Method for producing IMP+GMP by anti-solvent cooling crystallization based on solvent spray oscillation

Abstract

The invention discloses a method for producing IMP+GMP by anti-solvent cooling crystallization based on solvent spray concussion, raw materials IMP and GMP are added to the water of crystallization kettle, heated and stirred to completely dissolved, and pH is adjusted; Anti-solvent is added dropwise, crystal seeding is added, and the temperature is lowered; Solvent water forms a fan-shaped water mist through a shower head and sprays on the raw material liquid surface of crystallization kettle, and the solvent water consumption of a solvent spray concussion is 25% to 50% of the total solvent amount, and a spray time is controlled to be 1 to 2min, and the speed of stirring to heating and stirring is restored, and the temperature is lowered to form a solvent spray concussion; Repeat solvent spray concussion 2‑4 times; Cooling and filtering, washing, drying, and obtaining crystallized product. Product of the present invention has narrow particle size distribution, large particle diameter, and good crystal form, high yield, easy control of operating conditions, improved according to factory process, and strong operability.

Description

Technical Field

[0001] The present invention claims a method for preparing 5'-flavor nucleotide disodium, belongs to the field of food seasonings, and specifically relates to a method for preparing 5'-flavor nucleotide disodium with narrow particle size distribution and large particle size by introducing solvent spray vibration. Background Art

[0002] Disodium 5'-Ribonucleotide (IMP+GMP, I+G) mainly includes 5'-inosinic acid disodium (IMP) and 5'-guanosine monophosphate disodium, or, Disodium 5'-guanylate (GMP). It has a flavoring effect and produces a synergistic effect when mixed with monosodium glutamate (monosodium glutamate), which can increase the freshness by several to dozens of times. At the same time, 5'-ribonucleotide disodium can improve the quality of food, enhance sweetness and saltiness, and inhibit or eliminate sourness, bitterness, fishy smell, and burnt taste. Generally, the taste of food added with I+G is significantly improved, and the sweetness, sourness, bitterness, spiciness, freshness, fragrance and saltiness are more intense and coordinated, and closer to the flavor of natural food.

[0003] High-quality flavor enhancers usually have complete crystals, uniform particle size, high bulk density, and good fluidity. The crystals of monosodium glutamate, salt, sugar, etc. sold on the market are mostly rod-shaped or block-shaped, and the main particle size is relatively large. Disodium ribonucleotide, as the main ingredient of super-fresh monosodium glutamate, chicken essence and other seasonings, should meet the requirements of large particle size, high bulk density, good fluidity, and high purity, so that the composite flavor enhancer obtained after mixing with monosodium glutamate still has the characteristics of uniform particle size and good fluidity, and a high-quality flavor enhancer can be prepared.

[0004] The main processes for producing flavor nucleotides include microbial fermentation, enzymatic hydrolysis, enzyme catalysis and chemical synthesis. The raw materials and stock solutions obtained by the above methods can be separated by concentration, crystallization, filtration, washing and drying to obtain their respective crude products. The crystallization process of IMP is easy to carry out, and crystals can be directly precipitated in the solution crystallization; while GMP is generally amorphous when precipitated in the solution. To obtain GMP crystals, a crystal transformation process must be carried out, and the process control is relatively complex. The crystal products usually obtained have poor morphology, low bulk density and are easy to agglomerate. Due to the differences in the crystal properties and powder characteristics of IMP and GMP, if the solid powder product obtained by simply mechanically mixing the fermentation broth of the two in proportion is obtained, not only will the mixing process be difficult to operate, but the mixing effect will also be unsatisfactory.

[0005] Solvent crystallization utilizes the difference in the interaction force between the separated substance and the solvent molecules to dissolve the solute in water or other solvents, and then add another solvent or lower the temperature to reduce the solubility of the solute in the original solvent, so that the solute precipitates and crystallizes. Solvent crystallization technology has important applications in many fields such as medicine, food, inorganic salts, and polymer materials. In order to solve the operational difficulties and uneven mixing problems caused by the differences in crystal form, powder shape, and powder properties between IMP and GMP, the existing method is to prepare disodium flavor nucleotide crystals (I+G) through mixed solvent crystallization technology to achieve molecular mixing.

