Freeze drying has been used in a number of applications for many years, most commonly in the food and pharmaceutical industries. There are, however, many other uses for the process including heat-sensitive sample preparation, plant material research, the stabilization of living materials such as microbial cultures, long term storage of HPLC samples, preservation of whole animal specimens for museum display, restoration of books and other items damaged by water, and the concentration and recovery of reaction products.
Specialized equipment is required to create the conditions conducive to the freeze drying process. This equipment is currently available and can accommodate freeze drying of materials from laboratory scale projects to industrial production.
what is freeze drying?
Freeze drying involves the removal of water or other solvent from a frozen product by a process called sublimation. Sublimation occurs when a frozen liquid goes directly to the gaseous state without passing through the liquid phase. In contrast, drying at ambient temperatures from the liquid phase usually results in changes in the product, and may be suitable only for some materials. However, in freeze drying, the material does not go through the liquid phase, and it allows the preparation of a stable product that is easy to use and aesthetic in appearance.
Advantages of freeze drying
Freeze-drying is viewed as the optimal method of choice for dehydration because of the preservation of quality, meaning characteristics of the food product such as aroma, rehydration, and bioactivity, are noticeably higher compared to foods dried using other techniques.
Shelf-life extension is a result from low processing temperatures in conjunction with rapid transition of water through sublimation.With these processing conditions, deterioration reactions, including nonenzymic browning, enzymatic browning, and protein denaturation, are minimized.When the product is successfully dried, packaged properly, and placed in ideal storage conditions the foods have a shelf life of greater than 12 months.
If a dried product cannot be easily or fully re-hydrated, it is considered to be of lower quality. Because the final freeze dried product is porous, complete re-hydration can occur in the food. This signifies greater quality of the product and makes it ideal for ready-to-eat instant meals.
Effect on nutrients and sensory quality
Due to the low processing temperatures and the minimization of deterioration reactions, nutrients are retained and color is maintained. Freeze-dried fruit maintains its original shape and has a characteristic soft crispy texture.
Disadvantages of freeze drying
Since the main method of microbial decontamination for freeze drying is the low temperature dehydration process, spoilage organisms and pathogens resistant to these conditions can remain in the product. Although microbial growth is inhibited by the low moisture conditions, it can still survive in the food product. An example of this is a hepatitis A outbreak that occurred in the United States in 2016, associated with frozen strawberries. If the product is not properly packaged and/or stored, the product can absorb moisture, allowing the once inhibited pathogens to begin reproducing as well.
Freeze-drying costs about five times as much as conventional drying, so it is most suitable for products which increase in value with processing. Costs are also variable depending on the product, the packaging material, processing capacity, etc.The most energy-intensive step is sublimation.
Silicone oil leakage
Silicone oil is the common fluid that is used to heat or cool shelves in the freeze-dryer. The continuous heat/cool cycle can lead to a leakage of silicone oil at weak areas that connect the shelf and hose. This can contaminate the product leading to major losses of food product. Hence, to avoid this issue, mass spectrometers are used to identify vapors released by silicone oil to immediately take corrective action and prevent contamination of the product.
Principles of Freeze Drying
The freeze drying process consists of three stages: prefreezing, primary drying, and secondary drying.
Since freeze drying is a change in state from the solid phase to the gaseous phase, material to be freeze dried must first be adequately prefrozen. The method of prefreezing and the final temperature of the frozen product can affect the ability to successfully freeze dry the material.
Rapid cooling results in small ice crystals, useful in preserving structures to be examined microscopically, but resulting in a product that is more difficult to freeze dry. Slower cooling results in larger ice crystals and less restrictive channels in the matrix during the drying process.
Products freeze in two ways, depending on the makeup of the product. The majority of products that are subjected to freeze drying consist primarily of water, the solvent, and the materials dissolved or suspended in the water, the solute. Most samples that are to be freeze dried are eutectics which are a mixture of substances that freeze at lower temperatures than the surrounding water. When the aqueous suspension is cooled, changes occur in the solute concentrations of the product matrix. And as cooling proceeds, the water is separated from the solutes as it changes to ice, creating more concentrated areas of solute. These pockets of concentrated materials have a lower freezing temperature than the water.
