It works better than the physical mixture of two drugs.

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.

Better solubility

The two drugs were ground for Dr. Shanmukha Prasad Gopi (first left) and Prof. Gautam Desiraju (right) at IISc. Photo: Special Arrangementnearly 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.

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.

Combating microbes

“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.

Potency tested

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 salt has properties that are more than the aggregate of the individual properties,” Prof. Desiraju says.EOM