The Freeze Drying Process

The sublimation process can also be observed in nature. If wet laundry is hung on the clothes-line in winter, it freezes and becomes stiff. After a certain period of time, the laundry will be dry, although the temperature was continuously below the freezing point. If such a freeze-dried piece of clothing is compared with one which was dried over a heater, it can be ascertained that the freeze-dried piece of clothing feels softer. Thus, the method of drying must have had a considerable impact on the texture of the material. 

Basically, all products which contain water can be dried in this manner. After freezing, the ice crystals remain at first at their original location in the structure. If vacuum is applied, the ice sublimates directly without melting. This results in a porous, dry product which has retained its original form. The volume has hardly changed, the cell walls have been little affected, flavour and other main constituents have been treated gently. If the product is to be restored to its former condition - to be reconstituted -only water has to be added. Water sorption in freeze dried materials proceeds faster than in conventionally dried products. For detailed studies on the fundamentals of freeze drying see the literature [1-10]. 

The core of a freeze drying plant (Fig. 2.61) consists of a drying chamber and a set of vacuum pumps. The pump should not be overexposed to water vapour, which possesses a very large volume in the low pressure range, and a cold trap is, therefore, always inserted before the pump - a so-called ice-condenser . The material to be dried is positioned on special trays which are put onto heater plates. These heater 

Other heating methods, such as IR and microwaves have also found application [13-151 

---

Freeze Drying. Commercial freeze drying of instant coffee has been a common practice in the United States since the mid-1960s. The freeze-drying process provides the opportunity to minimize flavor degradation due to heat (34). 

Fig. 7 Collapse is characteristic of amorphous materials, and can occur either during the freeze-dry process or during storage. 

A. P. MacKenzie, The physicochemical basis for the freeze-drying process Dev. Biol. Stand., 36, 51-67 (1977). 

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... 

The freeze-drying process is initiated by the freezing of the biopharmaceutical product in its final product containers. As the temperature is decreased, ice crystals begin to form and grow. This results in an effective concentration of all the solutes present in the remaining liquid phase, including the protein and all added excipients. For example, the concentration of salts may increase to... 

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. 

The next phase of the freeze-drying process entails the application of a vacuum to the system. When the vacuum is established, the temperature is increased, usually to temperatures slightly in excess of 0 °C. This promotes sublimation of the crystalline water, leaving behind a powdered cake of dried material. Once satisfactory drying has been achieved, the product container is sealed. 

Willemer, H. Water vapour pressure, its influence on the freeze-drying process and its control. 40th Annnual Congress of the International Association for Pharmaceutical Technology, Abstracts 1-67, Medpharm GmbH, Scientific Publishers, Stuttgart, Marz 1994... 

Chase [2.32] presents an alternative method to monitor and control the freeze drying process by measuring the flow of nitrogen to keep the operation control pressure, pc, constant. The Mass Flow Controller (FMC) consists of a proportional valve, an integral flow meter and a capacitance manometer (CA). The CA measures the total pressure in the plant, the valve opens, if the pressure gets below the preset value and vice versa. The flow of... 

With this start-up the most critical machine data are to check No remaining ice, cooling and heating working, and leak rate acceptable. The procedure takes some time, but minimizes problems occuring during the freeze drying process. 

An important step in the freeze drying process with vials is the stoppering or closing of the vials either at the end pressure of SD, or at a chosen partial pressure of a specific gas. This avoids handling of open vials, which can lead to contamination and adsorption of water vapor from the atmosphere. 

Therefore, it is decisive for the freeze drying process which follows that the filled vials during this time pass through a known and reproducible course of temperature. The prod-... 

The merit of Malinin s work is the comparative study of water content of bones by reproducible methods. The measurement of water vapor pressure during the drying cannot be used dirctly to determine the RM, as Malinin correctly states. Measurement of the description rates (DR) provide a means to follow quantitatively the course of desorption drying. The method is described in Section 1.2.2, but cannot be applied in an installation used by Malinin because the condenser cannot be separated from the chamber by a valve. By using the data given in the paper of Malinin it is possible to estimate the freeze drying process of bone transplants as follows ... 

In Section 2.2.8, possible failures during the freeze drying process are classified in four categories, and the preventions and necessary actions briefly discussed. In this chapter, some unexpected or undesirable events are studied which, by experience may happen. The problems listed here are selected from the course of the freeze drying process. A breakdown of single components, for example pumps, compressors or valves are not included in this chapter. The list will be incomplete, but an attempt has been made to mention some of the more frequent events. The problems with leaks and their hunting is discussed in Section 2.2.8. 

Continuous freeze-drying equipment has been developed(60), and chopped meat and vegetables may be dried in a rotating steam-jacketed tube enclosed in the vacuum chamber. A model of the freeze-drying process has been presented by Dyer and Sunderland191 , and further details are given in Section 15.8 on freeze crystallisation. 

Simulate the freeze drying process to perform an empty chamber temperature distribution study. 

Prepare vials containing an inert material (e.g., 5% w/v mannitol solution) and run the freeze drying process after the actual product run. Analyze the vials with inert material for the active content of the previous product. 

The drying chamber is rectangular in shape and is equipped with a door. It is vacuum- and pressure-resistant and designed for the freeze-drying process and sterilization with pure steam at an overpressure of (provide value) bar corresponding to (provide temperature in °C). 

Other semi-2-IPNs [52] processed by the freeze-drying method included IPN from 4,4 -bismaleimido diphenylmethane (BMI) and linear BTDA/3,4 -ODA polyamic acid that were dissolved in 1,3,5-trioxane (Fig. 16). The resulting semi-2-IPNs exhibited higher Tgs and reduced phase separation, and contained no plasticizing solvent. A comparison of unidirectional properties of composites prepared by the freeze-dry process to those by traditional solvent evaporation process is presented in Table 13. The freeze-drying method for the preparation of IPNs appears to be superior to previous technology. 

Mac Kenzie, A. P The physico-chemical basis for the freeze-drying process. Developments in Biological Standardization Vol. 74, p. 51-67. Acting Editors Joan C. May, F. Brown S. Karger AG, CH 4009-Basel (Switzerland) 1992... 

---