Although a product may appear to be frozen because of all the ice present, in actuality it is not completely frozen until all of the solute in the suspension is frozen. The mixture of various concentration of solutes with the solvent constitutes the eutectic of the suspension. Only when all of the eutectic mixture is frozen is the suspension properly frozen. This is called the eutectic temperature.
It is very important in freeze drying to prefreeze the product to below the eutectic temperature before beginning the freeze drying process. Small pockets of unfrozen material remaining in the product expand and compromise the structural stability of the freeze dried product.
The second type of frozen product is a suspension that undergoes glass formation during the freezing process. Instead of forming eutectics, the entire suspension becomes increasingly viscous as the temperature is lowered. Finally the product freezes at the glass transition point forming a vitreous solid. This type of product is extremely difficult to freeze dry.
Several factors can affect the ability to freeze dry a frozen suspension. While these factors can be discussed independently, it must be remembered that they interact in a dynamic system, and it is this delicate balance between these factors that results in a properly freeze dried product.
After prefreezing the product, conditions must be established in which ice can be removed from the frozen product via sublimation, resulting in a dry, structurally intact product. This requires very careful control of the two parameters, temperature and pressure, involved in the freeze drying system. The rate of sublimation of ice from a frozen product depends upon the difference in vapor pressure of the product compared to the vapor pressure of the ice collector. Molecules migrate from the higher pressure sample to a lower pressure area. Since vapor pressure is related to temperature, it is necessary that the product temperature is warmer than the cold trap (ice collector) temperature.
It is extremely important that the temperature at which a product is freeze dried is balanced between the temperature that maintains the frozen integrity of the product and the temperature that maximizes the vapor pressure of the product. This balance is key to optimum drying. Most products are frozen well below their eutectic or glass transition point , and then the temperature is raised to just below this critical temperature and they are subjected to a reduced pressure. At this point the freeze drying process is started.
Some products such as aqueous sucrose solutions can undergo structural changes during the drying process resulting in a phenomenon known as collapse. Although the product is frozen below its eutectic temperature, warming during the freeze drying process can affect the structure of the frozen matrix at the boundary of the drying front. This results in a collapse of the structural matrix. To prevent collapse of products containing sucrose, the product temperature must remain below a critical collapse temperature during primary drying. The collapse temperature for sucrose is -32° C.
No matter what type of freeze drying system is used, conditions must be created to encourage the free flow of water molecules from the product. Therefore, a vacuum pump is an essential component of a freeze drying system, and is used to lower the pressure of the environment around the product. The other essential component is a collecting system, which is a cold trap used to collect the moisture that leaves the frozen product. The collector condenses out all condensable gases, i.e; the water molecules, and the vacuum pump removes all non-condensable gases.
It is important to understand that the vapor pressure of the product forces the sublimation of the water vapor molecules from the frozen product matrix to the collector. The molecules have a natural affinity to move toward the collector because its vapor pressure is lower than that of the product. Therefore, the collector temperature must be significantly lower than the product temperature. Raising the product temperature has more effect on the vapor pressure differential than lowering the collector temperature.
A third component essential in a freeze drying system is energy. Energy is supplied in the form of heat. Almost ten times as much energy is required to sublime a gram of water from the frozen to the gaseous state as is required to freeze a gram of water. Therefore, with all other conditions being adequate, heat must be applied to the product to encourage the removal of water in the form of vapor from the frozen product. The heat must be very carefully controlled, as applying more heat than the evaporative cooling in the system can remove warms the product above its eutectic or collapse temperature.
Heat can be applied by several means. One method is to apply heat directly through a thermal conductor shelf such as is used in tray drying. Another method is to use ambient heat as in manifold drying.
After primary freeze drying is complete, and all ice has sublimed, bound moisture is still present in the product. The product appears dry, but the residual moisture content may be as high as 7-8%. Continued drying is necessary at the warmer temperature to reduce the residual moisture content to optimum values. This process is called isothermal desorption as the bound water is desorbed from the product.
Secondary drying is normally continued at a product temperature higher than ambient but compatible with the sensitivity of the product. All other conditions, such as pressure and collector temperature, remain the same. Because the process is desorptive, the vacuum should be as low as possible (no elevated pressure) and the collector temperature as cold as can be attained. Secondary drying is usually carried out for approximately 1/3 to 1/2 the time required for primary drying.
Freeze Drying Methods?
Three methods of freeze drying are commonly used:
(1) manifold drying, (2) batch drying, and (3) bulk drying.
