Structural insights into novel coamorphous systems of azithromycin with faster dissolution profile

In this study, azithromycin, a broad-spectrum antibiotic compound used for the treatment of several bacterial infections, which is characterized by a very low water solubility, was combined with different small molecules to generate more soluble coamorphous solids. The multicomponent systems were prepared through fast precipitation from an ethyl acetate solution, facilitating the formation of amorphous phases in seven azithromycin-based systems. Differential scanning calorimetry confirmed the coamorphous nature in five out of seven systems (i.e., azithromycin–2-, 3-, and 4-aminobenzoic acids, –salicylic acid, –caprylic acid), while two systems (azithromycin–methyl salicylate, –glycerol) exhibited ambiguous thermal behavior. Stability assessments revealed that the homogeneous coamorphous systems remained stable for at least 140 days at 40 °C, while pure amorphous azithromycin, recrystallized within 72 h. The most suitable coamorphous systems were characterized through pair distribution function analysis, providing molecular-level insights into their structural organization. Notably, the azithromycin–caprylic acid system exhibited distinct molecular packing, likely attributable to the unique structural characteristics of its fatty acid-based coformer, which also led to a faster drug dissolution rate compared to the pure crystalline and amorphous azithromycin forms.