Preparation and characterization of a secnidazole-mandelic acid coamorphous system: enhanced dissolution profile, antibacterial properties, and theoretical druglikeness assessment

This work describes the successful preparation of the first secnidazole (SNZ) coamorphous system using mandelic acid (MND) as a coformer via the slow solvent evaporation method, aiming to develop improved antimicrobial dosage forms. The coamorphous nature of the SNZ-MND system was confirmed by powder X-ray diffraction (PXRD), which revealed that the 1:1 ratio remained stable and amorphous for over 180 days. Its hygroscopicity and the structural, spectroscopic, and thermal properties were thoroughly investigated, supported by computational calculations, including Hirshfeld surface analysis, density functional theory (DFT), and in silico pharmacokinetic simulations. DFT calculations in the gas phase and ethanol provided insights into the thermodynamic, geometric, electronic, and vibrational parameters of the SNZ-MND heterodimer. The optimized geometry indicated that a hydrogen bond between the imidazole ring of SNZ and the carboxylic group of MND is a key stabilizing interaction. Thermodynamic data confirmed the spontaneity of this interaction, with an interaction energy of -2.02 kcal/mol in the gas phase. Vibrational modes were securely assigned by correlating experimental and calculated infrared spectra. Thermoanalytical analysis revealed a glass transition temperature of 106.5 °C, highlighting the system's thermostructural stability. Dissolution studies in phosphate buffer (pH 6.80) showed that the SNZ-MND coamorphous system exhibits a 1.22-fold higher dissolution rate than crystalline SNZ, a critical factor for bioavailability. The final plateau concentrations reflected the experimental setup under sink conditions. Similarly, apparent solubility measurements indicated a 22 % (39.5 ± 1.2 mg/mL) increase in dissolved concentration compared to the crystalline form of the drug. Importantly, the SNZ-MND (1:1) coamorphous system exhibited enhanced antibacterial activity against Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa compared to the isolated compounds. These findings underscore the potential of the newly developed SNZ-MND coamorphous system as a promising antimicrobial binary composition with improved physicochemical and biological properties to be used in pharmaceutical dosage forms.