Effect of ultrasound-controlled nucleation on structural and morphological properties of freeze-dried mannitol solutions

Abstract To complete our first studies carried out on controlled nucleation with ultrasounds during freeze drying of pharmaceutical formulations, new investigations were performed on crystalline structure and permeability of freeze-dried mannitol systems. We observed that for solutions at 10 wt.% mannitol and for nucleation temperatures above −5 °C the δ phase – the metastable form of crystallized mannitol – was predominant for both cooling rates investigated. This limit temperature corresponds approximately to an increase of the slope of sublimation rate curve as a function of nucleation temperature. For samples having a higher nucleation temperature, both mannitol concentration and freezing rate had an influence on freeze-dried cake permeability. As the permeability is directly related to the freeze-dried cakes morphology, SEM analyses were also realized. Sheet structure was dominating for high nucleation temperatures and this structure seemed to prevail in samples that present a maximum content of δ phase. Finally, addition of surfactant to mannitol solution did not improve the nucleation triggering and induced unstable polymorph. Moreover, the uncontrolled power of the ultrasound pulse (very high power) might also lead to δ-phase polymorph.