What do you mean by crystallization and recrystallization? area of application

The difference between crystallization and recrystallization of1:kw = s's compound directly affects its stability/absorption rate/hygroscopicity/purity, etc. General principles for selecting crystallization solvents and methods for judging crystallization purity. The general principle of choosing crystallization solvent is that the components to be separated have high solubility when they are hot and low solubility when they are cold; Insoluble or soluble in cold and heat to form impurities. The boiling point should be appropriate, neither too high nor too low, such as ether. Or the method of selecting solvents uses the solubility difference of substances and impurities in different solvents to judge the purity of crystals: the physical and chemical properties are uniform; The mel distance of that solid compound is less than or equal to 2 DEG C; TLC or PC showed a single spot; Modern crystallography with single peak by HPLC or GC analysis mainly includes the following branches: (1) Cryogenesis: the study of the process and mechanism of occurrence, growth and change of natural and artificial crystals, as well as the factors that control and influence them. (2) Geometric crystallography: the study of the shape and regularity of geometric polyhedron on the crystal surface. (3) Crystallography: Study the regularity of particle arrangement in the internal structure of crystals and the imperfection of crystal structure. (4) Crystal chemistry (also called crystal chemistry): Study the regularity of the relationship between chemical composition and crystal structure, as well as the physical and chemical properties of crystals. (5) Crystal physics: study the physical properties and mechanism of crystals. Let me talk about some of my views: solvent: the key to preparing crystals. In addition to the above, when the package is cold and hot, a small amount of different solvents can be used to test its solubility. Ethanol is generally preferred. In addition, choose a single solvent as much as possible, so that the problem of mother liquor recovery can be better solved in large-scale production and the cost can be reduced. In the study, the mixed solvent is generally better. Safety and low price are also considerations. Crystallization conditions: mainly refers to temperature, pressure, whether stirring, etc. Temperature is very important. Generally, we are refrigerated at low temperature. In fact, sometimes we need high temperature insulation! This mainly needs to find out the relationship between solubility and crystallization temperature. Stirring is also an influencing factor, which affects the crystal form and crystallization speed of crystallization. Determination of crystal purity: It is a general routine method. But some products do too much, and you can rely on experience. For example, after repeated recrystallization, we can see the crystal form that should appear. According to the previous test results, its content should be close to 10%. Don't trust HPLC! In addition, the condition of gradient cooling has a great influence on the crystal form and yield. The timing of adding seeds: the seeds are added too early, and the dissolved or produced crystals are generally fine; If it is added too late, crystal nuclei may have formed in the solution, which may lead to crystallization of impurities. Recrystallization method is to use the solubility difference of each component in a certain solvent to separate them from each other. The simple procedure of recrystallization is to dissolve impure solid matter in an appropriate hot solvent to prepare a nearly saturated solution, filter while it is hot to remove insoluble impurities, cool the filtrate, and precipitate crystals from the supersaturated solution, while soluble impurities remain in the mother liquor. Then filtering, separating crystals from the mother liquor, and measuring the melting point after drying. If the purity still does not meet the requirements, recrystallization can be carried out again until it meets the requirements. Choosing suitable solvents is of great significance to the success of recrystallization operation. A good solvent must meet the following conditions: 1, which does not react chemically with the purified substance; 2. It can dissolve a large number of purified substances at higher temperature, but only a small amount of purified substances at room temperature or lower temperature; 3. The solubility of impurities is very large or small. In the former case, impurities are left in the mother liquor, and in the latter case, impurities are filtered out when it is hot; 4. The boiling point of solvent should not be too low or too high. When the boiling point of solvent is too low, the temperature difference between preparing solution and cooling crystallization is small, and the solubility of group changes little, which affects the yield, and the operation of low boiling point solvent is inconvenient. The boiling point of the solvent is too high, and the solvent attached to the crystal surface is not easy to remove. 5. It can produce better crystallization. When several solvents are suitable, they should be selected according to the recovery rate of crystallization, the difficulty of operation, the toxicity of solvents, whether they are flammable and the price. As for the precipitation of crystals, crystals will precipitate after the filtrate obtained by filtration is cooled. When the solution is rapidly cooled with cold water or ice water and stirred vigorously, crystals with very small particles can be obtained. When the hot solution is left standing at air temperature and slowly cooled, a uniform and large product can be obtained. If the solution does not crystallize after cooling, you can rub the glass to control the container wall under the liquid level, or add varieties, or further reduce the temperature of the solution (cool it with ice water or other frozen solutions). If no product is precipitated after the solution is cooled and oil is obtained, it can be reheated until a clear hot solution is formed, and it can be cooled by itself, and