Investigation of the Particle Growth of Fenofibrate following Antisolvent Precipitation and Freeze–Drying

Submicron to small-micron-sized particles of the hydrophobic drug, fenofibrate, were prepared by controlled crystallization in order to influence its dissolution behavior. An antisolvent precipitation process successfully generated particles (200–300 nm) which matched the size and dissolution behavior of a commercial wet-milled formulation of the drug. Although the preparation of submicron-sized particles was straightforward, retaining their size in suspension and during isolation was a challenge. Additives were employed to temporarily stabilize the suspension, and extend the time window for isolation of the submicron particles. Precipitated particles were isolated primarily by immediate freeze–drying, but drying stresses were found to destabilize the fragile submicron system. The growth pathway of particles in suspension and during oven and freeze–drying were compared. Although the growth pathways appeared considerably different from a visual morphological perspective, an investigation of the electron diffraction patterns and the inner-particle surfaces showed that the growth pathways were the same: molecular addition by Ostwald ripening. The observed differences in the time-resolved particle morphologies were found to be a result of the freeze–drying process.