Expelling ice or other kinds of solidified solvents from an item through the sublimation procedure and removing the bound molecules of water through the desorption procedure is known as Freeze Drying. The terms freeze drying and lyophilization are utilized correspondently based on the location and industry where actually the drying process is happening. The controlled freeze drying maintain the temperature of the product low enough during the procedure for avoiding modifications in the dried item characteristics and appearance. This is a marvellous technique for storing a large number of heat-sensitive items like microbes, tissues, plasma, and proteins.
Concept of Sublimation
In a sublimation procedure, a solid change without going through the phase of liquid, directly into vapour. Understand the sublimation concept thoroughly as it is a crucial step, in acquiring the freeze-drying knowledge. Low pressures are needed for sublimation process to happen. this process is a change of phase in the energy of heat has to be included to the frozen item, so that to occur. The freeze-drying procedure the sublimation process can be described in a simple way as –
- Freeze: The item is solidified, it happens in a flask, tray, or in a vial.
- Vacuum: The item is placed in a deeper vacuum which is below the water triple point.
- Dry: Here, the heat energy is included to the item which causes the solid to sublime or purify.
These are the steps needed in lyophilizing an item in the batch procedure and it can be summarised as mentioned below-
- Pre-treatment or formulation
- Loading or container
- Freezing at the atmospheric pressure
- Primary drying under vacuum
- Secondary drying under vacuum
- Backfill and stoppering under partial vacuum
- Eradication of the dried item from freeze dryer
Additionally, offering an expanded shelf life and outstanding freeze-drying procedure has to result into an item that possess a short time of reconstitution with the acceptable levels of potency. This procedure should be repeatable with the temperature, pressure, and time parameters that are well defined for every step. The functional and visual characteristics of the dried item is also crucial for most of the applications.
The Working Principle of Freeze drying
Freeze -drying is carried out using the principle of sublimation drying technique , the material to be dried is frozen rapidly at low temperature , and then under the appropriate vacuum , so that the sublimation of frozen water molecules directly into a steam escape process. Frozen the product was dried to obtain a lyophilisate called (lyophilizer), the process is called lyophilized (lyophilization).
Always in substance before drying at low temperature ( frozen ) , and ice crystals evenly distributed in the material , the sublimation process does not occur due to dehydration concentrated phenomenon , avoiding the side effects produced by vapor bubble oxidation. Dry material was dry porous sponge , is essentially the same volume , highly soluble in water and restitution. Prevention of dry matter in the physicochemical and biological variability maximum extent .
Freeze-drying machine is from the refrigeration system, vacuum system , heating system, electrical instrumentation control system components. The main part of the oven , a condenser , refrigeration units , pumps, heating / cooling devices . Its working principle is to be freeze -dried items to the triple point temperature, and then the articles under vacuum solid water ( ice ) sublimate directly into water vapor , are excluded from the article, the article dry. After the materials are processed before being sent to the freezing of frozen positions , and then into a dry warehouse sublimation dehydration , after the post-processing plant packaging. Vacuum sublimation drying warehouse system established low pressure conditions, the heating system to provide the latent heat of sublimation materials , refrigeration systems to provide the required amount of cold and dry ice condenser chamber . The device uses highly efficient radiant heating , the material is heated evenly ; efficient use of water-cooled trap to catch , and to achieve rapid defrost ; adopt efficient vacuum unit , and to achieve oil-water separator ; centralized refrigeration system using parallel , multi-channel on-demand cooling, working conditions stable , favorable energy efficiency ; using artificial intelligence control , high control accuracy , easy to operate.
Freeze drying equipment
The main components of freeze drying equipment are:
- Refrigeration System
- Vacuum System
- Control System
- Product Chamber or Manifold
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. Advanced controllers will allow the programming of a complete “recipe” for freeze drying and will include options to monitor how the freeze drying process is progressing. Choosing a control system for the freeze dryer depends on the application and use (i.e. lab vs. production).
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.
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. Advanced shelf freeze dryers can provide a heat source to control/expedite the drying process and they can also employ the refrigeration system to allow freezing of product inside the unit.
Freeze dryers can be informally classified by the type of product chamber: (1) Manifold dryers where the product is typically pre-frozen & in flasks (2) Shelf dryers where the product is placed in a tray or directly on a shelf (3) Combination units with both drying options.
Freeze-dryers can also be grouped by size & use: (1) laboratory bench-top units for R&D (2) pilot units for process development and scale-up, and (3) larger production-sized units. It should be noted that in addition to process scale-up work, pilot-sized freeze dryers are often used for product R&D as well as small volume production applications.
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.
Choosing a Freeze Dryer:
Picking a freeze dryer and Lyophilizers relies upon the item qualities just as numerous other application-based factors incorporating the holder that the item will be dried in. The rack zone or number of ports required to oblige the amount to be dried in each cluster. The entire ice volume of ice to be consolidated and whether there are any natural solvents. The sort and state of item being dried and its end-utilization additionally should be examined.
