Supercritical fluids based techniques to process pharmaceutical products difficult to micronize: Palmitoylethanolamide

•Different supercritical micronization processes are tested on the same compound.•Relative performance of different processes has been compared.•Successful palmitoylethanolamide micronization has been obtained.

Palmitoylethanolamide (PEA) is a relevant anti-inflammatory and neuroprotective drug whose poor solubility is currently addressed by micronization with traditional fluid technology. In this work, three different supercritical carbon dioxide based techniques were used to improve PEA particle size reduction down to 1–5 μm range; we used supercritical antisolvent (SAS), supercritical assisted atomization (SAA) and supercritical emulsion extraction (SEE) processes and various organic solvents. SAS was substantially unsuccessful since PEA was in some cases extracted and in some other precipitated in form of very long needle-like crystals. SAA and SEE were successful in the micronization of PEA in some cases: the problem to overcome was the very fast crystallization rate of this compound that tends to form flat crystals, more than amorphous microparticles. However, the selection of the proper solvents and operative conditions strongly reduced this inconvenience, since it was possible to limit the evolution of the liquid droplets, that operating as confined reactors, restrained the solidification/crystallization of PEA within the limits of the droplets boundaries. Quasi-spherical PEA microparticles with a mean diameter of 1.48 μm were produced at the most successful micronization conditions.

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