the solution is constantly stirred with a glass rod, rubbed against the wall or thrown at people to accelerate the separation of products. If oil still emerges, it should be stirred vigorously immediately to disperse the oil droplets. From my experience, it is very important to choose the solvent for recrystallization, but for some compounds, it is often difficult to choose the appropriate recrystallization solution, and the number of samples that need recrystallization should not be too small. Recrystallization is also a great loss to the sample, and it is difficult to separate isomers, such as the two isomers of biflavone I shared recently. Please let us know if you have any good suggestions. This is a family statement. I didn't know what a crystallization master was until I had an X-ray today, and I have never seen it before. This is what the X-ray teacher taught me: the preparation of single crystal samples is probably the most important stage of crystal structure analysis, because without high-quality diffraction data, many analyses will be proved to be problematic. On the contrary, diffraction data is not difficult to process, and the efforts and time spent on crystallization are rarely wasted. There are many literatures related to crystal growth, including the Special Journal of Crystal Growth (Amsterdam: Elsevier). Used for structural analysis. Crystallization process includes the orderly entry of ions, atoms or molecules in gas, liquid or solution into regular positions in solid state. The initial stage is the formation of crystal nucleus, followed by the deposition on the crystal surface, which can be considered as the dynamic balance between fluid and crystal. When the forward speed is dominant, the crystal grows, and the factors affecting the balance include the chemical properties of the crystal surface, the concentration of crystalline substances, and the properties of the medium in and around the crystal. The formation of crystal occurs after the critical size of crystal nucleus appears, when the free energy of formation changes from positive value to negative value. The nucleation rate increases significantly with supersaturation. In order to limit the number of crystal nuclei, the supersaturation should be as low as possible, and the supersaturation should be reached slowly. Once this low supersaturation is reached, it should be carefully controlled to make a few crystal nuclei grow slowly in a quasi-equilibrium state. In the process of nucleation, external objects, such as dust particles, often make the nucleation process more favorable in thermodynamics, so these particles should be removed by centrifugal separation or filtration in advance. Seed method is also often a method to control the number of crystal nuclei. There are probably the following methods to grow crystals of low molecular weight organic and inorganic compounds: 1), single solvent evaporation 2), binary solvent mixed evaporation 3), intermittent crystallization 4), liquid-liquid diffusion 5), sitting vapor diffusion 6), temperature change 7), gel crystallization 8), sublimation 9) and curing. When using two-phase solvent for recrystallization, you should dissolve your things in it. If you leave it at room temperature and let it evaporate slowly, you can get pure substances, and it is possible to get single crystals! This 8-crystallization method is a good one, and I often use it. But crystallization usually takes a long time, and sometimes it can't be separated after half a month in winter. It is necessary to strictly control the ratio of the two solvents, especially the amount of soluble solvents, and try to use the least solvent with greater solubility. This amount of recrystallization should be considered relatively easy. It should be noted that it is very important to obtain seeds from crystallization, especially for compounds with crystallization difficulties. I'm a chemist, and I don't do protein crystallization. As far as the crystallization of compounds is concerned, there are two difficulties: 1 The choice of solvent has a great influence on the purity and crystallization yield of the compound. Steroid recrystallization has been done before, and it is used more. 2. The technology of recrystallization is also very important and needs more practice. My tutor really has to admire in this respect. The technique is very clever. In the long-term crystallization, everyone has his own set of methods, which is a kind of capital for everyone. It can be said that recrystallization technology can not be simply called technology, but should be called an art, but it can be suggested that the amount of more than 20mg or about 20mg can be separated by column chromatography or thin layer chromatography, and the loss may be greater, sometimes not less than the amount obtained by recrystallization. The key to crystallization lies in the choice of solvents, especially the composite solvent system. There is also careful operation. I have done a crystallization experiment, and I always get sticky things, which is very miserable. You can drop a little methanol, and crystals will precipitate immediately, but it is still sticky. Later, slowly added, the crystallization effect is good. Two methods: 1 Dissolve the sample with acetone, stir slowly, and then add petroleum ether dropwise with a dropper. When the solution changes from clear to opaque, stop dropping and stir slowly overnight, and crystals usually precipitate. 