Freeze, drying is a process used to dry extremely heat-sensitive materials. It allows the drying, without excessive damage, of proteins, blood products and even microorganisms, which retain a small but significant viability.
In this process the initial liquid solution or suspension is frozen, the pressure above the frozen state is reduced and the water removed by sublimation. Thus a liquid-to-vapour transition takes place, as with all the previous driers discussed, but here there are three states of matter involved: liquid to sold, then solid to vapour. The theory and practice of freeze drying is based, therefore, on an understanding and application of the phase diagram for the water system.
The phase diagram for water
The phase diagram for the water system is shown in figure 26.14. The diagram consists of three separate areas, each representing a single phase of water, either solid, liquid or vapour. Two phase can coexist along a line under the conditions of temperature and pressure defined by any point on the line. The point 0 is the one unique point where all three phases can coexist, and is known as the triple point. Its coordinates are a pressure of 610 Pa and a temperature of 0.0075°C.
The lines on the phase diagram represent the interphase equilibrium lines, which show:
1. The boiling point of water as it is lowered by reduction of the external pressure above the water ( BO in Fig. 26.14) ;
2. The variation of the melting point of ice on reduction of the external pressure above it. There is a very slight rise in the melting point (AO);
3. The reduction of the vapour pressure exerted by ice as the temperature is reduced (CO).
On heating at constant atmospheric pressure ice will melt when the temperature rises to 0°C.
At this constant temperature rises to 0˚C. At this constant temperature and pressure it will then change to eater. Continued heating will raise the temperature of the water 100 CIf however, solid ice is maintained at a pressure below the triple point then on heating the ice will sublime and pass directly to water vapour without passing through the liquid phase. This sublimation and therefore drying can occur at a temperature below 0 C. this will only happen if the pressure is prevented from rising above the triple point pressure and to ensure that this is the case, the vapour must be removed as fast as it is formed.
It may be thought that as the process takes place at a low temperature the heat required to sublime the ice will be small. In face, the latent heat of sublimation of ice at 2900 kJ kg is appreciably greater than the latent heat of evaporation of water at atmospheric pressure, and this heat must be supplied for the process to take place.
Application of the phase diagram of water to freeze drying
the freeze drying of products such as blood plasma, although simple in theory, presents a number of practical problems.
1.The depression of the freezing point caused by the presence of dissolved solutes means that the solution must be cooled to well below the normal freezing temperature for pure water and it is usual to work in the range -10 to -30 C . in part this is becauseit is obviously not pure water that is being dried, and thus the presence of dissolved solutes will shift the pure-water phase diagram
2. sublimation can only occur at the frozen surface and is a slow process
(approximately 1 mm thickness of ice per hour).for all but very small volumes the surface area must therefore be increased and the liquid thickness prior to freezing be reduced in order to reduce the thickness of ice to be sublimated.
3. At low pressures large volumes of water vapour are produced which must be rapidly removed to prevent the pressure rising above the triple point pressure
4.The dry material often needs to be sterile, and it must be prevented from regaining moisture prior to final packing.
Stages of the freeze dying process:
The liquid material is frozen before the application of vacuum to avoid frothing, and several methods are used to produce a large frozen surface.
Shell freezing . this is employed for fairly large volumes such as blood products. The bottles are rotated slowly and almost horizontally in a refrigerated bath. The liquid freezes in a thin shell around the inner circumference of the bottle. Freezing is slow and large ice crystals form, which is a drawback of this method as they may damage blood cells and reduce the viability of microbial cultures.In vertical spin freezing, the bottles are spun individually in a vertical position so that centrifugal force forms a circumferential layer of solution, which is cooled by a blast of cold air. The solution super cools and freezes rapidly, with the formation of small ice crystals.
Centrifugal evaporative freezing. This is a similar method, where the solution is spun in small containers within a centrifuge. This prevents foaming when a vacuum is applied. The vacuum causes boiling at room temperature and this removes so much latent heat that the solution cools quickly and snap freezes. About 20% of the water is removed prior to freeze drying and there is no need for refrigeration. Ampoules are usually frozen in this way, a number being spun in a horizontal angled position in a special centrifuge head so that the liquid is throuwn outwards and freezes as a wedge.
Vacuum applications stage
The containers and the frozen material must be connected to a vacuum source sufficient to drop the pressure below the triple point and remove the large volumes of low-pressure vapour formed during drying. Again an excess vacuum is normal in practice, to ensure that the product in question is below its triple point.