[0006] Chinese invention patent 201210214154.1 discloses a process for crystallization and purification of I+G. The method uses the pretreated I+G mother liquor as raw material, dissolves it at 45℃~65℃, dissolves and precipitates crystals with ethanol, cools it to 20~40℃, then heats it to 65℃, and then continues to cool it to 10℃, and the average particle size of the product is improved. The method initially precipitates crystals by continuously adding ethanol to dissolve and crystallize, and the crystal nucleation is not strictly controlled. The solubility of I+G in the pure water system decreases rapidly with the increase of alcohol content, which is easy to cause explosive nucleation and the product crystals are relatively fine. After cooling to a large amount of crystals, the feed liquid is heated to 65℃ to eliminate fine crystals. The disadvantages of this method are that the temperature increase is too large (~35℃), the reaction lag effect is poor, and a large amount of energy is consumed. The crystals are flaky, the product bulk density is low, the morphology is poor, and it is easy to agglomerate.

[0007] Chinese invention patent CN105031963A discloses a method for manufacturing undersaturated antisolvent cooling crystallization by vacuum evaporation of solvent. In the preparation process, the sample is first dissolved, and a sufficient amount of antisolvent is added to completely precipitate the crystal. Repeated vacuum evaporation operation is performed to reduce the pressure. Due to the large volatility difference, the antisolvent evaporation amount is more than the solvent evaporation amount, and the solubility increases and dissolves the crystal particles, and then cools or cools and crystallizes to the end point, filters, washes, and dries to obtain a crystal particle product. The method initially continuously adds antisolvent crystallization, and no crystal seed is added to control the supersaturation in the initial stage of crystallization, which is very easy to nucleate and produce fine particles; although vacuum evaporation of antisolvent is adopted in the later stage to increase the solubility and dissolve the crystal particles, the particles are not distinguished, and large particles and small particles are dissolved at the same time to consume undersaturation. The amount of antisolvent evaporated each time is small, and the solubility is limited, which takes a long time, and the operation is more complicated and energy-consuming, and the effect is limited and it is easy to cause antisolvent waste and increase costs.

[0008] Comprehensive analysis shows that in order to obtain I+G crystals with large particle size and narrow distribution, the existing technology needs to control the supersaturation during the crystallization process to keep the supersaturation in the metastable zone, and the crystals are more inclined to grow rather than nucleate. The primary nucleation after the accumulation of supersaturation and the secondary nucleation caused by the complexity of the crystallization environment are also important factors that produce fine particles and seriously affect the particle size distribution of the product, which need to be effectively controlled. Summary of the invention

[0009] The purpose of the present invention is to overcome the disadvantages of low feasibility, poor effect, high energy consumption and greatly prolonged batch production time in existing fine particle dissolution technologies. A process is provided for using solvent spray vibration for anti-solvent cooling crystallization, thereby achieving efficient dissolution of small solid particles in the solution and effective control of the product particle size.

[0010] The principle of the present invention is as follows:

[0011] According to the general practice of factories to improve the efficiency of pre-treatments such as dissolution and decolorization at higher temperatures, a slightly higher concentration of crystallization solution can be prepared at this time, and a portion of the volume of solution can be reserved for solvent oscillation. For the control of primary burst nucleation, the method of adding crystal seeds is adopted, and the solvent spray oscillation is used to dissolve the fine crystals of secondary nucleation. The feasibility of solvent oscillation is improved by introducing high temperature and pressurized spray feeding. Increasing the temperature of the solvent will make the solvent have a higher dissolving power. The pressurized spray feeding method makes the addition of the solvent almost without time lag, and can make the upper solution form instantaneous local undersaturation. Reducing the stirring speed will cause the particles to naturally settle and stratify according to Stokes' law, and the fine particles will dissolve faster than large particles. In this way, fine particles can be dissolved in a targeted manner. When the solute precipitates again, due to the addition of a certain amount of solvent, the supersaturation is low, and it will grow on sufficient crystal surfaces instead of nucleating.

