Naproxen-bipyridine cocrystallization assisted by pressurized carbon dioxide

Cocrystals of S-naproxen (S-NPX) or RS-naproxen (RS-NPX) and 4,4′bipyridine (BiPY) were prepared by the Gaseous Anti Solvent (GAS) method using CO2 as antisolvent. S-NPX and BiPY cocrystals were also produced by Cocrystallization with Supercritical Solvent (CSS) using CO2 as a solvent though leading to mixtures of cocrystals and homocrystals. Hydrogen-bond networks and stoichiometries of produced cocrystals were identical whatever the mode of preparation (evaporation, grinding and CO2-assisted processes) and matched those already described in literature: S-NPX2:BiPY1 and RS-NPX2:BiPY1. The effects of the NPX:BiPY molar ratio and of the processing conditions were investigated. By GAS, an excess of BiPY in the initial processed mixture was mandatory to produce pure S-NPX2:BiPY1 cocrystals whereas pure RS-NPX2:BiPY1 cocrystals were identically produced from mixtures of 2:2 and 2:1 NPX:BiPY initial ratio. No enrichment of the product in any of the naproxen enantiomer was reached, even when mixtures of S- + RS-NPX were coprocessed with bipyridine.