Primary freeze-drying stage

The objective of the primary drying stage of the freeze-drying process is to remove the ice as quickly as possible without undue risk of product loss... 

As the temperature is lowered further, the viscosity of the unfrozen solution increases dramatically until molecular mobility effectively ceases. This unfrozen solution will contain the protein, as well as some excipients, and (at most) 50 per cent water. As molecular mobility has effectively stopped, chemical reactivity also all but ceases. The consistency of this solution is that of glass, and the temperature at which this is attained is called the glass transition temperature Tg-. For most protein solutions, Tg- values reside between -40 °C and -60 °C. The primary aim of the initial stages of the freeze-drying process is to decrease the product temperature below that of its Tg- value and as quickly as possible in order to minimize the potential negative effects described above. 

Before concentrating on process parameters (Section III), we will briefly outline the behavior of the product during the three separate but interdependent stages of freeze-drying freezing, sublimation (primary drying), and desorption (secondary drying). 

This paper presents the application of a model based predictive control strategy for the primary stage of the freeze drying process, which has not been tackled until now. A model predictive control framework is provided to minimize the sublimation time. The problem is directly addressed for the non linear distributed parameters system that describes the dynamic of the process. The mathematical model takes in account the main phenomena, including the heat and mass transfer in both the dried and frozen layers, and the moving sublimation front. The obtained results show the efficiency of the control software developed (MPC CB) under Matlab. The MPC( CB based on a modified levenberg-marquardt algorithm allows to control a continuous process in the open or closed loop and to find the optimal constrained control. 

A.I. Liapis, R. Bruttini 1994 A theory for the primary and secondary drying stages of the freeze drying of pharmaceutical crystalline and amorphous solutes comparison between experimental data and theory. Separation Technology, 4, 144-155. 

N. Daraoui, P. Dufour, H. Hammouri 2007 Model predictive control of the primary drying stage of a freeze drying of solutions in vials a apphcation of the MPC CB software (part 1). The 5th Asia-Pacific Drying Conference, Hong Kong, China, 2 883-888. 

In practice, at the beginning of the primary drying stage, more than 90% of the water in the initial solution has frozen. The ice is then removed by sublimation. Unlike the freezing process, ice sublimation is amenable to some measure of control. The heat flow to the ice front must be adjusted to balance exactly the heat absorbed by the sublimation of ice at the operating temperature of sublimation. In this chapter, we discuss the contributing mechanisms by which heat is transferred from the shelves of the freeze-drier to the ice front and the mechanisms by which water vapour is transferred to the condenser (mass transfer), and their relative contributions to the overall sublimation process. 

The secondary drying stage involves the removal of solvent (water) that did not freeze (this is termed sorbed or bound water). The secondary drying stage starts at the end of the primary drying stage, and the desorbed water vapor is transported through the pores of the material that is dried. 

The structural stability of a material relates to its ability to go through the freeze drying process without change in size, porous structure, and shape. The maximum allowable temperature in the frozen layer is determined by both structural stability and product stability (e.g., product bioactivity) factors that is, the maximum value of the tanperature in the frozen layer during the primary drying stage must be such that the drying process is conducted without loss of product property (e.g., bioactivity) and structural stability. 

---