Get along with life in a light and measured way!A beautiful encounter with you!- Shun freeze-dried
With the rapid development of biopharmaceutical technology, freeze dryer, an efficient, energy-saving and environmentally friendly drying technology, is more and more widely used in the field of biopharmaceutical. It is like a magical existence, which brings great convenience to the production and preservation of medicines. In the pharmaceutical production line, freeze-drying technology magically converts liquid drugs into solid form, which is not only convenient for storage and transportation, but also greatly improves the stability of drugs and prolongs the shelf life of drugs.
First, the history of freeze drying technology
Freeze drying technology, also known as sublimation drying, is the magician of dehydration. It freezes aqueous substances below freezing, using the principle of ice sublimation at low temperatures. The moisture in the substance, such as frost in winter, is directly sublimated from the solid state to the gaseous state, so that the substance is rejuvenated and dry.
As early as the 18th century, the wise ancestors had a glimpse of the mystery of freeze-drying, but it was not until the mid-20th century that the wings of technology and people's desire for delicious food were intertwined, which promoted freeze-drying technology to shine in food, medicine, biological products and other fields. In the smoke of the First World War, this technology became a magician in the manufacture of dehydrated vegetables, providing a solution to the problem of food ** in wartime.
With the passage of time, the technology has become more and more full-fledged, and freeze-drying technology has gradually become a bright star in the field of food processing, which is widely used in the production of instant noodles, instant coffee, instant soup and other foods. Not only that, but it also shines in the fields of biological products, pharmaceuticals, etc. Because freeze-drying technology can preserve the original structure and activity of substances to the greatest extent, it has become one of the essential technologies for the preparation of vaccines, biological products and some drugs.
Second, the principle and process of freeze-drying technology
Freeze-drying technology, like nature's meticulous carver, sublimates the object in the magic of freezing, removing the stubborn moisture. Its mystery lies in the principle of sublimation of ice crystals, which condenses the moisture of the item at low temperature, captures the moisture in it like a dreamcatcher, and sublimates it when the time is ripe and the temperature is suitable, so as to perfectly remove the moisture from the item.
During the freeze-drying journey, items are baptized with a pre-treatment to remove impurities and unnecessary components for sublimation. Afterwards, the object is invited onto the low-temperature dance floor, where the ice crystals are dreamlike, and their moisture is carefully woven into beautiful ice flowers. Once the ice crystals have been weaved, the object is invited into a vacuum, where there is no restraint and only freedom. On the stage of the vacuum, the enthusiastic heating makes the ice crystals dance, light and agile, and then dissolve into invisible water vapor. They happily pass through the condenser, are condensed into droplets, streak across the night sky like meteors, and finally merge into the bosom of nature.
The process of sublimation is like a dream, and the ice crystals gradually disappear in the dance, turning into nothingness. When the sublimation comes to a perfect end, the moisture in the item has disappeared, leaving only the dry and pure object, as if it has passed through the rainbow after the rain, and has been given new life and meaning.
Freeze drying of drugs is generally carried out in three steps, namely pre-freezing, sublimation drying (or first-stage drying), and analytical drying (or second-stage drying).
1.Pre-freezing of the product
In the journey of freeze-drying, the pre-freezing link can be called the starting step. Its core mission is to lead every drop of water in the product to the dance floor of ice crystals, so that it can be lightly waved away on the sublimated and dry stage, and it can be drifted away as water vapor. In order for this feast of ice crystals to take place, we need to cool the product below its freezing point and allow all the free water to hibernate with the bound water. The duration of the pre-freeze is like the rhythm of the dancer, which needs to match the characteristics and size of the product and the rhythm of the freeze dryer.
(1) Pre-freezing temperature:The choice of pre-freezing temperature is crucial, it should be below the freezing point (eutectic point temperature), within a narrow range of 5, or at the eutectic temperature10 15. The lyophilization curve clearly indicates this eutectic point temperature, and the jump point of the product temperature is an excellent proof of this temperature when cooling. The subtle difference in pre-freezing temperature has a profound impact on the lyophilization effect. At slightly higher temperatures, the product may not freeze completely, resulting in irreversible changes such as bubbles, shrinkage, concentration, or spray bottles during vacuuming, which not only affects the appearance of the product, but can also lead to the failure of the entire lyophilization process. If the temperature is too low, it is a waste of resources and may also affect the molding of the product. Therefore, careful selection of the pre-freezing temperature is key to ensuring that the lyophilization process runs smoothly.
(2) Vacuum degree of pre-freezing:During the sample cooling phase, the temperature of the plate is always lower than the temperature of the product, resulting in a pressure gradient due to the temperature difference. This pressure gradient results in the sublimation of the moisture in the product even without vacuum treatment. In actual production, the sublimation at this stage will form a dry layer in the product, which will often hinder the subsequent sublimation process, which will cause the product to peel, shrink, delaminate and other phenomena, and even lead to freeze-drying failure in serious cases.
In order to solve this problem, after the product is put into the freeze-drying cabinet, we should fill it with a certain amount of inert gas to form a positive pressure in the box. This reduces the sublimation of the product at the pre-freezing stage and thus avoids the above-mentioned problems.
