Briefly: Bo Yikang has been committed to the R&D and production of small-scale, pilot-scale, production-type vacuum freeze-drying equipment. In the process of long-term service to customers, it has been found that the production of lyophilized preparations is frequent . The successful experience of collecting and lyophilizing preparations is now available for the majority of users.

Overview:

First, the mechanism of lyophilized preparation

The large size of the lyophilizer is inevitably irritating. In fact, from the freeze-drying mechanism, the freeze dryer is nothing more than a structure of two large refrigerators plus a vacuum pump. One of the refrigerators was first responsible for freezing the drug into ice cubes and then turning on the vacuum pump to create a low vacuum environment. In this reduced pressure environment, the thermal constants such as the boiling point and melting point of the object are correspondingly reduced, so that the drug in the tank can be sublimated from the solid to the gas under low temperature conditions after being slightly heated. These gases then flow to another large refrigerator, which is captured and recondensed into ice. When the moisture of the drug is completely drained, a lyophilization process is completed.

The most critical part of the freeze-drying operation is to grasp the temperature of the eutectic point (or eutectic point) of the product. If you can pump most of the water before the temperature of the product rises to the eutectic point, then success is not far off. The so-called eutectic point is the temperature at which the solution is completely condensed.

Commonly used eutectic point measuring instruments are mainly based on the principle of resistivity abrupt change in the phase change process. However, many varieties do not need to be too precise for the temperature of the eutectic point (or eutectic point). Generally speaking, experts can obtain the change of product traits through the window during the pre-freezing stage. When the product begins to freeze, the temperature detected by the thermocouple immersed in the product suddenly rises due to the exothermic phenomenon of the icing process. At this time, the temperature recorded by the experts is roughly close to the eutectic point (or eutectic point) temperature.

The process of extracting more than 90% of the moisture before the eutectic point (or eutectic point) is referred to in the technical term as a drying period. It is also important to judge the time at which a dry end is completed. Judging too early or too late will result in reduced lyophilization quality or energy and time consumption. The most intuitive method is to judge according to the shape of the product. At the end of a dry period, most of the water is removed. It seems that as the flood recedes, the waterline on the wall continues to drop. Experts can observe that there is also a waterline on the product that continues to drop until it disappears. The disappearance of the waterline means that a dry season is coming to an end. The second method can be judged according to the trend of the pressure in the tank. When most of the tank is removed, the pressure in the tank will continue to decrease until it is linear. The third method can be judged based on the change in the temperature of the product. When most of them are removed, experts will find that the temperature of the product will be closer to the temperature of the shelf.

In order to shorten the drying time, in addition to the crystal form in the pre-freezing stage , it is also possible to appropriately incorporate a gas in the sublimation stage so that the vacuum value fluctuates within a certain range (generally not more than 30 Pa ). This method makes the heat transfer method no longer rely on heat conduction, but also enhances the way of heat convection and accelerates the speed of moisture analysis.

Second, the pre-freezing rate

The pre-freezing process largely determines the speed of the drying process and the quality of the lyophilized product. Generally speaking, the literature on freeze-drying theory will mention that the greater the cooling rate, the larger the degree of supercooling and supersaturation of the solution, the smaller the particle size of the critical crystal, the faster the nucleation rate, and the smaller the size of the particles. Fine crystal. Therefore, after the ice crystals sublimate, the pore size formed in the material is small, the drying rate is low, but the rehydration after drying is good; on the contrary, the slow freezing tends to form large particles of ice crystals , and the water vapor escape channel formed by the ice crystal sublimation is larger in size. It is beneficial to increase the drying rate, but the rehydration after drying is poor. Of course, there is nothing wrong with this, but don't forget that this theory is derived on the premise of uniform heat. However , the freeze-drying conditions provided by ordinary freeze dryer manufacturers are not so ideal. The so-called fast freeze and slow freeze is not heat conduction. The speed of the oil cooling can be a word.

Quick freezing and slow freezing are divided into the following categories: 1. The plate temperature drops faster, and the plate temperature is much lower than the product temperature. The bottom of the product freezes first to produce crystals, but the upper liquid is still hot, so it does not crystallize all at once. The crystallization will grow slowly and the effect of slow freezing will be obtained. 2 , the plate temperature drops slowly, the plate temperature and the product temperature are not much different, the product as a whole is evenly cooled, and formed too cold, when the energy accumulation is sufficient, all crystals instantaneously, get the effect of quick freezing. 3 , the plate temperature drops very slowly, and at a suitable temperature below the eutectic point (or slow cooling), the product forms a small degree of subcooling, a small amount of crystals appear in the liquid, continue to cool crystal growth, to obtain large crystals This is the real slow freezing. 4. The product is immersed in an ultra-low temperature environment (such as liquid nitrogen), and the whole crystal is instantaneously formed, forming a very fine crystal (or in an amorphous state), which is the real quick freezing.

