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Foundations and Process Engineering

Freeze-drying or lyophilization is a drying process in which the solvent and/or the suspension medium is crystallized at low temperatures and thereafter sublimed from the solid state directly into the vapor phase.

Freeze-drying is mostly done with water as solvent. Figure 1.1 shows the phase diagram of water and the area in which this transfer from solid to vapor is possible.

Figure 1.1 Phase diagram of water.

Table 1.1 shows the relation of temperature (°C), mTorr, and mbar.

Table 1.1 Vapor pressure of water.

Temperature (°C) mTorr mbar Temperature (°C) mTorr mbar 0 4579 6.108 -40 96.6 0.1238 -4 3280 4.372 -44 60.9 0.0809 -8 2326 3.097 -48 37.8 0.0502 -12 1832 2.172 -52 23.0 0.0300 -16 1132 1.506 -56 13.8 0.0183 -20 930 1.032 -60 8.0 0.0107 -24 526 0.6985 -64 4.6 0.0061 -28 351 0.4669 -68 2.8 0.0034 -32 231 0.3079 -72 1.4 0.0018 -36 150 0.2020

This step is relatively straightforward for pure water. If the product contains two or more components in true solutions or suspensions, the situation can become so complicated that simplified model substances have to be used to make the process more understandable. Such complex systems occur ubiquitously in biological substances.

The drying transforms the ice or water in an amorphous phase into vapor. Owing to the low vapor pressure of the ice, the vapor volumes become large, as can be seen in Figure 1.2. During the second step of the drying, the water adsorbed on the solids is desorbed.

Figure 1.2 Specific volume of water vapor as a function of the water vapor pressure. The temperature of the vapor in this diagram is that of ice.

The goal of freeze-drying is to produce a substance with good shelf stability and which is unchanged after reconstitution with water, although this depends also very much on the last step of the process: the packing and conditions of storage.

The advantages of freeze-drying can be summarized as follows:

• The drying at low temperatures reduces degradation of heat-sensitive products.
• The liquid product can be accurately dosed.
• The moisture content of the final product can be controlled during the process.
• The dry product can have an appealing physical form.
• The dry product with a high specific surface area is rapidly reconstituted.

The disadvantages are as follows:

• The high investment, operating and maintenance costs.
• The complexity of the process and the equipment requires a team of skilled and permanently trained collaborators.

1.1 Freezing

To freeze a substance, it must be cooled to a temperature at which the water and the solids are fully crystallized or at which areas of crystallized ice and solids are enclosed in zones in which amorphous concentrated solids and water remain in a mechanically solid state (see Section 1.1.2). In the zone of freezing, the ice crystals first grow, thus concentrating the remaining solution, which can vary the pH value. In many substances an eutectic temperature can be determined, but in many others this value does not exist. The crystallization depends on several factors that influence each other: cooling rate, initial concentration, end temperature of cooling, and the time at this temperature. In several products, no crystallization takes place and the product remains in an amorphous, glass-like phase or a mixture of both occurs.

1.1.1 Amount of Heat, Heat Conductivity, Heat Transfer, and Cooling Rate

For pure water, the melting heat to be withdrawn for freezing (Qtot) can be calculated by Eq. (1.1), if the starting and the desired final temperatures are known:

(1.1)

where

cw = specific heat capacity of water; Qe = melting heat of ice; ce = specific heat capacity of ice; T0 = freezing temperature of ice; T1 = initial temperature of water; T2 = final temperature of ice.

The temperature dependences of cw between +20 and 0 °C and ce between 0 and -50 °C have to be adopted as average values.

For solutions and suspensions, the solid content has to be recognized. This is reflected in Eq. (1.2):

(1.2)

where

xw = part of water above 0 °C; cf = specific heat of solids, for example: for animal products ~ 1.47 kJ/kg °C for plant products ~ 1.34 kJ/kg °C for some solids: carbohydrates ~ 1.42 kJ/kg °C proteins ~ 1.55 kJ/kg °C fats ~ 1.7 kJ/kg °C salts ~ 0.8 kJ/kg °C; xf = part of solids; xw´ = part of ice, which freezes until temperature T2 is reached. If not all water is frozen at T2, an additional term has to be introduced, which reflects the cooling of the unfrozen water.

Table 1.2 shows the unfreezable water (UFW) in various foods. The reasons and the consequences are described in Sections 1.1.3 and 1.1.4. In comparing these data with other publications, for example, Ref. [1], smaller values may be found. This can depend not only on the different raw materials and the history of the probe until measurement but also on the methods of measurement.

Table 1.2 Percentage of water frozen out at various temperatures for some foods.

Product Frozen out water at °C (% of the total water) UFW (% of total water) -10 -15 -20 -30 Lean beef 82 85 87 88 12 Haddock 84 87 89 91 9 Whole eggs, liquid 89 91 92 93 7 Yolk 85 86 87 87 13 Egg white 91 93 94 6 Yeast 80 85 88 89 11 Fruit juice 85 90 93 96 (3) Peas 80 86 89 92 (7) Part of Table 1.1 in Refs [2,3].

For meat with less than 4% fat content, Riedel [2] has published an enthalpy diagram (shown in Figure 1.3). For some other foods, Table 1.3 shows enthalpy data at various temperatures. At -40 °C the enthalpy is set at 0 kJ/kg.

Figure 1.3 Enthalpy of lean beef meat as a function of its water content (0 kJ/kg at -40 °C). The temperatures at the beginning of cooling and the desired end temperatures for freezing are plotted as parameters. The dotted lines indicate the percentage of water frozen at the end temperatures (see also Figure 1 from Refs [2,3]). Example: Beef meat has 74% water. At +10 °C, the enthalpy is ~325 kJ/kg; at -20 °C, the enthalpy is ~40 kJ/kg; therefore, 285 kJ/kg have to be removed and 83% of the water frozen. The maximum possible (88%) (see Table 1.1) is reached at...