(3) Pre-freezing time:Due to the hysteresis of heat transfer, the temperature cannot be evenly distributed instantaneously, resulting in inconsistent internal temperatures in the sample. In order to ensure that the entire batch of samples can be kept in the same low temperature environment, when the temperature of the product drops to the freezing point, it needs to be kept warm for a period of time to ensure that the product is completely frozen and stabilized. The length of the pre-freezing time depends on a number of factors, including the amount of product loaded, the area of the layer, and the nature of the heat transfer medium.
2.Sublimation drying
In the journey of freeze-drying, sublimation drying is the graceful dancer who dances on the stage of dehydration. Its magic lies in the fact that, with just the right temperature and vacuum, the ice crystals gradually sublimate like dancers, turning into water vapor spirits, attracted by the magic wand of the vacuum, and gently withdrawn. In this process, the temperature and vacuum degree are the best conductors, not only to guide the ice crystals to dance gracefully, but also to avoid the appearance of crystallized dancing shoes on the surface of the product. Sublimation and drying, such a waltz of temperature and vacuum dancing with ice crystals and water vapor, light, elegant, and full of charm.
(1) The temperature at which the sublimation dries:In the sublimation phase, the temperature should usually be set below the eutectic point of the product, and the closer to the eutectic point, the faster the sublimation will be. However, in the actual production process, the temperature setting needs to be determined according to the characteristics of the product. For those products that are stable, easy to form, or contain a large amount of mannitol and other excipients, the temperature can be raised to the maximum allowable temperature at one time, and the heating time can be appropriately extended. Although the temperature of the heat transfer medium is higher than the eutectic point of the product, under certain vacuum conditions, the initial heat is mainly used for the sublimation of moisture in the product, and the temperature of the product itself does not rise, so it will not lead to lyophilization failure. This is not only convenient, but also helps to shorten the production cycle.
For those products with unstable properties, difficult production or process exploration, it is recommended to set the temperature below the eutectic point 2 5 for sublimation, and adopt the stepwise heating and drying method. This method is not only safe and effective, but also conducive to observing the changes in product characteristics in each temperature range, so as to optimize and improve the lyophilization process.
(2) Vacuum degree during sublimation drying:Theoretically, the lower the pressure, that is, the higher the vacuum, the more conducive to the sublimation of the substance. In practice, however, we have found that there is an optimal vacuum range in which the sublimation of the product is better. This is because the degree of vacuum has a significant effect on heat transfer and diffusion of water molecules. If the vacuum is too low, the sublimation rate will decrease significantlyHowever, if the vacuum is too high, the lyophilization rate will be reduced due to poor thermal convection conduction.
In order to ensure product quality and improve production efficiency, it is crucial to choose the right vacuum level. After a large number of experiments, the pressure is generally controlled to 15 30 Pa, and in this range, the lyophilization cycle can be shortened to the original 1 2 2 3. Therefore, pressure control in the sublimation drying stage is particularly necessary, which is not only related to the quality of the product, but also the key to shortening the production cycle and improving economic efficiency.
3.Resolve drying
In the material, after the ice crystals sublimate and dry, many cavities are left inside. However, about 10% of the unfrozen water remains in the substrate. This means that the process of resolving the drying process is necessary in order to reduce this residual moisture to 2% by mass. In this way, we can obtain a completely dry material. The maximum temperature at this stage depends on the nature of the product and the moisture content requirements of the finished product. In order for the moisture content to meet the requirements, we can increase the temperature appropriately (provided, of course, that the biological activity of the product is not destroyed). Usually, this temperature is controlled between 25 and 30.
In the re-drying stage, we need to adjust the high pressure and intensity appropriately, which is conducive to the heat transfer of the product, so as to speed up the heating rate. When the temperature of the product fully reaches the temperature set by the heat transfer medium, we return to the state of high vacuum. In this case, the time to return to the high vacuum is a key factor in pressure control, as this speeds up the sublimation and thus the drying time.
In the process of freeze-drying of medicines, the following issues need to be paid attention to:
1.The medicine is freeze-dried, in a vacuum, like a dancer dancing on an endless stage, but oxygen is a potential opponent for the dancer. In order to prevent the medicine from coming into close contact with oxygen, we add an inert gas to the pharmaceutical packaging container, as if building an oxygen-free stage for the dancers, ensuring that the dance of the medicine is not disturbed.
2.The temperature in the freeze-drying process of drugs is the key conductor and leads the fate of drugs. If the temperature is too high, the activity of the drug may disappear;If the temperature is too low, the medicine may fall into an icy embrace. Therefore, we must strictly follow the process requirements of the drug to carry out temperature control, like a gardener who carefully cares for the flowers, to ensure that each flower can bloom at the right temperature.
3.In the freeze-drying process of pharmaceutical products, hygienic conditions are like pure water sources, which are indispensable. Equipment, pipelines, containers, etc. must be kept clean and sterile to avoid contamination of drugs. At the same time, operators also need to carry out strict hygiene management to ensure that the production process is as clear as spring water, and to protect the safety and purity of the drug.