Exploring the aqueous solubility and intermolecular interactions of diclofenac Diethylammonium: A molecular modeling study in solid state and solvation processes

Abstract

Diclofenac, a widely used non-steroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties, presents a challenge in oral administration due to its low aqueous solubility and subsequent low bioavailability. This issue, primarily attributed to the drug's high hydrophobicity, can lead to adverse side effects. To address this, our study delves into the aqueous solvation process of diclofenac through molecular modeling, employing both Carr-Parrinello molecular dynamics and Density Functional Theory. This combined approach enables a comprehensive investigation of the molecular interactions that influence solubility, encompassing non-polar interactions (van der Waals dispersion forces), dipole interactions, and hydrogen bonding. Our results highlight the formation of intermolecular interactions with water molecules through OH⋯Owater and CO⋯Hwater hydrogen bonds. Additionally, we observe intramolecular hydrogen bonds within diclofenac (NH⋯OH and NH⋯Cl) and weaker interactions involving CH⋯Cl. Notably, the protonation of diclofenac contributes to molecular rigidity, hindering hydrogen bonding with adjacent water molecules further. These insights offer a deeper understanding of the solubility challenges associated with diclofenac, paving the way for improved drug formulations that enhance bioavailability. The application of Carr-Parrinello molecular dynamics and density functional theory in this study highlights their valuable role in addressing complex drug solubility and design issues.