According to the research on the pre-freezing process of the shelf of the bottled product, the higher the initial temperature of the sample, the larger the temperature gradient of the upper and lower parts of the liquid, and the slower the growth rate of the ice crystal. If the solution is cooled slowly, the ice crystals will be coarser, the ice interface will be slower from the bottom to the top, the solute migration time will be sufficient in the solution, and the solute accumulation on the surface of the solution will be more. As a result, the solute of the upper surface layer tends to be more, the density is higher, and the density of the lower bottom layer is smaller, and the structure is loose. At the same time, the samples frozen at different pre-freezing temperatures showed significant differences in the pore size of the stent after drying . The lower the pre-freezing temperature, the smaller the pore diameter of the stent. This stratification phenomenon is most evident in products with poor skeletons, or the bottom is atrophy, or the middle fault, or the top protrusion, or the top part of a hard shell, and so on.

In order to solve bottle of cold stratification phenomenon, in practice, some people advocate the use of a three-step method, the sample was cooled from room temperature to coming to the initial freezing temperature of the sample (freezing); stop the cooling process, the temperature of the sample self-balancing, eliminate internal The temperature gradient; then rapid cooling, because the overall temperature of the sample is close to the crystallization temperature, and the sample temperature is slower during the freezing process, the temperature gradient of the sample during the freezing process will be relatively small, the ice crystal growth rate It must be relatively fast. In this way, the pre-freezing rate is increased, and the problem that the solute accumulates in the upper layer is solved. However, not all varieties have achieved significant results after using the three-step method.

Third, the pros and cons of solvent crystallized products and freeze-dried products

Theoretically, the active ingredient in the lyophilized product exists in crystalline or amorphous form (amorphous form). Generally speaking, for antibiotics, when it exists in a crystalline state, it has higher stability. During storage, the amorphous form always has a tendency to change to a crystalline state. Therefore, experts can only say that antibiotics in solvent crystallization may be better in many cases. However, this difference is sometimes not particularly large, and the price of the solvent crystallized product may be several times the freeze-dried product. The two-phase trade-off, some people will still choose the lyophilized product. However, the experts are a bit confused. In theory, the solubility of the crystalline structure is worse than that of the amorphous form. However, it has been found that for some antibiotic drugs, the solubility of the solvent crystallized product is better than that of the lyophilized product. Regarding this phenomenon, the experts could not find theoretical support for a time, and they were very confused. As for biological products, it is not necessarily welcome to crystallize, because the growth of ice crystals during freezing will cause damage to tissues and structures. Incidentally, amorphous materials mainly include metals, inorganic substances and organic substances. The glassy state originally referred to the amorphous form of silicates, but it was later used in general, and all amorphous forms (amorphous) were also called glassy states.

4. About clarity and visible foreign objects

1 , the ingredients process.
Such as the water temperature of the ingredients, the order of feeding, the adsorption time and temperature of the activated carbon, the time of the liquid storage, and the like.
2 , material stability
Some raw materials have polymorphism, and the stability of different crystal forms is different; some raw materials are sensitive to temperature; some raw materials are sensitive to pH ; some raw materials are sensitive to oxidation. Decomposition of unstable substances is likely to be the source of foreign matter.
3 , liquid properties
The concentration of the liquid is a very important factor, and I don't need to emphasize this. In addition, sufficient attention should be paid to the pH stability of the feed liquid . For example, when using buffer pairs, the three principles of analyzing textbooks should be kept in mind: pka is as close as possible to pH , try to make the buffer ratio close to 1 , and the concentration is appropriately large.
4 , the nature of the auxiliary materials (such as volatility, etc.)
The most obvious ones are examples of hydrochloric acid and sodium hydrogencarbonate.
5 , pre-freezing
Regarding the topic of quick-frozen, slow-frozen, and so on, it doesn't matter whether it is repeated or not. Repeated pre-freezing can reduce the ice crystal size difference and the drying rate non-uniformity due to the nucleation temperature difference, improve the drying efficiency and product uniformity , strengthen the crystallization, and increase the crystallization rate of the crystal component and the unfrozen water. You can try to figure out the beauty of it in practice.
6 , sublimation
The speed and temperature of sublimation will have an impact on the clarity. The experts have learned the following two main points.

First, it is mainly a sublimation period. If the temperature of the first dried material rises too fast, when the disintegration temperature is reached , the porosity of the porous skeleton is lowered, and the particles in the dried layer are detached, which will close the microporous passage in the dried portion, prevent the sublimation from proceeding, and make the sublimation rate. Slowing down, even slightly shrinking the lower part, affecting the residual moisture content of the product, resulting in poor rehydration, stability and clarity.

