GEA: Fundamentals of pharmaceutical freeze drying

Freezing

When aqueous products are cooled, crystallization nuclei form. The surrounding water is absorbed around the nucleation sites, forming crystals of various sizes and shapes. The freezing rate, the composition of the base product, the water content, the viscosity of the liquid, and the presence of non-crystallizing substances are among the factors that determine the shape and size of the crystals and influence the subsequent sublimation process. Large crystals have a relatively open lattice structure after sublimation, while small ice crystals have little space in the dried product, which reduces the removal of water vapor.

The freezing point of pure water is 0 °C. If other substances are dissolved in the water, this lowers the freezing point. If inorganic salts are present, the freezing point can also be significantly below 0. When a weak solution is frozen, the pure ice initially separates out, increasing the concentration of the dissolved substance in the remaining solution (and lowering the freezing point even further). The effect of this product concentrate varies from case to case and must be taken into account when selecting the appropriate freezing method.

The most suitable freezing method for a specific product and the corresponding parameters should always be determined prior to freeze-drying. The freezing behavior of the product can be investigated using DSC (differential scanning calorimetry), for example. Two different freezing methods are used for pharmaceutical products: freezing by contact with a cooling surface (the shelves are cooled in the freeze dryer) and freezing in a cold gas stream (blast freezing).

The first method is a static freezing method, in which the freeze dryer must be flexible and able to adapt the freezing rate to the respective product and control the freezing speed. In most cases, a final temperature of -40 to -50 °C is sufficient. The second method is used when small quantities of a liquid product need to be frozen quickly. The appropriate freezing method also produces a frozen product that is suitable for sublimation – that is, it must be uniform and as thin as possible to ensure a short drying time.

Primary drying

At the beginning of the primary drying phase, ice sublimation occurs on the product surface. As the process continues, the sublimating surface retreats into the product and the resulting vapor must be passed through the previously dried outer layers. This means that the drying process depends on the speed of vapor transfer and vapor removal, as well as the necessary sublimation heat. The heat required for sublimation is supplied by convection, heat conduction, and, to a lesser extent, heat radiation.

In addition to heat transfer by thermal conduction and thermal radiation, heat transfer by convection must be optimized. However, it should be noted that convection almost ceases to occur at pressures below 10-2mbar. For this reason, the pressure in the drying chamber is set to the maximum permissible value during the primary drying phase, depending on the required sublimation temperature. The sublimation heat is not required at the product surface, but at the edge of the ice core, which retreats into the interior of the product during the drying process.

So while the water vapor flows from the inside of the product to the outside, the heat must flow in the opposite direction. Due to the low thermal conductivity of the dried product layers, the temperature gradient required for heat transfer increases continuously. To avoid damaging the product, the maximum permissible temperature for the dried product must not be exceeded. At the same time, care must be taken to maintain the required sublimation temperature during the drying process, keep the heat supply to the edge of the ice core in balance, and avoid overheating the sublimation zone. The primary drying phase continues until all the ice in the product has sublimated.

Secondary drying

During the secondary drying phase, i.e., the final drying phase, the residual moisture content is reduced as much as possible to ensure that the product is in a condition that allows for long-term storage. The water bound by adsorption to the inner surface of the product must be removed. To achieve this, it is often necessary to overcome the capillary forces of the water. The freeze-drying plant must therefore be designed in such a way that a high pressure gradient is achieved during the secondary drying phase (in most cases, it is not possible to increase the temperature without damaging the product). The secondary drying process must be precisely controlled to prevent over-drying of the product.