Each method has a specific purpose, and the method used depends on the product and the final configuration desired.
In the manifold method, flasks, ampules or vials are individually attached to the ports of a manifold or drying chamber. The product is either frozen in a freezer, by direct submersion in a low temperature bath, or by shell freezing, depending on the nature of the product and the volume to be freeze dried. The prefrozen product is quickly attached to the drying chamber or manifold to prevent warming. The vacuum must be created in the product container quickly, and the operator relies on evaporative cooling to maintain the low temperature of the product. This procedure can only be used for relatively small volumes and products with high eutectic and collapse temperatures.
Manifold drying has several advantages over batch tray drying. Since the vessels are attached to the manifold individually, each vial or flask has a direct path to the collector. This removes some of the competition for molecular space created in a batch system, and is most ideally realized in a cylindrical drying chamber where the distance from the collector to each product vessel is the same. In a “tee” manifold, the water molecules leaving the product in vessels farthest from the collector experience some traffic congestion as they travel past the ports of other vessels.
Heat input can be affected by simply exposing the vessels to ambient temperature or via a circulating bath.For some products, where precise temperature control is required, manifold drying may not be suitable.
Several vessels can be accommodated on a manifold system allowing drying of different products at the same time, in different sized vessels, with a variety of closure systems. Since the products and their volumes may differ, each vessel can be removed from the manifold separately as its drying is completed. The close proximity to the collector also creates an environment that maximizes drying efficiency.
In batch drying, large numbers of similar sized vessels containing like products are placed together in a tray dryer. The product is usually prefrozen on the shelf of the tray dryer. Precise control of the product temperature and the amount of heat applied to the product during drying can be maintained. Generally all vials in the batch are treated alike during the drying process, although some variation in the system can occur. Slight differences in heat input from the shelf can be experienced in different areas. Vials located in the front portion of the shelf may be radiantly heated through the clear door. These slight variations can result in small differences in residual moisture.
Batch drying allows closure of all vials in a lot at the same time, under the same atmospheric conditions. The vials can be stoppered in a vacuum, or after backfilling with inert gas. Stoppering of all vials at the same time ensures a uniform environment in each vial and uniform product stability during storage. Batch drying is used to prepare large numbers of ampules or vials of one product.
Bulk drying is generally carried out in a tray dryer like batch drying. However, the product is poured into a bulk pan and dried as a single unit.
Although the product is spread throughout the entire surface area of the shelf and may be the same thickness as product dried in vials, the lack of empty spaces within the product mass changes the rate of heat input.
Bulk drying does not lend itself to sealing of product under controlled conditions as does manifold or batch drying. Usually the product is removed from the freeze dry system prior to closure, and then packaged in air tight containers. Bulk drying is generally reserved for stable products that are not highly sensitive to oxygen or moisture.
Applications of freeze drying
Freeze-drying causes less damage to the substance than other dehydration methods using higher temperatures. Nutrient factors that are sensitive to heat are lost less in the process as compared to the processes incorporating heat treatment for drying purposes.Freeze-drying does not usually cause shrinkage or toughening of the material being dried. In addition, flavours, smells, and nutritional content generally remain unchanged, making the process popular for preserving food. However, water is not the only chemical capable of sublimation, and the loss of other volatile compounds such as acetic acid (vinegar) and alcohols can yield undesirable results.
Freeze-dried products can be rehydrated (reconstituted) much more quickly and easily because the process leaves microscopic pores. The pores are created by the ice crystals that sublimate, leaving gaps or pores in their place. This is especially important when it comes to pharmaceutical uses. Freeze-drying can also be used to increase the shelf life of some pharmaceuticals for many years.
Pharmaceuticals and biotechnology
Lyophilized 5% w/v sucrose cake in a pharmaceutical glass vial
Pharmaceutical companies often use freeze-drying to increase the shelf life of the products, such as live virus vaccines, biologics and other injectables. By removing the water from the material and sealing the material in a glass vial, the material can be easily stored, shipped, and later reconstituted to its original form for injection. Another example from the pharmaceutical industry is the use of freeze drying to produce tablets or wafers, the advantage of which is less excipient as well as a rapidly absorbed and easily administered dosage form.
Freeze-dried pharmaceutical products are produced as lyophilized powders for reconstitution in vials and more recently in prefilled syringes for self-administration by a patient.
