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Lyophilized preparation

Font Size: [Big][Mid][Small] 2017/4/12    Views: 904    
For the freeze-dried preparations, I have accumulated some experience in the learning process. However, limited space, in this only choose its meaning, generally described.
First, freeze-dried preparations is not difficult
Freeze-drying machine is huge, easily filling the surplus housing. Monsters, the total can not help but make people difficult to control the illusion.
In fact, from the freeze-drying mechanism point of view, freeze-drying machine is nothing more than a two large refrigerator plus a vacuum pump structure. One of the first refrigerators is responsible for freezing the medicine into ice, and then starting the vacuum pump to create a low vacuum environment. In this decompression environment, the object's boiling point, melting point and other thermal constants are correspondingly reduced, so the drug inside the box after a slight heat can be low temperature conditions from sublimation of gas as a gas. The gas then flows to another large refrigerator and is captured and re-condensed into ice. When the water of the drug is completely drained, a freeze-dried process is completed.
The most critical aspect of the freeze-drying operation is the grasp of the number of pairs of eutectic (or eutectic) temperatures. If the temperature of the product rises to the eutectic point before the majority of the water is removed, then the success is not far away. The so-called eutectic point, that is, all the temperature of the solution condensation.
Commonly used eutectic point measuring instruments are mainly based on the principle of resistivity mutation during phase change. But many varieties of eutectic (or eutectic point) temperature requirements do not need to be too precise, in general, we can in the pre-freeze stage through the window to observe the changes in product properties to obtain. When the product begins to freeze, the temperature of the thermocouples that are immersed in the product will suddenly rise, due to the exothermic phenomenon of the icing process. At this time, we recorded the temperature is close to the eutectic (or eutectic) temperature.
The process of pumping more than 90% of the moisture before the eutectic (or eutectic) is referred to as a dry period in the technical term. It is also important to judge the time of the end of a drying. Premature or too late to judge, will cause cold sensation, dry quality reduction or energy and time consumption.
The most intuitive way is to judge the shape of the product. After a dry period, most of the water is pumped. As if the floods receded, the water lines of the wall were declining, and we could observe that there was a waterline that had fallen on the product until it disappeared. Water lines disappear, which means that a dry end is coming. The second method, according to the trend of changes in the pressure inside the box to be judged, when most of the pumping, the pressure inside the box will continue to decline until the emergence of linear. The third method, according to the product temperature changes to determine. When the majority is pumped away, we will find that the temperature of the product and the temperature of the shelf will be getting closer.
In order to shorten the drying time, in addition to the pre-frozen stage of the article to do the article, but also in the sublimation phase of the appropriate incorporation of gas, so that the vacuum value in a certain range of fluctuations (generally not more than 30Pa). This approach makes the heat transfer is no longer by heat conduction to the main, but also enhance the way the heat convection, speed up the analysis of the speed of water, often work.
Second, the pre-freeze rate
I admit to the notion that the pre-freezing process largely determines the speed of the drying process and the quality of the freeze-dried product.

Generally speaking, the theory of freeze-drying theory will be mentioned, the greater the rate of cooling, the solution of the degree of undercooling and supersaturation, the smaller the critical grain size, the faster the nucleation rate, easy to form particles smaller size Of fine grain. Therefore, after the sublimation of ice crystals, the pore size of the material is small, the drying rate is low, but the dry water is good; on the contrary, the slow freezing is easy to form large particles of ice crystals, ice water sublimation after the formation of water and gas escape channel size larger , Is conducive to improving the drying rate, but after the dry water is poor.

