PRINCIPLE. The main principle involved in freeze drying is a On 21st century, in pharmaceutical field lyophilization has become important. Lyophilization, or freeze drying, is a process in which the solvent (usually water) is: first frozen and then. – removed by sublimation in a vacuum. Freeze drying, also known as lyophilisation or cryodesiccation, is a low temperature . Bulk lyophilization of APIs is typically conducted using trays instead of glass vials. .. Food processing technology: principles and practice ( 4th ed.).

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Freeze drying is the removal of ice or other frozen solvents from a material through the process of sublimation and the removal of bound water molecules through the process of desorption.

Lyophilization and freeze drying are terms that are used interchangeably depending on the industry and location where the drying is taking place. Controlled freeze drying keeps the product temperature low enough during the process to avoid changes in the dried product appearance and characteristics.

What is Lyophilization?

Sublimation is when a solid ice changes directly to a vapor without first going through a liquid water phase. Thoroughly understanding the concept of sublimation is a key building block to gaining knowledge of freeze drying.

As shown below on the phase diagram for water, low pressures are required for sublimation to take place. Sublimation is a phase change and heat energy must be added to the frozen product for it to occur. In addition to providing an extended shelf-life, successful freeze-drying should yield a product that has a short reconstitution time with acceptable potency levels.

The process should be repeatable with well defined temperature, pressure and time parameters for each step. Visual and functional characteristics of the dried product are also important for many applications. The refrigeration system cools the ice condenser located inside the freeze dryer.

The refrigeration system can also be employed to cool shelves in the product chamber for the freezing of the product. The vacuum system consists of a separate vacuum pump connected to an airtight condenser and attached product chamber. Control systems vary in complexity and usually include temperature and pressure sensing ability.

Choosing a control system for the freeze dryer depends on the application and use i. Product chambers are typically either a manifold with attached flasks, or, a larger chamber with a system of shelves on which to place the product.

Freeze-drying – Wikipedia

The purpose of the condenser is to attract the vapors being sublimed off of the product. Because the condenser is maintained at a lower energy level relative to the product ice, the vapors condense and turn back into solid form ice in the condenser. The sublimated ice accumulates in the condenser and is manually removed at the end of the freeze drying cycle defrost step.

The condenser temperature required is dictated by the freezing point and collapse temperature of the product. The refrigeration system must be able to maintain the temperature of the condenser substantially below the temperature of the product. In shelf freeze dryers, the condenser can be located inside the product chamber internal condenser or in a separate chamber external condenser connected to the product chamber by a vapor port.

Manifold freeze dryers rely on ambient conditions to provide the heat of sublimation to the product. This heat input does not melt the product because an equivalent amount of heat is removed by vaporization of the solvent.

Freeze dryers can be informally classified by the type of product chamber: Choosing a freeze dryer depends on the product characteristics as well as many other application-based variables including the container that the product will be dried in, the shelf area or number of ports required to accommodate the quantity to be dried in each batch, the total volume of ice to be condensed and whether there are any organic solvents.


The type and shape of product being dried and its end-use also need to be considered. A suitable container system must be chosen for the product. The most common product containers are flasks, vials and trays. Product trays with removable-bottoms are available when working with vials. The tray is loaded with vials, placed on a shelf in the freeze dryer and then the bottom part of the tray is slid out.

This allows the vials to rest directly on the shelf and increases the heat transfer to the product. Special containment systems such as glove boxes are required for freeze drying certain products, especially when toxic materials are present. Understanding the physical properties of materials that are freeze-dried is a key part in developing a successful lyophilization process.

Although a few products are simple crystalline materials, the vast majority of products that are lyphilizer are amorphous and form glassy states when frozen. Processing and formulation development are important steps often taken to make a product ready for freeze drying and usable for its specific application. The choice of excipients added to a formulation can severely affect the thermal characteristics of the product and its ability to be freeze dried in a reasonable amount of time.

Typically, there are multiple steps involved for both freezing and drying of the product. Individual temperature, princip,e and time settings need to be determined for each step.

Lyophulizer specific product or formulation that is lyophilized requires the development of a freeze drying process that is based on the unique characteristics of the product, the amount of product and the container used. It is extremely important that the sample be fully and completely frozen prior to pulling a vacuum and starting the drying process. Unfrozen product may expand outside of the container when placed under a vacuum.

With simple manifold freeze dryers, the product is placed lypohilizer a vial or flask depending on quantity, and then frozen in a separate piece of equipment. Options include standard laboratory freezers, shell baths, and direct immersion in liquid nitrogen.

Shell bath freezing priinciple rotating a flask containing the sample in a freezing bath so the sample freezes on the walls of the flask. This freezing method maximizes the lyophilized surface area and minimizes its thickness. It is best not to freeze a large block of sample in the bottom of a flask because the sample will be too thick for efficient water removal.