Examples of lyophilized biological products include many vaccines such as live measles virus vaccine, typhoid vaccine, and meningococcal polysaccharide vaccine groups A and C combined. Other freeze-dried biological products include antihemophilic factor VIII, interferon alfa, anti-blood clot medicine streptokinase, and wasp venom allergenic extract.
Many bio-pharmaceutical products based on therapeutic proteins such as monoclonal antibodies require lyophilization for stability. Examples of lyophilized biopharmaceuticals include blockbuster drugs such as etanercept (Enbrel by Amgen), infliximab (Remicade by Janssen Biotech), rituximab, and trastuzumab (Herceptin by Genentech).
Freeze-drying is also used in manufacturing of raw materials for pharmaceutical products. Active Pharmaceutical Product Ingredients (APIs) are lyophilized to achieve chemical stability under room temperature storage. Bulk lyophilization of APIs is typically conducted using trays instead of glass vials.
Cell extracts that support cell-free biotechnology applications such as point-of-care diagnostics and biomanufacturing are also freeze-dried to improve stability under room temperature storage.
Dry powders of probiotics are often produced by bulk freeze-drying of live microorganisms such as lactic acid bacteria and bifidobacteria.
Freeze drying of food
The primary purpose of freeze drying within the food industry is to extend the shelf-life of the food while maintaining the quality.Freeze-drying is known to result in the highest quality of foods amongst all drying techniques because structural integrity is maintained along with preservation of flavors. Because freeze drying is expensive, it is used mainly with high-value products.Examples of high-value freeze-dried products are seasonal fruits and vegetables because of their limited availability, coffee; and foods used for military rations, astronauts/cosmonauts, and/or hikers.
NASA and military rations
Because of its light weight per volume of reconstituted food, freeze-dried products are popular and convenient for hikers, as military rations, or astronaut meals.A greater amount of dried food can be carried compared to the same weight of wet food. In replacement of wet food, freeze dried food can easily be rehydrated with water if desired and shelf-life of the dried product is longer than fresh/wet product making it ideal for long trips taken by hikers, military personnel, or astronauts. The development of freeze drying increased meal and snack variety to include items like shrimp cocktail, chicken and vegetables, butterscotch pudding, and apple sauce.
Coffee contains flavor and aroma qualities that are created due to the Maillard reaction during roasting and can be preserved with freeze-drying.Compared to other drying methods like room temperature drying, hot-air drying, and solar drying, Robusta coffee beans that were freeze-dried contained higher amounts of essential amino acids like leucine, lysine, and phenylalanine. Also, few non-essential amino acids that significantly contributed to taste were preserved.
With conventional dehydration, berries can degrade in quality as their structure is very delicate and contains high levels of moisture. Strawberries were found to have the highest quality when freeze dried; retaining color, flavour, and ability to be re-hydrated.
Freeze-drying is used extensively to preserve insects for the purposes of consumption. Whole freeze-dried insects are sold as exotic pet food, bird feed, fish bait, and increasingly for human consumption. Powdered freeze-dried insects are used as a protein base in animal feeds, and in some markets, as a nutritional supplement for human use. Farmed insects are generally used for all of the aforementioned purposes versus harvesting wild insects, except in the case of grasshoppers which are often harvested out of field crops.
Freeze-drying is among the methods used to preserve animals in the field of taxidermy. When animals are preserved in this manner they are called “freeze-dried taxidermy” or “freeze-dried mounts”. Freeze-drying is commonly used to preserve crustaceans, fish, amphibians, reptiles, insects, and smaller mammals. Freeze-drying is also used as a means to memorialize pets after death. Rather than opting for a traditional skin mount when choosing to preserve their pet via taxidermy, many owners opt for freeze-drying because it is less invasive upon the pet’s body.
Organizations such as the Document Conservation Laboratory at the United States National Archives and Records Administration (NARA) have done studies on freeze-drying as a recovery method of water-damaged books and documents. While recovery is possible, restoration quality depends on the material of the documents. If a document is made of a variety of materials, which have different absorption properties, expansion will occur at a non-uniform rate, which could lead to deformations. Water can also cause mold to grow or make inks bleed. In these cases, freeze-drying may not be an effective restoration method.
In bacteriology freeze-drying is used to conserve special strains.
