Systematic Characterization of Naproxen Diastereomeric Salts with Cinchona Alkaloids toward Naproxen Resolution: Insights from a Multidisciplinary Approach

The solid forms of three new diastereomeric quinine-based salts (two hydrated naproxen salts (S-Nap_RS-Quin_W and R-Nap_RS-Quin_W) and one anhydrous ibuprofen salt (S-Ibu_RS-Quin) were investigated using a combination of experimental techniques (e.g., X-ray diffraction, thermal analyses, infrared spectroscopy) and in silico methods. Additionally, the solid-state form of a naproxen-cinchonine salt (S-Nap_SR-Cinch) was studied, and for comparison, the crystal structure of a related quinine-based salt with flurbiprofen (R-Fbu_RR-Quin) was included. Structural characterization and phase stability studies, including hydration and dehydration behavior, offered valuable insights into the stability profiles of these compounds. Detailed in silico analyses further clarified the molecular interactions and packing arrangements underlying the solid-state structures. Together, these results provide a structural explanation for the enantioselective crystallization observed, highlighting the superior intrinsic stability of the S-Nap_RS-Quin_W crystal packing as a key factor driving chiral discrimination. This integrated approach advances our understanding of the molecular determinants that govern selective salt formation, with potential implications for the design of improved chiral separation strategies in pharmaceutical development.