2 Add petroleum ether to the sample, then heat and reflux, and then drop acetone. When the solution changes from turbid to clear, stop dropping, stop heating and leave it at room temperature. Crystallization process is indeed a science, and domestic experts in crystallization are the first to recommend Academician Wang Jingkang from the School of Chemical Engineering of Tianjin University. There are many theoretical books about this, but when it comes to every substance or every substance, they are not exactly the same. What is * * * may be theoretical, and the discussion of the crystallization process of each kind of compound may be most helpful to everyone. Selection of solvent (single or compound), crystallization temperature, stirring speed, stirring mode, selection of supersaturation, crystal growth time, way and speed of solvent dropping, etc. In addition, in the process of dissolution, crystallization and crystal growth, the above temperature, stirring speed, time, adding method and speed are not exactly the same. So many factors are superimposed, which is even more difficult. Generally speaking, the main conditions should be selected first, so that the crystallization process can be continued and crystals can be obtained, and then the above conditions can be optimized. When the conditions are ripe, pilot test and production can be carried out. If it is theoretical study, the emphasis may be different. If it is applied research, the solvent is relatively easy to choose. The key is whether the supersaturation point can be found with this solvent and whether the supersaturation point interval is well controlled. If the supersaturation point is not easy to choose, or the supersaturation is not enough, it is difficult to crystallize, let alone grow crystals. At this time, it may be necessary to consider the composite solvent and adjust the supersaturation interval. So I think the crystallization process is the crystallization process, and the control of various conditions is the most important at this time. The crystallization process is well controlled, and the crystallization process is about 60% complete. The crystal growth process is relatively easy to control, mainly by optimizing parameters and control conditions. Generally, there is no problem, and the amplification process is basically no problem. If you do basic research, the physical properties are not very clear, and the study of crystallization process may take a lot of time and energy. But once you understand the whole process, it is still very valuable. Basically, we can't find a single solvent for recrystallization in a sample we made. If we use a composite solvent, such as acetone/ether, and slowly add ether through a dropper after dissolution, white powdery objects will precipitate after reaching a certain level, but after suction filtration, we will find that the things left on the filter paper are sticky, and the samples are also white powdery substances after drying. At the same time, it is found that its liquid phase purity is not high, which is normal. It's just that what you get is disorderly flocculent precipitation, not crystallization. Without the regular crystal arrangement of crystals, crystals can be obtained by composite solvents. When white flocculent precipitate appears, it is heated in a water bath. If the precipitate is dissolved, it can be left to crystallize. If it does not dissolve, slowly add acetone dropwise, and when it just dissolves, it can be placed for crystallization. Solvent crystallization: solvent crystallization refers to the final purification method of APIs. For example, for cephalosporin raw materials, if solvent crystallization is indicated, it means that the final purification step of raw materials is through the difference of solubility (for example, the solubility change of drugs in the same solvent due to temperature difference; Or the solubility change caused by the polarity difference caused by the change of solvent ratio in mixed solvents), the crude drug is first made into a solution, and then the above properties are adjusted to precipitate it (for example, the crude drug is dissolved in water first, and then an organic solvent is added to reduce the solubility of the drug and precipitate it). This purification method is called solvent crystallization. Solvent crystallization can remove more impurities, especially impurities with similar structures, which can be understood by people familiar with the principle of crystallization purification. Because the impurity content in the mother liquor during crystallization is much higher than the initial state, the product purity is generally higher than that of ordinary purification methods (such as the following freeze-drying method), and the yield is slightly lower, so the price of solvent crystallization raw materials is higher than that of freeze-drying raw materials. The principle of freeze-drying is to make the medicine into solution, and then freeze-dry the water solution directly to get the product. The yield is high, but the ability of removing impurities with similar structure is not as good as that of solvent crystallization. So the price is slightly lower. But no matter solvent crystallization or other methods, they are only purification methods of raw materials. No matter what means are adopted, the final product must meet the medical standards. In terms of quality standards, there is no difference between them. You can go to China Pharmacopoeia. The raw materials of cephalosporin powder injection don't distinguish this. In essence, it mainly refers to the process of separating APIs from solvent systems (such as ethanol, acetone, methanol, THF, ethyl acetate, water, etc.). ) In the final purification process. Impurities remain in the solvent system, and raw materials are precipitated in the form of crystals. However, both solvent crystallization and freeze-drying processes can meet the pharmacopoeia standards. But the quality of the two is different, and the application materials must be clear. It is embodied in 1. The crystallization of the solvent leads to the birefringence and extinction of the crystal. The freeze-drying process is basically absent, or only a part, which is not obvious, indicating that it is not crystal or only a part. 2. The purity of the products obtained by the two processes is different. 3. Their stability is different. The expiration date may be different, because one is crystal and the other is not. 4. Pharmacopoeia distinguishes the quality standards of solvent crystallization and freeze-dried products, such as cefoperazone, birefringence, extinction position and so on. So because of the difference in quality, the prices in different countries are also different. This is clear in the bidding process, and the price of solvent method can be higher than that of freeze-drying method.