Study on formability of solid nanosuspensions during solidification: II novel roles of freezing stress and cryoprotectant property.

The freezing stress and cryoprotectants were known to be the crucial factors for solidification formability of nanosuspensions during freeze-drying. However, there has been controversy as to whether an aggressive or conservative freezing stress (freezing temperature or freezing rate) prevents from irreversible aggregation of nanosuspensions. And the screening of cryoprotectants for solidification formability of nanosuspensions has largely relied on empirical approaches. A systematic investigation was presented herein regarding the effect of both the freezing stress and property of cryoprotectants on solidification formability of drug nanosuspensions during freeze-drying. It was found that at different freezing stresses (-20 °C, -80 °C, and -196 °C), the redispersibility of BCN, NGN, RCN, and RVL nanosuspensions stabilized, respectively, by seven stabilizers, was RDI(-20 °C)>RDI(-80 °C)>RDI(-196 °C). But the redispersibility of UDCA and OCA nanosuspensions stabilized, respectively, by seven stabilizers, was RDI(-20 °C)<RDI(-80 °C)<RDI(-196 °C). These phenomena could be explained by proposed novel crystal-stabilizer separation hypothesis in nano-concentrated phase during freezing, based on freezing rate, the diffusion characteristics of the drug crystals and stabilizer molecules. The two key properties of cryoprotectant that played an important role on the formability of nanosuspensions during freeze-drying were glass transition temperature and osmotic pressure. The cryoprotectant candidates with moderate π and Tg values, sucrose achieved the excellent solidification formability of drug nanosuspensions. And the firstly proposed classify guideline based on roles of freezing stress and cryoprotectant property could give a reference for process screening of solid nanosuspensions. This study will facilitate an in-depth understanding of formability of solid nanosuspensions during freeze-drying.