The process of freeze drying begins with freezing the product to a temperature that is low enough to render all product constituents solid.  That is, to cool the product to below that temperature is commonly called freezing below the eutectic temperature. 

Eutectic:

     The eutectic temperature is exhibited for every crystalline material, as being “the one mixture of a set of substances able to dissolve in one another as liquids that, of all such mixtures, liquefies at the lowest temperature. If an arbitrarily chosen liquid mixture of such substances is cooled, a temperature will be reached at which one component will begin to separate in its solid form and will continue to do so as the temperature is further decreased. As this component separates, the remaining liquid continuously becomes richer in the other component, until, eventually, the composition of the liquid reaches a value at which both substances begin to separate simultaneously as an intimate mixture of solids. This composition is the eutectic composition and the temperature at which it solidifies is the eutectic temperature; if the original liquid had the eutectic composition, no solid would separate until the eutectic temperature was reached; then both solids would separate in the same ratio as that in the liquid, while the composition of the remaining liquid, that of the deposited solid, and the temperature all remained unchanged throughout the solidification.”  [1] 

Amorphous [Glass-like]

     The Eutectic in freeze dried product is rarely seen, and this commonly used term “to below the eutectic” is a simplified jargon statement that means that the product, whether crystalline or amorphous [glass like properties], is solidly frozen so as to retain its shape and macroscopic visual appearance during and after freeze drying is completed.  Of course the freezing method must also keep the product integrity and efficacy.  Most products that are freeze dried are mixtures of glassy substances, and substances that show crystalline properties upon freezing or thawing.  In freeze drying, it is mostly the thawing that is to be avoided, and the objective of the process if it is to be successful is to more or less keep the product cold enough to avoid this melting or softening until the product is completely dry. Many pharmaceutical products that are freeze dried have minuscule amounts of active ingredients [API] mixed in a solution or suspension of excipients, buffers, cryo-protective agents, and other substances such as surfactants,  when formulated properly allow the product to be administered to humans, or animals. 

Efficacy

     The efficacy of the product after freeze drying is measured by whatever means the manufacturer of the product submits to the FDA or the USDA or other regulatory body when registering the product deems necessary to ensure that batch after batch of product is processed within the stated analytical tests. The process of freezing the product in freeze drying also can confer properties that enhance the release of water vapor from the product during the primary drying [sublimation of water vapor] by enhancing the flow of water vapor as it exits the freeze dried product, ice gas interface. Many substances are freeze dried.  For example, diamond dust slurries, blood analyzer standards, vaccines, fine powdered precious metals, ceramic forms, pharmaceuticals, berries, vegetables, meats, fruits and even whole meals like astronaut foods, to name a few, are freeze dried.

Freezing Methods

     Different freezing methods can and are carried on depending upon product types.  Freeze dried foods for instance are usually frozen before being put onto the shelves of the freeze dryer, usually in a suitably cold walk in freezer, in a freezing tunnel, or a blast freezer.  Most pharmaceutical products are frozen inside the freeze dryer whilst maintained under very clean conditions.  Aseptic Practice during formulation, filling, partial stoppering, loading practices eliminate any adulterants such as bacteria, molds, particulates, from the product.  This entire process, including cleaning in place, sterilization of the interior of the dryer in place with steam, or with a gaseous sterilants [Hydrogen Peroxide, Chlorine Dioxide] requires validation.   Therefore the entire process ensures the purity of the product.  The freezing methods utilized are complex.

 Thermal Treatment

     Thermal treatment is one such complex method of freezing product.  When mannitol is in a product formulation, the freezing process must take into account that this substance exhibits glassy properties when frozen, and can be made to produce crystalline properties by using this method of first cooling the product to a low temperature, then warming the product to a temperature, and holding that temperature for a while, and then reducing the temperature to a low temperature again, and then moving on to the next step in the freeze drying process.  If the mannitol containing product contained in glass vials is frozen and then dried without thermal treatment, the sudden changeover from amorphous to crystalline form can occur.  This sudden changeover can pop the bottoms out of glass vials and cause a big mess inside the freeze dryer.  Imagine that the product contains minute amounts of a potent compound and what a very dangerous job it can be for workers to clean up afterward.  The thermal treatment freezing process is therefore available to eliminate vial breakage because if the crystalline form of mannitol is produced during freezing, glass breakage will be minimized or eliminated completely.

 Controlled Nucleation

     Another method of freezing product involves producing an ice fog into the freeze drying chamber during freezing.  This ice fog can be induced by two means.  One is to freeze the product in the presence of pressurized gas such as nitrogen, and at a particular product dependent temperature, releasing the gas suddenly, thereby producing the ice fog.  The ice fog generates sterile ice crystals from the humidity resulting from the product in the freeze dryer.  When these ice fog crystals fall into the product the water in the product suddenly, within fractional seconds, freezes from the top downward throughout the product volume, thereby capturing the residual product between ice crystals.  Upon further freezing or even thermal treatment, the remainder of the product is solidified.  These ice crystals then sublime freely, allowing further sublimation pathways deep inside the product matrix thereby allowing faster primary and even secondary drying [desorption phase] to occur.

     Freezing is therefore a very important step in the process of freeze drying.  If done properly it may allow many substances [High sugar containing food products for instance] to dry quickly because the efficient release of vapor from the product ice gas interface deep within the product may allow for vapor to escape more rapidly.  Hours can be safely cut from otherwise long food freeze drying cycles thereby improving process efficiency and lowering process costs.

[To be continued…]

[1] https://www.britannica.com/science/eutectic