Abstract
Crystallization assisted by supercritical CO2 has been long ago developed for micronization purposes, but its application to fabricate cocrystals is in its infancy. In this work, the cocrystallization of naproxen and nicotinamide was investigated using CO2 as an antisolvent. In the so-called SAS technique (Supercritical AntiSolvent) a solution of the species dissolved in acetone was injected into a continuous flow of CO2. The conditions of temperature and pressure were constant and set at 37°C and 10MPa whereas the CO2 and solution feed rates were varied. For CO2/solution flow ratios between 2 and 11 in wt basis yielding an overall mixture composition between 75 and 93mol% in CO2, the powders were almost cocrystals-pure with a cocrystal content ranging between 94 and 100wt%. The yield of precipitation ranged between 60 and 70wt%. The cocrystal had a 2:1 naproxen to nicotinamide molar ratio and exhibited the same hydrogen bond interactions and crystalline structure than cocrystals obtained by conventional or GAS techniques. The cocrystal particles exhibited a thin plate-like morphology and a size distribution ranging between 20μm and 1mm. When the flows ratio was increased to 36 (wt basis), heterogeneous powders made of cocrystals and homocrystals of naproxen were produced. The simulation was developed to get insight of the mixing scale and of the supersaturation field within the injection zone and it enabled to construct reasonable assumptions about the appearance of naproxen homocrystals. Since the solution and the CO2 were well mixed at micrometric levels, the evolution of the ternary phase diagram with the CO2/acetone composition was considered. A richer environment in solvent seems then to be favorable conditions for the formation of naproxen-nicotinamide cocrystals.
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