This is certainly not wrong, but do not forget that this theory is heated under the premise of the uniform, but our factory in the freeze-drying machine provided by the freeze-dried conditions are not so ideal, the so-called quick freezing, Is not a hot oil cooling speed of a word can be amazing. Relatively speaking, I am still more in favor of the medical network forum comrades tinybayonet mention. He is divided into the following categories: 1, the board temperature drop faster, and the board temperature is much lower than the temperature, the product at the bottom of the first freeze to produce crystallization, but the upper liquid is still hot, so not all instantaneous Crystallization, crystallization will grow slowly, it was the effect of slow freezing. 2, the board temperature drop slowly, the board temperature and the temperature difference is not, the whole product uniform cooling, and the formation of supercooled, when the energy accumulation is sufficient, the moment all the crystallization, get the effect of quick freezing. 3, the board temperature is very slow, and below the eclipse of the appropriate temperature to maintain (or slow cooling), the product to form a smaller degree of subcooling, the liquid first appeared in a small amount of crystallization, continue to cool crystal growth, , That is the real slow freezing. 4, the product immersed in ultra-low temperature environment (such as liquid nitrogen), the overall instantaneous crystallization, the formation of very small crystals (or in the amorphous state), which is really fast frozen. For the tinybayonet mentioned these phenomena, I have been found in the test process, so I still prefer this division method.
Moreover, most of the enterprise or the use of frozen freeze-drying method, the freezing of the uneven heat is even more obvious. According to the pre-freezing process of the bottled product shelf, the higher the initial temperature of the sample, the higher the temperature gradient of the upper and lower part of the sample liquid, the slower the growth rate of ice crystals. If the solution is slow to cool down, the formation of ice crystals is relatively coarse, the ice interface from the bottom up to the slow speed, solution solute migration time is sufficient, the solution surface frozen layer solute accumulation is also more. Resulting in the upper surface of the solute is often more, higher density, while the lower substrate density is small, loose structure. At the same time, the samples were frozen at different pre-freezing temperatures, and the size of the stents after drying was significantly different. The lower the pre-freezing temperature, the smaller the pore diameter of the stent. This layered phenomenon, in the skeleton of poor products on the most obvious, or the bottom of the atrophy, or intermediate fault, or the top of the protrusion, or the top off a layer of hard shell, and so forth.
In order to freeze the stratification phenomenon, in practice, it was advocated the use of three-step method, that is, the sample from the room temperature first cooled to the initial freezing temperature of the sample; stop the cooling process, so that the sample temperature automatically balanced to eliminate the temperature gradient; And then quickly cool down, because the sample at this time the overall temperature from the crystallization temperature is close, and the sample in the freezing process, the sample temperature drop slowly, so the sample temperature gradient during the freezing process will be relatively small, ice crystal growth rate will be relatively fast The This will increase the pre-freeze rate, solves the problem of solute aggregation in the upper layer. However, not all varieties of the use of a three-step method can achieve significant results.
Third, the crystallization of crystal products and the advantages and disadvantages of freeze-dried goods
Ministry of Commerce has a colleague asked me, the crystallization of crystal products and freeze-dried goods, which is better? I did not know how to answer. In my opinion, it is difficult to keep silent.
Theoretically, the active ingredient in the lyophilized product is present in crystalline or amorphous form (amorphous). Generally for the antibiotics, in the presence of crystalline, with a higher stability. In the storage process, the amorphous state has a tendency to transition to the crystalline state. Therefore, I can only say that in many cases the stability of the solvent crystallization of antibiotics may be better. However, this difference is sometimes not particularly large, and the price of solvent crystal products may be several times freeze-dried goods, two-phase trade-off, some people will choose to freeze-dried goods.

Just, I'm a bit confused. In theory, the solubility of the crystalline structure is worse than the amorphous state, but some studies have found that, for some antibiotics, solvent dissolution of the better than freeze-dried products. On this phenomenon, I can not find a theoretical support for a time, very confused.

As for the biological products do not necessarily welcome the crystalline state, because the freezing process of ice crystal growth will cause damage to the organization and structure. Incidentally, amorphous materials are mainly metal, inorganic and organic three categories. The glassy state originally refers to the amorphous form of the silicate, but later it is used, and all the amorphous (amorphous) is also called the glassy state.
Fourth, on the clarity and visible foreign body
There is a fourth military doctors big friends package teacher, like to learn from people freeze the problem. He believes that the appearance of turbidity, opalescence or visible foreign matter is related to the size of insoluble particles. Less than 10nm particles is clear and transparent; when the particles are greater than 100nm, the particles appear in the solution, can cause turbidity; in the range of 10-100nm, resulting in light scattering, you can observe the milk, turbidity; particles and then larger , There is precipitation and crystallization, and this is the μm level.

I do not know where he is here, but according to my own experience, I agree.
As for the reasons for the formation of particles, numerous. Talk about a few cases.

1, 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, and so on.

2, material stability
Some raw materials exist polymorphic, different crystal stability is not the same; some raw materials on the temperature sensitive; some raw materials sensitive to pH; some raw materials sensitive to oxidation, and so on. The decomposition of unstable substances is likely to be the source of foreign matter.

3, the nature of liquid
The concentration of liquid is a very important factor, I am afraid that do not need to emphasize.
In addition, the pH stability of the feed solution should be given sufficient attention. For example, when using buffer pairs, analyze the three principles on the textbook to keep in mind: pka as close as possible to pH, try to make the buffer ratio close to 1, the concentration is appropriate.

4, the nature of materials (such as volatile, etc.)
The most obvious is the hydrochloric acid, sodium bicarbonate and other examples.

5, pre-frozen
On the frozen, slow and other cliche of the topic do not mention worth mentioning, it touches on the pre-freeze a little mean. Repeated pre-freezing can reduce the difference in ice crystals due to differences in nucleation temperature and the nonuniformity of the drying rate, improve the drying efficiency and product uniformity; and strengthen the crystallization to improve the crystallinity of the crystalline component and the unfrozen water. We can in practice try to figure out its beauty.