Containers of Product and Containment Systems
For the product, an appropriate framework of container must be chosen. The most prominent holders of item are cups, plate, and vials. If conceivable, it is prudent in picking a holder that keeps the most extreme thickness of the item to not exactly ¾”. The extraordinary holders made of Tyvek and Gore-Tex are likewise accessible for the explicit applications where item defilement is a worry. When working with vials, item plate with removable bottoms are accessible. The plate is stacked with vials then put on a rack in the freezing dryer. Later, the base piece of the plate is slid out. This enables the vials to lay specifically on the rack and builds the warmth exchange to the item.
The control frameworks that are extraordinary, for example, glove boxes are required for freeze drying certain items, particularly when lethal materials are available.
Materials Physical Properties and Formulation
Understanding the materials physical properties that had been freeze dried is the crucial part in building up a fruitful process of lyophilization. Even though a couple of items are basic crystalline materials, most by far of items that are lyophilized are nebulous and shape polished states when solidified. Preparing and development of formulation are essential advances that regularly are taken to make an item prepared for the freeze drying. And is usable for its particular application. The excipients choice added to a detailing can seriously influence the warm product attributes and its capacity to be solidify dried in a sensible measure of time.
Freeze Drying Recipe
For the lyophilization process to take place in a rack freeze dryer requires the working procedure plan or cycle. This in some cases alluded as a Recipe. Ordinarily, there are different advances required for both solidifying and drying of the item. Time settings, singular temperature, and weight should be resolved for each progression. Every particular item or plan that is lyophilized requires the advancement of a stop drying process that depends on the one of a kind attributes of the item, the measure of item and the compartment utilized. There is no all-inclusive safe recipe that will work with each item.
It is critical that the specimen be completely and totally solidified preceding pulling a vacuum and beginning the procedure of drying. The item that is unfrozen may extend holder outside when it is set under a vacuum. Item is set in a vial or carafe relying upon the amount and after that solidified in a different bit of hardware with simple manifold freeze dryers. Choices incorporate standard research facility coolers, shell showers, and direct drenching in nitrogen in liquid form. The shell freezing includes pivoting a jar containing the specimen in a solidifying shower. So, the specimen solidifies on the flask dividers. This solidifying technique augments the item surface territory and limits its thickness. It is better not to solidify a huge square of test in the base of a carafe, if the specimen will be unreasonably thick for effective expulsion of water expulsion. Additionally, the jar may break because of pressure that is uneven.
Further developed, shell freeze dryers have the capacity of freezing incorporated within the shelf of item, which permits the item solidifying to be cultivated inside freeze dryer. Item is either pre-stacked into vials which are then exchanged to the rack or it is stacked in mass frame specifically onto an item plate. These dryers permit the exact control of cooling rates which influences item solidifying rates and size of crystal. Bigger ice crystals enhance the speed of the process of freeze drying on account of the bigger vapor pathways left behind in the dried bit of the item as the crystals of the ice are sublimated. Slower cooling rates of shelf don’t really yield bigger crystals of ice based on the super cooling impacts. At the point, when the super-cooled fluid at last stops, it occurs very rapidly that results into little crystals of ice. In a spotless room condition with not very many particulates for nucleation of ice, there is a fundamentally more prominent super cooling measure. Few natural items cannot endure expansive crystals of ice. And they should be freeze dried with little crystal sizes of ice.
Eutectic or Collapse Temperature
Assurance of the basic fall temperature of an item is an analytic advance in setting up and upgrading a procedure of freeze drying. This basic temperature decides the most extreme temperature that the item can withstand amid essential drying without softening or crumbling. The thermal analysis and dielectric resistance investigation are basic techniques utilized to determine this product critical temperature. The solidified items can be classified as either amorphous glass or crystalline in structure. The items which are crystalline items have an all-around characterized eutectic solidifying or liquefying point which is its crumple temperature. The products of amorphous have a relating glass change temperature and they are substantially harder to freeze drying. Undefined items collapse temperature is regularly a couple of degrees hotter than its temperature of glass transition. Even though most of the materials that are freeze dried are really amorphous. But the eutectic expression is frequently utilized to depict the point of solidifying or liquefying any item.
Inspections of lyophilization of parenterals states that the producer should realize the item’s eutectic point. It is great practice in portraying the fall temperature for all new injectable or ingestible medication definitions to remain freeze dried. Not knowing the product’s critical temperature, an experimentation approach is required in deciding the suitable essential temperatures of drying. A moderate traditionalist cycle with temperatures that are low and weights can be utilized at first. The weight and temperature would be raised on ensuing cycles until proof of fall or soften back is seen which demonstrates that the item was excessively warm.
Few of the products of amorphous frame a metastable glass with deficient crystallization when initially solidified. These items can profit by a procedure of warm treatment process, which is additionally called as Annealing. Amid this process, the temperature of item is cycled to acquire increasingly total crystallization. Toughening has the additional preferred standpoint of bigger crystal development and equivalent shorter times of drying.
The utilization of the organic solvents needs much care in the process of freeze drying. For freezing and condensing solvents, low temperatures are necessary. And they can simply pass through the condenser and tends to cause harm to the pump of vacuum. The refrigeration designs of freeze drying are accessible in giving the lower rack and temperatures of condenser expected to stop and after that gather some natural solvents. Liquid nitrogen or special filter cartridges traps might be required to gather or catch certain solvents with extremely low frosty temperatures. Security contemplations must be made when taking care of unpredictable or strong destructive materials.