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

Abstract

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