Effects of controlled nucleation on freeze-drying lactose and mannitol aqueous solutions

The lyophilization of lactose and mannitol aqueous solutions was investigated with an emphasis on analyzing the effects of controlled nucleation, temperature of nucleation, and pore size distribution on the freeze-drying process. The experimental procedure involved the depressurization technique of controlled nucleation, in-vial temperature measurements as well as measurements of the chamber pressure, which allowed the analysis of the product batch, loaded in the laboratory lyophilizator. The average pore enlargement was 93 and 58% with the incorporation of the controlled nucleation step in the lyophilization of 6 wt% lactose and 6 wt% mannitol solutions, respectively. Consequently, the primary drying times were lowered from 450 to 500 min in both cases. The pore sizes were determined to be as important as the solid material itself in the scope of the sublimation rates. Namely, the average equivalent diameter of the pores was larger in the dried mannitol cake compared to the lactose cake. However, despite the higher porosity of the dried mannitol cake, the end of the sublimation in the primary drying step was observed approximately 500 min earlier during the lyophilization of the lactose solution with the same initial concentration as the mannitol solution in a comparable freeze-drying protocol. In addition, an increase in mannitol concentration from 3 to 12 wt% was found to substantially extend the time required for the sublimation phase of the lyophilization.