Naproxen–Nicotinamide Cocrystals: Racemic and Conglomerate Structures Generated by CO2 Antisolvent Crystallization

Cocrystallization of naproxen racemic mixture and nicotinamide was investigated in this work, using compressed CO2 as antisolvent. A novel racemic cocrystal structure containing both enantiomers of naproxen linked to nicotinamide has been produced thanks to the CO2 antisolvent batch crystallization process. The structure of the molecular complex and its intermolecular interactions were investigated by single-crystal X-ray diffraction and attenuated total reflectance Fourier transform infrared spectroscopy. The antisolvent feed rate was found to have a direct influence on the cocrystallization outcome. The racemic cocrystal was obtained at slow and moderate CO2 feed rate, while very fast introduction of CO2 resulted in the formation of a mixture of chiral cocrystals (conglomerate). Cross-seedings, thermal analysis, and temperature-resolved X-ray powder diffraction were used to probe the relationship between the different phases. In addition, all powders produced with CO2 technology were obtained as cocrystal-pure, without significant excess of naproxen or nicotinamide homocrystals.