Advanced ceramics processes sometimes use freeze-drying to create a formable powder from a sprayed slurry mist. Freeze-drying creates softer particles with a more homogeneous chemical composition than traditional hot spray drying, but it is also more expensive.
A new form of burial which previously freeze-dries the body with liquid nitrogen has been developed by the Swedish company Promessa Organic AB, which puts it forward as an environmentally friendly alternative to traditional casket and cremation burials.
Determining Drying Endpoints
Several means can be used to determine the endpoint of primary drying. The drying boundary in batch drying containers has moved to the bottom of the product container and inspection reveals that no ice is visible in the product. No visible ice indicates only that drying at the edges of the container is complete and gives no indication of the conditions in the center of the product. An electronic vacuum gauge can be used to measure condensable gases in the system. When the pressure indicated by the electronic gauge reaches the minimum pressure attainable by the system, as no more water vapor is leaving the product.
As the heat input to the product is increased, evaporative cooling keeps the product temperature well below the temperature of its surrounding atmosphere. When primary drying is complete, the product temperature rises to equal the temperature of its environment. In manifold systems and tray dryers with external collectors, the path to the collector can be shut off with a valve and the pressure above the product measured with a vacuum gauge. If drying is still occurring, the pressure in the system increases.
Contamination in a Freeze Dry System
Two types of contamination can occur in a freeze dry system. One results from freeze drying microorganisms and the other results from freeze drying corrosive materials.
The potential for contamination of a freeze drying system by microorganisms is real in any system where microorganisms are freeze dried without a protective barrier such as a bacteriological filter. Contamination is most evident in batch tray dryer systems where large numbers of vials are dried in a single chamber. Evidence for contamination may be found by sampling the surfaces of the vials, shelves and collector. The greatest degree of contamination is usually found on the vials and on the collector. Although some vial contamination may be due to sloppiness in dispensing the material originally, contamination on the collector is due to microorganisms traveling from the product to the collector through the vapor stream.
The potential for contamination must be considered every time microorganisms are freeze dried, and precautions must be taken in handling material after the freeze dry process is completed. Recognizing that the vials are potentially contaminated, the operator should remove the vials to a safe area such as a laminar flow hood for decontamination. Decontamination of the freeze dry system depends upon the type of freeze dry system used. Some tray dryer systems are designed for decontamination under pressure using ethylene oxide sterilization. Ethylene oxide is considered hazardous, corrosive and detrimental to rubber components. Its use should be carefully monitored.
Coupled with the risk of contamination in a freeze dry system is the risk of cross contamination when freeze drying more than one product at time. It is not good practice to mix microbiological products in a freeze dry system unless some type of bacteriological filter is used to prevent the microbial product from leaving the vial itself.
While freeze drying of corrosive materials does not necessarily present a risk to the operator, it does present a risk of damaging the freeze dry system itself. Although freeze dry systems are designed using materials that resist corrosion and prevent the build up of corrosive materials, care should be taken to clean the system thoroughly following each use to protect it from damage.
Stability of Freeze Dried Products
Several factors can affect the stability of freeze dried material. Two of the most important are moisture and oxygen.
All freeze dried products have a small amount of moisture remaining in them termed residual moisture. The amount of moisture remaining in the material depends on the nature of the product and the length of secondary drying. Residual moisture can be measured by several means: chemically, chromatographically, manometrically or gravimetrically. It is expressed as a weight percentage of the total weight of the dried product. Residual moisture values range from <1% to 3% for most products.
By their nature, freeze dried materials are hygroscopic and exposure to moisture during storage can destabilize the product. Packaging used for freeze dried materials must be impermeable to atmospheric moisture. Storing products in low humidity environments can reduce the risk of degradation by exposure to moisture. Oxygen is also detrimental to the stability of most freeze dried material so the packaging used must also be impermeable to air.
The detrimental effects of oxygen and moisture are temperature dependent. The higher the storage temperature, the faster a product degrades. Most freeze dried products can be maintained at refrigerator temperatures, i.e. 4-8° C. Placing freeze dried products at lower temperatures extends their shelf life. The shelf life of a freeze dried product can be predicted by measuring the rate of degradation of the product at an elevated temperature. This is called accelerated storage. By choosing the proper time and temperature relationships at elevated temperatures, the rate of product degradation can be predicted at lower storage temperatures.
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