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

Numerical and experimental modeling of lyophilization of lactose and mannitol water solutions in vials

The paper reports on the development of a numerical model for the simulation of a lyophilization process in a vial. Lactose and mannitol-water mixtures are used as the working media. Experimental analysis of the lyophilization dynamics inside a single vial in a laboratory scale lyophilizer is reported, with the main focus on the primary drying phase. In order to assess the primary drying kinetics, the temperature distribution along the vertical axis of the samples is measured. In the numerical model, a one-dimensional (1D) vial approximation is used, and governing equations of the heat and water vapor transport with moving front between the frozen and the porous part of the filling are solved by a finite difference method in a time stepping nonlinear iteration procedure. A dedicated mapping of heat transfer boundary conditions, derived for the axisymmetric vial case, is applied for the case of the 1D vial geometry approximation. The main difference in the drying of lactose and mannitol solutions lies in the fact that the lactose shows undercooling effects during the primary drying phase, which is not the case for the mannitol solution. This effect is a consequence of shrinking behavior of the lactose porous cake, leading to a loss of contact with the vial side and hence to a decrease in the overall heat input to the vial. In order to account for the shrinking process in the numerical model, a linear approximation of the decrease of the heat transfer from the vial side wall during the simulation is introduced. The comparison of the numerical and experimental results shows that the developed numerical model is able to accurately capture the movement of the sublimation front, dividing the frozen from the porous part of the filling, at typical locations inside the vial, accompanied also by an accurate capturing of the temperature levels inside the drying material, with the derived numerical model also able to reproduce the temperature drop during the primary drying of the lactose solution