Thermo-acoustic and computational studies for the mixture of drug (NSAIDs) and D-mannitol in an aqueous system: Implications for pharmaceutical formulation

Background: The interactions of non-steroidal anti-inflammatory drugs (NSAIDs) with excipients significantly influence their solubility, stability, and bioavailability, and have a significant impact on the therapeutic efficacy of drugs. Objectives: The present study explores the molecular interactions between the NSAID and D-mannitol in an aqueous system over the temperature range 293.15 to 313.15 K, using thermo-acoustic and computational techniques. Methods: Thermo-acoustic parameters, including apparent and partial molar volume ?(??_v, ?_v^°), apparent and partial molar isentropic compressibility (?_k,?_k^°), and transfer partial molar volume ?(??_tr ?_v^°), etc, were calculated using experimental data of density (?) and sound velocity (u). Results: The positive values of partial molar volume and the negative value of partial molar isentropic compressibility indicate the existence of molecular interactions. The positive values of ??????????????° indicate the existence of ion-hydrophilic and hydrophilic-hydrophilic interactions. Hepler’s constant ((?^2 ?_v^°)/??T?^2 )_p indicates that Sodium naproxen (Na-NAP) acts as a structure-maker in the presence of D-mannitol in the aqueous solution. In addition to volumetric and acoustic studies, computational work involving HOMO–LUMO analysis, single-point energy calculations, dipole moments, and global reactivity descriptors highlights the stability and reactivity of the interacting species. In the gas phase, the HOMO–LUMO gap decreased significantly (0.29 eV), but it increased in aqueous medium (2.83 eV), suggesting that the complex has stabilized. Conclusion: These findings offer a strong foundation for stabilizing drugs through structure-making behaviour, providing a rational basis for developing effective pharmaceutical formulations.