Naproxen–nicotinamide cocrystals produced by CO2 antisolvent

• Cocrystals of naproxen and nicotinamide were successfully prepared by CO2 antisolvent recrystallization.
• The cocrystals content in product is quantified.
• A cocrystal stoichiometry of NPX2:NCTA1 was obtained whatever the conditions.
• The product purity in cocrystals was of 98 ± 2% for initial processed NPX:NCTA ratios of 3:1, 2:1 and 1:1.
• Cocrystal size and production yield were sensitive to stirring and CO2 introduction rates of GAS, but not the purity neither the cocrystal stoichiometry.

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.

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