Nonsteroidal Anti-Inflammatory Drugs-1-Phenylethylamine Diastereomeric Salts: A Systematic Solid-State Investigation

The solid-state investigation of the diastereomeric salts (S)-ibuprofen (S-Ibu), (S)-naproxen, (S-Nap), and (S)-ketoprofen (S-Ket) with (R)-(+)- and (S)-(-)-1-phenylethylamine, R-PEA, and S-PEA respectively, has been carried out by using a combination of experimental and in-silico tools. The focus was on their crystal packing and on the stability/transformation of their solid forms under different experimental conditions with the final aim of extracting useful information on the forces/features which could be exploited for the chiral separation of the corresponding racemic compounds. All the salts are 21-column crystals, each column consisting of API and 1-phenylethylamine ions assembled via the 1-phenylethylammonium-carboxylate supramolecular heterosynthon which originates a R43 (10) pattern, the intercolumns contacts being definitely weaker. In spite of an overall similarity in the crystal packing forces and motifs of the anhydrous salts, the temperature stability range suggests that the homochiral species are the most stable. The fact that the homochiral salt of S-Ket (S-Ket_S-PEA) is stable toward the hydration, at variance with the heterochiral one (S-Ket_R-PEA), further confirms this hypothesis. On the other hand, preliminary sorption tests show that S-Ket and S-Ibu preferentially capture the homochiral PEA (S-Nap is not selective). This behavior has been correlated to the almost planar boundary surfaces which characterize and differentiate the 21 sheets in S-Ket_S-PEA and S-Ibu_S-PEA salts with respect to the corresponding heterochiral ones.