Process Principles

Examples of freeze dried products are antibiotics, bacteria, sera, vaccines, diagnostic medications, protein-containing and biotechnological products, cells and tissues, and chemicals. The product to be dried is frozen under atmospheric pressure. Then, in an initial drying phase — defined as primary drying — the water (as ice) is removed by sublimation; in the second phase — secondary drying — it is removed by desorption. Freeze drying is done under vacuum.

The conditions under which the process takes place will determine the quality of the freeze dried product. Some important aspects to be considered during the freeze drying process are as follows:

Freezing: transforming the basic product by abstracting heat to create a state that is suitable for sublimation drying. When an aqueous product is cooled, crystal nuclei are formed. The surrounding water is taken up around the nucleation sites, resulting in crystals of different sizes and shapes. Freezing speed, composition of the basic product, water content, viscosity of the liquid and the presence of non-crystallizing substance are all decisive factors in determining the crystal shape and size, and in influencing the following sublimation process. Large crystals comprise a relatively open lattice post-sublimation, whereas small ice crystals contain small spaces in the dried product, slowing down the removal of water vapor.

The freezing point of pure water is 0 °C. Any other substances dissolved in the water will lower the freezing point. When inorganic salts are present, it may be considerably lower. If a weak solution is frozen, pure ice will initially separate, thereby increasing the concentration of the dissolved substance in the residual solution (further reducing the freezing point). The effect of this product concentration varies from case to case and should be taken into account when selecting the most appropriate freezing technique.

The most suitable freezing technique for a specific product should be determined and its parameters ascertained prior to sublimation drying. The freezing behaviour of the product may be investigated, for instance, using the resistance-measurement method. Two different freezing methods are used for pharmaceutical products: freezing by contact with cooled surface; or rotation/dynamic freezing in a coolant bath.

The first method is a static freezing technique in which a versatile freeze dryer must be capable of adjusting the freezing rate to the specific product and control the freezing speed. A final temperature of -50 °C will, in many cases, be sufficient to meet most requirements. The second method is used whenever larger quantities of a liquid product are to be frozen and dried in flasks or large bottles. The appropriate freezing technique will also deliver a frozen product that is suitable for sublimation; that is, uniform and as thin as possible to achieve a short drying time.

Primary Drying

At the beginning of the primary drying phase, ice sublimation takes place at the product surface. As the process continues, the subliming surface withdraws into the product and the resulting vapor must be conducted through the previously dried outer layers. This means that the drying process depends on the speed of vapor transfer and removal, as well as the necessary heat of sublimation. The heat required for sublimation is supplied by convection and thermal conduction and, to a lesser degree, by thermal radiation.

Apart from heat transfer by thermal conduction and radiation, heat transfer by convection must be optimized. It should be noted, however, that convection will almost cease at pressures below 10^-2 mbar. This is why, as a function of the required sublimation temperature, the pressure in the drying chamber is adjusted during primary drying to the highest permissible value. Sublimation heat is not needed at the product surface, but at the boundary of the ice core that is withdrawing into the centre of the product as drying proceeds.

Whilst water vapor flows from within the product to the outside, heat transfer must go in the opposite direction. Owing to the low thermal conductivity of the dried product layers, the temperature gradient required for heat transfer steadily increases. To avoid product damage, the maximum possible temperature for the dried product must not be exceeded. By contrast, care must be taken to maintain the required sublimation temperature throughout drying, keep the heat supply to the ice-core boundary in equilibrium and avoid overheating the sublimation zone. The primary drying phase continues until all the ice in the product has been sublimated.

Secondary Drying

In the secondary or final drying phase, the residual moisture content is reduced as much as possible to ensure that the product is in a permanently storable state. The water bound by adsorption at the internal surface of the product has to be removed. To achieve this, it is often necessary to overcome water’s capillary forces. The freeze drying plant must therefore be designed to produce a high pressure gradient during the secondary drying phase (in most cases, it is not possible to raise the temperature without damaging the product). The secondary drying process must be precisely controlled to prevent over-drying the product.