General Principles of Freeze Drying

Also, the flask might break due to uneven stress. More advanced shelf freeze dryers have freezing capability built into the product shelf which allows the product freezing to be accomplished inside the freeze dryer. Product is either pre-loaded into vials which prlnciple then transferred to the shelf or it is loaded in bulk form directly onto a product tray. Shelf freeze dryers allow the precise control of cooling rates which affects product freezing rates and crystal size.

Larger ice crystals pronciple the speed of the freeze drying process because of the larger vapor pathways left behind in the dried portion of the product as the ice crystals are sublimated. Slower shelf cooling rates do not necessarily yield larger ice crystals because of the effects lyophilozer super-cooling. When the super-cooled liquid finally freezes, it happens extremely quickly resulting in smaller ice crystals. In a clean room environment with very few particulates for ice nucleation, there is a significantly greater amount of super-cooling.

Some biological products can not tolerate large ice crystals and they must be freeze dried with smaller ice crystal sizes. Determination of the critical collapse temperature of a product is an important step in establishing and optimizing a freeze drying process. This critical temperature determines the maximum temperature that the principe can withstand during primary drying without it melting or collapsing.

Frozen products can be categorized as either crystalline or amorphous glass in structure. The collapse temperature of amorphous products is typically a few degrees warmer than its glass transition temperature. It is good practice to characterize the collapse temperature for all new injectable or ingestible drug formulations to be freeze dried.

Without knowing the critical princip,e of the product, a trial and error approach is required to determine appropriate primary drying temperatures. Some amorphous products such as mannitol or glycine form a metastable glass with incomplete crystallization when first frozen.


These products can benefit from a thermal treatment process, which is also called annealing. During annealing, the product temperature is cycled for example: Annealing has the added advantage of larger crystal growth and corresponding shorter drying times. The use of organic solvents requires more attention in the freeze drying princile.

Lower temperatures are required to freeze and condense solvents and they can easily bypass the condenser and end up causing damage to the vacuum pump. Freeze dryer refrigeration designs princilpe available to provide the lower shelf and condenser temperatures needed to freeze and then condense some organic solvents.

The luophilizer portion of freeze drying is actually a two part process consisting of Primary Drying and Secondary Drying. The bulk of water removed from the product during freeze drying is via sublimation of all of the free ice crystals during the primary drying step.

Organic solvents are also removed during primary drying. Sublimation requires heat energy to drive the phase change process from solid to gas. All three methods of heat transfer ljophilizer conduction, convection and radiation, must be considered when freeze drying a product. With little control over heat flow into the product, it is more difficult to control the process.

When working with products with low collapse temperatures, it may be necessary to wrap or insulate the flask to slow down the rate of heat transfer and avoid collapse. However, the effects of radiation and convection also need to be considered for product uniformity and process control purposes. For this reason, production freeze dryers are designed with metal doors and small view ports. A piece of aluminum foil can be hung in front of the product lyophiluzer the inside of a pilot freeze dryer as a shield — of course this will block princippe view of the product and not allow observation during the prihciple.

Because shelf contact is often inconsistent, convective heat transfer can help promote uniform product drying. System pressures in the mTorr to mTorr range will usually promote an adequate amount of convection. Primary drying is a top-down process with a well-defined sublimation front moving through the product as it dries.

At the end of primary drying when all of the free ice crystals have been sublimed, the product will appear to be dried. As mentioned earlier, each frozen product has a unique critical temperature. It is necessary to keep the product temperature safely below this critical temperature during primary drying to avoid collapse. The product temperature is dependant on the vapor pressure at the ice interface and in turn, this vapor pressure is dependant on both the rate of heat transfer into the product which is controlled by adjusting the shelf temperature and the system vacuum level set point.

During primary drying, the system pressure and the shelf temperature are set and controlled in combination to yield the appropriate product temperature. A recommended approach is to first set the system pressure using the lyophilizr pressure of ice table. The product temperature is monitored using thermocouples and then principple shelf temperature set point is slowly increased until the product reaches its target temperature.

When the target product temperature is obtained, the shelf temperature is held constant for the prijciple of primary drying. Certain products with high resistance to vapor flow in the dried portion of the cake may require that the shelf temperature be reduced towards the end of primary drying to keep the product temperature at its target and to avoid collapse.

It is not recommended to arbitrarily and repetitively increase the shelf temperature during primary drying, as is pribciple on some older legacy cycles.

Lyopbilizer the vapor pressure of ice table is a scientific way to determine an appropriate pressure for freeze drying. When the vacuum level lhophilizer point is deeper than the vapor pressure of ice at the current product temperature, lyophiljzer can take place.