Azithromycin Salt/Cocrystal with Glycine and Acetamide for Superior Drug Performance: Experimental, Characterization and DFT Study

Medicines often face a hidden hurdle before they can heal a patient: the journey from a pill to the bloodstream. For a drug to work, it must first dissolve in the watery environment of the body. If a medicine dissolves too slowly or not at all, it cannot reach the infection it is meant to fight, no matter how powerful its chemical formula might be. This is a common problem for many antibiotics, including a widely used one called azithromycin. While effective against a broad range of bacterial infections, this drug struggles to dissolve quickly in water, which limits how well the body can absorb it. To solve this, scientists have turned to a field of chemistry that treats solid medicines not just as single substances, but as partners. By carefully pairing a drug molecule with a harmless, food-grade partner, researchers can build new solid structures that behave differently than the original drug alone. These new structures, known as salts or cocrystals, can change how a medicine feels, how stable it is, and most importantly, how fast it dissolves.

In a recent study, researchers set out to improve the performance of azithromycin by creating two such new solid forms. They paired the antibiotic with two different, simple molecules: glycine, which is the most basic building block of proteins found in the human body, and acetamide, a common chemical used in various industrial and pharmaceutical processes. The team mixed the drug and these partners in equal amounts using a simple method of dissolving them in water and methanol, then letting the liquid evaporate slowly. As the liquid disappeared, the molecules rearranged themselves into new, stable crystals. The goal was to see if these new combinations would dissolve faster and work better than the standard form of the drug.

To confirm that they had successfully created these new structures and not just a simple mixture of the two ingredients, the scientists used a suite of advanced tools to look at the materials on a molecular level. They examined the crystals with light-based techniques that measure how molecules vibrate and absorb energy. The results showed clear signs that the drug and its partners had bonded in specific ways. In the case of the drug paired with glycine, the evidence pointed to a salt formation, where a tiny particle of electricity, known as a proton, moved from the glycine to the drug, creating a strong electrical attraction between them. With the acetamide partner, the molecules held together through a network of hydrogen bonds, a slightly different but equally stable type of connection. The researchers also used computer simulations to model these interactions, confirming that the new structures were energetically favorable and stable.

The physical properties of these new materials were just as promising as their chemical makeup. When the team tested how well the new forms dissolved in liquid, they found a significant improvement over the original drug. The new salt and cocrystal forms released their active ingredient much faster, particularly in conditions that mimic the human body. This faster dissolution is crucial because it means the medicine can enter the bloodstream more quickly and effectively. Furthermore, when tested against common bacteria like those that cause stomach and respiratory infections, the new forms showed stronger antibacterial activity than the pure drug, even though they contained less of the antibiotic by weight. This suggests that by making the drug more available to the body, its ability to fight infection is enhanced.

The study also looked at how these new crystals behave under heat and over time. One of the new forms, the salt with glycine, was found to absorb moisture from the air, which is a trait known as being hygroscopic. The other form, the cocrystal with acetamide, remained dry and stable. These differences are important for manufacturers, as they dictate how the medicine should be stored and packaged to remain effective on the shelf. While the researchers noted that further testing in living animals would be needed to fully confirm these benefits for human patients, the laboratory results provide a strong foundation. By simply rearranging the solid structure of a familiar antibiotic, the team demonstrated a practical way to overcome the limitations of poor solubility, offering a potential path to more effective treatments for bacterial infections.