosages of norfloxacin drug are generally used,” says Prof. Gautam R. Desiraju from the Solid State and Structural Chemistry Unit at IISc and the corresponding author of the paper.
The salt has properties that are more than the aggregate of the individual drug properties.But in the case of the binary salt, a “large enhancement in overall solubility” was seen at pH 7.4, which is generally seen in the small intestine where most of the absorption takes place. Most importantly, both the drugs showed comparable solubility when present in the salt form.
Similarly, in the case of permeability, the amount of binary salt diffusing through the membrane was much higher in the first hour. In contrast, the parent drugs show much lower diffusion. When the drugs are present together in a physical mixture, each one has a different rate of diffusion across the membrane. “But in the case of the binary salt both diffuse together. It is like sulfathiazole pulls norfloxacin across the membrane so both the drugs are available at the same time at the site of action to combat the microbes together,” he says.
“We are trying to study the mechanism behind the increased diffusion so that we have molecular level understanding of what precisely is happening,” Prof. Desiraju says.
“Generally the salt form increases solubility and because of high solubility or concentration gradient diffusion gets enhanced,” says Dr. Shanmukha Prasad Gopi from IISc and the first author of the paper.
The potency of the salt and the physical mixture of the drugs was tested on E. coli, Staphylococcus aureus and fungi. Studies showed that the salt was able to achieve the same result of inhibiting bacterial and fungal growth at about half the concentration of the physical mixture.
For the same dosage, the salt had nearly five times greater area that was clear of microbes than the physical mixture of the two drugs. The greater inhibition of microbes around the salt might be due to greater solubility and faster release of norfloxacin from the salt compared with the pure form and the simultaneous presence of both the drugs at the site of action when present as a salt. “The salt has properties that are more than the aggregate of the individual properties,” Prof. Desiraju says.
Due to enhanced solubility, the amount of norfloxacin required will be less and, therefore, lesser chances of developing resistance against the drug. The team has patented the salt. A Mumbai-based pharmaceutical company has already shown interest in the salt.