Second, it is mainly the second sublimation period. Small crystals are thermodynamically unstable due to their high surface energy, especially small ice crystals formed during rapid cooling. Recrystallization may occur during heating, and small ice crystals combine to form large ice crystals. The ratio of surface area to volume is minimized, while large ice crystals make the lyophilized product look poor and have poor rehydration. Therefore, sublimation or heat preservation at too high or too long may sometimes be detrimental to certain varieties, the most obvious example being unacceptable clarity.
7 , product formability, residual water
Some varieties, not afraid of the air, are afraid of temperature or moisture. Once water and temperature are obtained, the change is very rapid.
8 , vacuum, nitrogen filling
Whether there is vacuum, whether there is nitrogen filling, whether the product can be completely isolated from oxygen, avoiding slow oxidation, sometimes it is particularly important.
9 , inner packaging material.
The most common example is a rubber stopper. The rubber stopper may not only adsorb the main drug, but may also contain many additives such as a vulcanizing agent. Vulcanization is indispensable in the production of butyl rubber medicinal stoppers. In the vulcanization process, different vulcanization systems produce different cross-linking types and transportable substances, so that the stability of the migration molecular bonds of the oligomers in storage, high-temperature sterilization, and drug packaging are all Different, thus affecting the compatibility of the drug. Further, the stopper production, processing, packaging, storage and transportation process, are inevitably occur between the stopper and the device, the friction between the stopper and the stopper, the friction inevitably produced particles. Therefore, as a preparation company, how to avoid excessive friction during the rubber plug cleaning process is also a place that workshop technicians need to pay attention to. There is also the permeability of the stopper, which is easy to cause moisture-sensitive preparations to absorb moisture. As a preparation factory, experts must at least ensure that the rubber plug after cleaning can be well dried.
10 , the principle of crystallization
Whether it is a small water needle or a lyophilized product, it is often heard who is asking for a certain variety of clarity or visible foreign matter is unqualified. Experts suspect that some of the reasons may be related to crystallization . In general, soluble particles in a higher concentration solution have the potential to become a pre-nuclear junction in the theory of crystallization. When there are certain conditions for crystal formation, these pre-nuclear junctions will continue to merge to form crystals. nuclear. Once the crystal nucleus is produced, the crystal grows. The crystallization principle tells the experts that whether it is the crystal growth line rate or the mass growth rate of the crystal depends on the supersaturation of the solution or the degree of subcooling of the melt , depending on the temperature, pressure, stirring strength and characteristics of the liquid phase. , the presence of impurities, etc.
( 1 ) Stirring can promote diffusion to accelerate crystal growth, but at the same time accelerate the formation of crystal nuclei.
( 2 ) The increase in temperature is conducive to diffusion, and is also conducive to an increase in the surface chemical reaction rate, thereby increasing the crystallization rate.
( 3 ) The increase in supersaturation generally increases the crystallization rate, but at the same time causes the viscosity to increase and the crystallization rate is hindered.
( 4 ) As for impurities, the mechanism of action is more complicated. The following focuses on:

Inorganic and organic soluble impurities can have a large effect on supersaturation, new phase nucleation and crystal growth. The mechanism of these actions may be different depending on both the nature of the impurities and crystalline materials and the conditions of the crystallization. When impurities are present, the solubility of the substance may change, eventually leading to a change in the supersaturation of the solution. The cause of the change in solubility may be different, either due to salting out effects, ionic effects of the solution, or chemical interactions. Impurities may also act directly on the new phase grains that are formed. It may be that the impurity particles are directly involved in the growth process of the pre-nuclear associate, and may also be adsorbed on the surface of the crystal center. At the same time, the speed of nucleation may be slowed down or accelerated. Impurities may also result in changes in the crystalline form of the crystalline material, and in particular, a change in the ratio of crystal face size. For example, a few dendrites are crystallized from an ammonium chloride solution containing no impurities, but in an ammonium chloride solution containing impurities, dendritic crystals are decomposed into individual arrow-shaped and cruciform continuums. Even the gradient is a lotus leaf shape, a rose petal crystal, and the crystal which finally becomes which shape depends on the concentration of impurities. The concentration of impurities at the time when the crystal face shape starts to change is called the limit concentration. (Note: the crystal form is different from the crystal form. The change of the crystal form refers to the change of the crystal face size ratio. The change of the crystal face size ratio will not affect the crystal lattice structure, that is, the crystal form, no matter what the crystal shape changes, The lattice structure is the same.)

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