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Lecture 4. Supplementary Material - Freeze Drying

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109 views4 pages

Lecture 4. Supplementary Material - Freeze Drying

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Prof C.S.Purushothaman
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FREEZE DRYING Freeze drying or lyophilization is a drying process where water is removed from a product below the freezing

point. The wet substance is frozen and the ice is sublimed directly from the solid state to the vapour stat as is illustrated in the phase diagram and the process diagram below. The operation is usually carried out in three steps: freezing, primary drying by sublimation in vacuum, secondary drying at elevated temperature to remove traces of water.

The phase diagram of water and an aqueous solution processing of freeze drying (Rupprecht (1993)) Freeze drying requires a high energy supply at low gas pressure. The advantages of freeze drying are in particular: minimum damage to sensitive materials and that the product can be rapidly and completely rehydrated. The disadvantages are high capital and operation costs and long process time Rupprecht, H. (1993).

after Rupprecht (1993) Rate and temperature of the freezing determines the structure of the frozen product. The primary drying occurs at conditions below the triple point. By freezing at low rates crystals are formed. However, at higher rates or when the crystallization is hampered by e.g. anti-freezing peptides, a glass may form instead, which is a solid having the molecular structure and the energy level of a liquid. Different freeze drying techniques differ mainly in terms of rate of freezing. The freezing rate on a shelf occurs in the range 1 2 K/min. In vials that are submersed into a cooling liquid the freezing rate is about 6 K/min. If liquid nitrogen is used the rate can be as high as 160 K/min. So called shock freezing is obtained by spraying the solution as drops into liquid nitrogen or in contact with solid carbon dioxide by which the cooling rate may reach about 200 K/min. In dynamic freezing the shelf or the container is rotated by which thin layers are obtained. The sublimation energy of water is about 380 kJ/kg, and the vapour pressure of ice at 0 C is 6,11 mbar and at 18 C it is 1,25 mbar and at 40 C it is 0,13 mbar. These values explain why freeze drying is a slow process. The requirements for an effective process include low partial pressure (not necessarily low total pressure), a short distance between the product and the condenser surface and sufficient energy transfer to the product. Temperature must be maintained low enough to avoid melting. At very low temperature however the drying vanishes. Strongly bound water therefore has to be removed at higher temperature called the secondary drying.

Since the vapour pressure during freeze drying is very low very large volumes are occupied by the vapour. It is not realistic to pump out these volumes but instead condensers are used and areoperated between -50 C and 80 C. The heat of sublimation is transferred by conduction from the walls or the shelf, gas convection or radiation, but for pharmaceuticals conduction and convection dominate. In the beginning the conduction is rapid and dominates. However, as the material close to the wall becomes gradually dryer and porous due to evaporation of the ice, the conduction rate decreases and for a significant part of the drying heat transfer by convection through the gas phase may dominate. The heat convection rate decreases with decreasing total gas pressure and essentially fades out at 0,01 mbar. Hence, the temperature and the pressure should be as high as possible during the primary drying. Heat transfer by infrared radiation is not used for pharmaceuticals since only the surface is heated and microwaves are not used because of the risk for local overheating. If the partial pressure is kept low throughout the process the following rules can be given: The drying time is proportional to the layer thickness raised to power 1,5, i.e.:
1, 5 t drying d layer

The drying time increases with decreasing ice crystal size. It takes 10 20 hours to dry a thickness of 1 cm. It takes 1 3 hours to dry spherical particles of 3 mm diameter. For the primary drying it is recommended: The layer thickness should be minimized The partial pressure of water should be as low as possible the surface temperature of the condenser should be about 20 K below the temperature of the ice. The chamber pressure should be about 1 mbar or higher. A periodic increase in pressure by feeding nitrogen may improve the drying process To keep the temperature just below the so called collapse temperature or the lowest eutectic temperature Add stabilizing excipients After the primary drying the product may still contain 5 30 % of water. This bound water may be hydrate water, intracellular water of adsorbed water. This water may be removed by heating under vacuum conditions, typically to between 15 C and 40 C for about 1/3 of the time used for the primary drying. The water vapour partial pressure should be maintained in the range 0,01 0,001 mbar. For these conditions the condenser needs to be about - 80C. Sadikoglu and Liapis (1997) developed a model to describe the primary and the secondary drying stages of freeze-drying on trays. It is found by comparison with

experimental data on skim milk drying, that the contribution of removal of bound water during the primary drying step is negligible. The model does not require a detailed description of the porous structure of the porous matrix. Sadikoglu et al (1998) used this model to develop a control strategy to minimize the drying time by using the heat input and the drying chamber pressure as the control variables inferring maximum interface (melting) and surface (scorch) temperatures as constraints. Literature Cited Rupprecht, H.; Basic physico-chemical principles of freeze-drying- lyophilisation; Pharmacevski Vestnik 44(4),193-213(1993) Sadikoglu, H. and A.I. Liapis; Mathematical modelling of the primary and secondary drying stages of bulk solution freeze-drying in trays: parameter estimation and model discrimination by comparison of theoretical results with experimental data; Drying Technology 15(3&4),791-810(1997) Sadikoglu, H., A.I. Liapis and O.K. Crosser; Optimal control of the primary and secondary drying stages of bulk solution freeze drying in trays, Drying Technology 16(3-5),399-431(1998)

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