Commonly a number of bott;es or vials are attached to individual outlets of a manifold, which is connected to a vacuum.
Heat of sublimation must be supplied. Under these conditions the ice slowly sublimes, leaving a porous solid which still contains about 0.5% moisture after primary drying.
Primary drying. Primary drying can reduce the moisture content of a freeze dried solid to around 0.5%. further reduction can be affected by secondary drying. During the primary drying, the latent heat of sublimation must be provided and the vapor removed.
Heat transfer. Heat transfer is critical: insufficient heat input prolongs the process, which is already slow, and excess heat will cause melting.Pre-frozen bottles-of blood, for example – are placed individually heated cylinders, or are connected to a manifold when heat can be taken from the atmosphere.
Shelf-frozen materials are heated from the drier shelf, whereas ampoules may be left on the centrifuge head or may be placed on a manifold, but in either case heat from the atmosphere is insufficient. In all cases the heat transfer must be controlled, as only about 5W m-2 K-1 is needed and overheating will lead to melting. It is important to appreciate here that although a significant amount of heat is required there should be no significant increase in temperature – the added heat should be sufficient to provide the latent heat of sublimation only and little sensible heat.
Vapour removal. The vapor formed must be continually removed to avoid a pressure rise that would stop sublimation. To reduce sufficiently it is necessary to use efficient vacuum pumps. usually two stage rotary pumps on the small scale, and ejector pumps on the large scale. On the small scale, vapour is absorbed by a desiccant such as phosphorus pentoxide, or is cooled in a small condenser with solid carbon dioxide, mechanically refrigerated condensers are used on the large scale. For vapour flow to occur the vapour pressure at the condenser must be less than that at the frozen surface, and a low condenser temperature is necessary. On the large scale vapour is commonly removed by pumping, but the pumps must be of a large capacity and not affected by moisture. The extent of the necessary pumping capacity will be realized from the fact that, under the pressure conditions used during primary drying, 1g of ice will form 1000L of water vapour. Ejector pumps are most satisfactory for this purpose.
Rate of drying. The rate of drying in freeze drying is very slow. The ice being removed at a rate of about only 1 mm depth per hour. The drying rate curve illustrated in figure 26.15 shows a similar shape to a normal drying curve, the drying being at constant rate during most of the time.
Computer control enables the drying cycle to be monitored. There is an optimum vapour pressure for a maximum sublimation rate and the heat input and other variables are adjusted to maintain this value.
Continuous freeze drying is possible in modern equipment, where the vacuum chamber is fitted with a belt conveyor and vacuum locks, but despite these advances the overall drying rate is still slow.
The removal of residual moisture at the end of primary drying is performed by raising the temperature of the solid to as high as 50 or 60 C. A high temperature is permissible for many materials because the small amount of moisture remaining is not sufficient to cause spoilage.
Attention must be paid to packaging freeze-dried products to ensure protection from moisture.
Containers should be closed without contacting the atmosphere. If possible, and ampoules, for example, are sealed on the manifold while still under vacuum.
Otherwise, the closing must be carried out under controlled atmospheric conditions.
Freeze drying in practice:
As a result of the character of the process, freeze drying has certain special advantages:
1. Drying takes place at very low temperatures, so that enzyme action is inhibited and chemical decomposition, particularly hydrolysis, is minimized.
2. The solution is frozen such that the final dry product is a network of solid occupying the same volume as the original solution. Thus, the product is light and porous.
3. The porous form of the product gives ready solubility.
4. There is no concentration of the solution prior to drying Hence, salts do not concentrate and denature proteins, as occurs with other drying methods.
5. As the process takes place under high vacuum there is little contact with air, and oxidation is minimized.
There are two main disadvantages of freeze drying:
1. The porosity, ready solubility and complete dryness yield a very hygroscopic product. Unless products are dried in their final container and sealed in situ, packaging requires special conditions.
2. The Process is very slow and uses complicated plant, which is very expensive. It is not a general method of drying, therefore, but is limited to certain types of valuable products which, because of their heat sensitivity, cannot be dried by any other means.
Uses of Freeze Drying:
The method is used for products that cannot be dried by any other heat method. These include biological products, for example some antibiotics, blood products, vaccines (such as BCG, yellow fever, smallpox), enzyme preparations (such as hyaluronidase) and microbiological cultures. The latter enables specific microbiological species and strains to be stored for long periods with a viability of about 10% on reconstitution.
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