6, sublimation
Sublimation speed and temperature will have an impact on clarity, I understand the situation mainly in the following two points.
First, mainly a sublimation period. If the temperature of the first drying of the upper material rises too fast to reach the collapse temperature, the porous skeleton stiffness decreases, the particles within the dry layer fall off, will close the dry part of the micro-channel, to prevent the sublimation of the sublimation rate Slow, and even lower part of the lower part of the contraction, affecting the residual moisture content of products, resulting in rehydration, stability and clarity at the same time worse.
Second, mainly the second sublimation period. Small crystals due to the high surface energy, is thermodynamically unstable, especially in the rapid cooling process of the formation of small ice crystals, heating may occur in the recrystallization, small ice crystals between the formation of large ice crystals, so that Its surface area and volume ratio to a minimum, and large ice crystals to freeze the appearance of poor goods, poor water recovery. Therefore, too high temperature or too long to sublimation or insulation, and sometimes for some varieties of adverse, the most obvious example is the clarity of failure.

7, product molding, residual water
Some varieties, not afraid of the air, is afraid of temperature or moisture. Once the water and temperature are obtained, the change is very fast.

8, vacuum, nitrogen
There is no vacuum, there is no nitrogen, whether the product and oxygen completely isolated, to avoid slow oxidation, and sometimes it is particularly important.

9, within the package material.
The most common example is the rubber stopper.
The plug can not only adsorb the main drug, but also may contain many additives, such as curing agent.
Butyl rubber chemical bottle stopper production process and ultimately vulcanization. In the process of its vulcanization, different vulcanization systems, the resulting cross-linked bond type and can be different from the transfer material, so that the plug in the storage, high temperature sterilization, drug packaging, the migration of oligomers of molecular stability Are different, thus affecting the compatibility of drugs.

In addition, in the cork production, processing, packaging, storage and transportation process, are inevitably between the cork and equipment, stoppers and corks with the same song friction, these friction will inevitably produce particles. Therefore, as a preparation business, how to avoid excessive friction during the cleaning process, but also workshop technicians need to pay attention to the place.

There is also the permeability of the stopper, water permeability is easy to cause moisture-sensitive formulations moisture absorption deterioration. As a preparation plant, we must at least ensure that the cleaning after the rubber plug can be a good drying.

10, the crystallization principle
Whether it is a small water needle or freeze-dried goods, are often heard who is seeking a certain species of clarity or visible foreign body failed. I suspect that some of the reasons may be related to crystallization. In general, the soluble particles in the higher concentration of the material have the possibility of becoming a nuclear nodule in the crystallization theory. When there is a certain condition for the formation of crystals, these pre-nuclear consensors will be combined to form crystals nuclear. Once the nuclei are produced, the crystals grow up.

The crystallization principle tells us that both the rate of crystal growth and the rate of crystal growth depends on the supersaturation of the solution or the degree of undercooling of the melt, depending on the temperature, pressure, agitation strength and characteristics of the liquid phase, The presence of impurities.

(1) agitation can promote diffusion to accelerate crystal growth, but also to accelerate the formation of nuclei.
(2) the temperature rise is conducive to the proliferation, but also conducive to surface chemical reaction speed, so that the crystallization rate faster.
(3) increased supersaturation will generally increase the crystallization rate, but at the same time caused by increased viscosity, crystallization speed blocked.
(4) As for the impurities, the mechanism of action is more complex. The following highlights:

Inorganic and organic soluble impurities can have a great impact on supersaturation, new crystal nuclei formation and crystal growth. The mechanism of these effects may be different, depending on the nature of the impurities and the crystalline material, as well as the conditions of the crystallization.

When the impurities are present, the solubility of the substance may change, resulting in a change in the supersaturation of the solution. The reason for the change in solubility may be different, either a salting-out effect, an ionic force effect of the solution, or a chemical interaction.

Impurities may also act directly with the new phase grains produced. It is possible that the impurity particles are directly involved in the growth process of the nuclear association and may also be adsorbed on the surface of the crystallization center. At the same time, the rate of nucleation may slow down or accelerate.

Impurities may also lead to changes in the crystalline form of the crystalline material, in particular, the change in the proportion of the crystal face size. For example, from the impurity-free ammonium chloride solution, the resulting dendritic crystals are obtained, but in the ammonium chloride solution containing impurities, the dendritic crystals are decomposed into separate arrows and crosses , And even gradually into a lotus leaf shape, rose petal-shaped crystal, as to what shape eventually become crystal, depending on the concentration of impurities. The impurity concentration at which the crystal face begins to change is called the limit concentration. (Note: crystal shape is different from the crystal type, crystal shape change is the ratio of the size of the crystal surface changes in the proportion of crystal surface size changes in any case will not affect the lattice structure, that is, crystal, no matter what shape changes, The lattice structure is the same.

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