Cocrystallization induced by compressed CO2 as antisolvent: Simulation of a batch process for the estimation of nucleation and growth parameters

• Cocrystals of naproxen and nicotinamide (2:1 stoichiometric ratio) were produced by CO2 antisolvent (GAS technique) with a size distribution below 300 μm.
• Successful modeling of the cocrystallization kinetics.
• Particle formation dominated by secondary nucleation.

A mathematical model describing the GAS antisolvent process applied to cocrystal formation has been developed with the aim of estimating nucleation and growth parameters that are critical issues in crystallization in general. The estimates are obtained by fitting the particle sizes distribution predicted by the model to experimental data. The investigated system was naproxen + nicotinamide that assembled as cocrystals when recrystallized by adding CO2 to acetone solution. The concentration of naproxen + nicotinamide in the liquid phase was calculated from the experimental data of the quaternary system. Particle formation was described by primary and secondary nucleations and a growth rate driven by diffusion. The population balance equation was solved by the standard method of moments assuming a log-normal distribution. Particles of NPX2:NCTA cocrystals of 40–80 μm mean size were experimentally produced and the experimental size distributions were well fitted by the proposed cocrystallization model.

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