Impact of controlled ice nucleation and lyoprotectants on nanoparticle stability during Freeze-drying and upon storage

The freezing step of the lyophilization process can impact nanoparticle stability due to increased particle con-centration in the freeze-concentrate. Controlled ice nucleation is a technique to achieve uniform ice crystal formation between vials in the same batch and has attracted increasing attention in pharmaceutical industry. We investigated the impact of controlled ice nucleation on three types of nanoparticles: solid lipid nanoparticles (SLNs), polymeric nanoparticles (PNs), and liposomes. Freezing conditions with different ice nucleation tem-peratures or freezing rates were employed for freeze-drying all formulations. Both in-process stability and storage stability up to 6 months of all formulations were assessed. Compared with spontaneous ice nucleation, controlled ice nucleation did not cause significant differences in residual moisture and particle size of freeze-dried nano-particles. The residence time in the freeze-concentrate was a more critical factor influencing the stability of nanoparticles than the ice nucleation temperature. Liposomes freeze-dried with sucrose showed particle size increase during storage regardless of freezing conditions. By replacing sucrose with trehalose, or adding trehalose as a second lyoprotectant, both the physical and chemical stability of freeze-dried liposomes improved. Trehalose was a preferable lyoprotectant than sucrose to better maintain the long-term stability of freeze-dried nano-particles at room temperature or 40 & DEG;C.

Automated summary

Controlled ice nucleation has minimal impact on nanoparticle stability, while the residence time in the freeze-concentrate has a greater influence. Replacing sucrose with trehalose improves the stability of freeze-dried liposomes.