Naproxen–nicotinamide cocrystals produced by CO2 antisolvent

Cocrystals of naproxen (NPX) and nicotinamide (NCTA) were successfully prepared in acetone using CO2 as antisolvent in the so-called GAS technique (Gaseous Anti Solvent). Infra-red spectroscopy and powder X-ray analysis evidenced the same hydrogen-bond network and stoichiometry than cocrystals produced by cooling crystallization, i.e. 2 NPX for 1 NCTA, which coincided with literature results as well. The purity of powders in cocrystals was evaluated thanks to chromatography analysis and the homocrystals identification by powder X-rays diffraction. The effect of initial mixture composition (NPX:NCTA ratio) and of CO2 and acetone mixing conditions (CO2 introduction rate, stirring speed) was investigated. Results showed that the cocrystal purity was closed to 98 ± 2% whatever the initial ratio in solution of 3:1, 2:1, 1:1 but levelled down to 67% when a 1:2 solution was processed. The mixing conditions did not influence the cocrystal stoichiometry or purity (experiments carried out from a 2:1 mixture) but impacted on precipitation yield and size distribution. In best conditions, 62% of the initial processed amount was collected in the vessel as a powder of sizes below 180 μm made at 98% of NPX2:NCTA1 cocrystals.