How To Optimize Lyophilization Process In Pharmaceutical Industry
Freeze-drying also called “lyophilization”, is mainly used to remove moisture from sensitive products (mainly biological products) without causing damage. Therefore, the product can be stored permanently, and then it can be restored to the original state by adding water.
There are many products that require freeze-drying, such as antibiotics, bacteria, serum, vaccines, diagnostic drugs, protein-containing products, and biotechnology products, cells and tissues, and chemicals. Freeze the product to be dried under atmospheric pressure. Then, in the first drying stage—also defined as “primary drying” — removing water (ie, ice) by sublimation; in the second stage — ”secondary drying” — removing water by desorption.
The specific processing conditions will determine the quality of the freeze-dried product. In this article, we will show you the lyophilization process in pharmaceutical industry and how to optimize the process to ensure the quality of the product.
Optimizing Lyophilization Process In Pharmaceutical Industry — Pre-Freezing
Pre-freezing in the lyophilization process in pharmaceutical industry is by removing heat to prepare the product for sublimation and drying. After the aqueous product cools, crystal nuclei are formed. The water near the crystal nucleus solidifies to form ice crystals of different sizes and shapes. The freezing rate, the composition of the basic product, the water content, the viscosity of the liquid, and the presence of non-crystalline substances are all factors that determine the shape and size of the ice crystals. They also affect the subsequent sublimation process. Large ice crystals form a relatively open lattice (to facilitate subsequent sublimation); while small ice crystals form a small lattice in the dried product, which will slow down the time to remove moisture.
During the lyophilization process in pharmaceutical industry, ideal freeze-drying methods for specific products should be determined and their important parameters verified before sublimation and drying. For example, resistance measurement can be used to measure the freezing status of a product. There are two freeze drying methods for pharmaceutical products: freezing by contact with a cooling surface, or rotating / dynamic freezing in a coolant.
The first freeze drying method is the static freezing method. The freeze dryer used at this time must have flexible functions, which can adjust the freezing slope and control the freezing speed according to the specific product. In general, the final temperature of -50 ° C is sufficient for most requirements. If a large amount of liquid product is frozen and needs to be dried in a chemical flask or large bottle, the second freeze drying method is needed. This method also makes the frozen product more suitable for sublimation and drying; this means that the product is frozen more evenly and the ice layer is as thin as possible, so the drying time can be very short.
Optimizing Lyophilization Process In Pharmaceutical Industry — Initial Drying
At the beginning of the initial drying phase, the ice on the surface of the product begins to sublime. As this process continues, the sublimation gradually penetrates into the product, and the generated water vapor must be discharged from the previously dried outer surface. This means that the lyophilization process in pharmaceutical industry depends on the speed of water vapor transmission and removal, as well as the heat required for sublimation. The heat required for sublimation is provided by convection and heat conduction, and sometimes also by heat radiation, to a lesser extent.
In addition to the heat transfer by heat conduction and heat radiation, the transfer by convection in the lyophilization process in pharmaceutical industry must also be optimized. However, it must be emphasized that convection will always stop at pressures below 10-2 mbar. This is why the pressure of the drying chamber should be adjusted to the maximum allowable value during the initial drying according to the required sublimation temperature.
Although water vapor tends to escape from the inside of the product to the outside, the direction of heat transfer is just the opposite. Due to the low thermal conductivity of the surface of the dried product, the temperature gradient required for heat transfer will increase steadily. To avoid damage to the product, during the lyophilization process in pharmaceutical industry, the maximum allowable temperature of the dry product must not be exceeded. In contrast, in order to maintain the required sublimation temperature, care must be taken throughout the drying process — to maintain the heat balance of the ice core boundary to avoid overheating the sublimation area. The initial drying stage continues until all the ice in the product sublimates.
Optimizing Lyophilization Process In Pharmaceutical Industry — Secondary Drying
In the secondary or final drying stage, the residual moisture will be minimized to ensure that the product can be permanently preserved. At this time, the moisture absorbed by the inner surface of the product must be removed. To achieve this, it is often necessary to overcome the capillary force of water. Therefore, freeze-drying equipment must be able to generate a pressure gradient in the secondary drying stage (in most cases, it is almost impossible to increase the temperature without damaging the product). The secondary drying process must be precisely controlled to avoid excessive drying of the product.
Optimizing Lyophilization Process In Pharmaceutical Industry — Subsequent Processing
This section describes how to protect dried products after drying (they tend to absorb water easily). If the product is dried in large bottles, chemical flasks or vials, it is best to close the container immediately after drying and before removing it from the equipment. Therefore, a special rubber stopper should be placed on the top of the bottle before loading the big bottle or vial into the device.
Optimizing lyophilization process in pharmaceutical industry also requires the container be vacuum-sealed or sealed under a protective gas environment. The specific method must be selected according to the product. In any case, we recommend that after the drying process is completed, the drying chamber is ventilated with dry nitrogen or inert gas (up to atmospheric pressure), but not with high humidity gas.
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