[0012] The purpose of the present invention is achieved through the following technical solutions:

[0013] A method for producing IMP+GMP by anti-solvent cooling crystallization based on solvent spray oscillation: adding raw materials IMP and GMP into water in a crystallization kettle, heating and stirring until completely dissolved, and adjusting pH; dripping anti-solvent, adding crystal seeds to grow crystals, cooling to 45-55°C, and reducing the stirring speed to allow precipitated crystal particles to settle and stratify; solvent water forms fan-shaped water mist through a nozzle and is sprayed onto the raw material liquid surface of the crystallization kettle, the amount of solvent water used in one solvent spray oscillation is 25%-50% of the total solvent amount, the spraying time is controlled to be 1-2 minutes, the stirring is restored to the speed of heating and stirring, the temperature is reduced, and one solvent spray oscillation is formed; the solvent spray oscillation is repeated 2-4 times, the temperature of each solvent spray oscillation is reduced by 10-20°C, and the temperature of the last solvent spray oscillation is above 25°C; cooling, filtering, washing, and drying are performed to obtain a crystal product.

[0014] To further achieve the purpose of the present invention, preferably, the solvent water is sprayed into the raw material liquid surface of the crystallization kettle through a nozzle to form a fan-shaped water mist, and the air pressure and solvent water pressure from the air compressor and the jacketed thermos cup are controlled by an air pressurized atomizer respectively, so that the injection speed of the solvent water is 0.5-1 mL / s; the volume ratio of air to solvent water is 800-1500:1.

[0015] Preferably, the amount of solvent water used in the solvent spray oscillation is 30% to 50% of the amount of solvent water used for dissolution in the initial crystallization kettle; after the raw materials IMP and GMP are added to the water in the crystallization kettle, the concentration of IMP and GMP is 20% to 35% g / mL.

[0016] Preferably, the spraying time is controlled to be 1 to 2 minutes.

[0017] Preferably, the mass ratio of IMP to GMP in the raw materials IMP and GMP is 0.95-1.05:1.

[0018] Preferably, the temperature for heating and stirring until complete dissolution is 60-70°C; and the pH is adjusted to 7.5-8.5.

[0019] Preferably, the volume ratio of the anti-solvent added to the water in the crystallization kettle is 1:2-2.3; the anti-solvent is an ethanol aqueous solution with a volume concentration of more than 90%.

[0020] Preferably, the seed crystals are crystals of IMP and GMP, and the mass ratio of IMP to GMP is 1:2 to 2:1; the amount of seed crystals added is 3% to 10% of the mass of the raw materials IMP and GMP; and the crystal growing time is 15 to 30 minutes.

[0021] Preferably, the stirring speed during the temperature rising dissolution and crystallization process is 150-200 rpm; the stirring speed during the temperature rising dissolution and crystallization process is 50-100 rpm.

[0022] Preferably, the cooling filtration is to reduce the temperature to 10-15°C, and the cooling process is carried out at a rate of 4-6°C / h, 7-9°C / h, 10-12°C / h, 12-14°C / h, 14-16°C / h to reduce the temperature to 10-15°C in 5-6 hours.

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] (1) Based on the solubility data of I+G in ethanol-water system, adding seeds when adding antisolvent to saturated solution can effectively inhibit the primary burst nucleation caused by supersaturation accumulation. The cooling rate is designed reasonably. In the early stage, the solubility of the solution decreases rapidly with the decrease of temperature, and the total surface area of ​​the crystals in the solution that can provide crystal growth is small. A slower cooling rate is adopted to control low supersaturation; in the later stage, the solubility of the solution decreases with the change of temperature, and the total surface area of ​​the crystals increases. The cooling rate is accelerated to meet the consumption of supersaturation.

[0025] (2) After the crystallization process reaches a certain extent, the stirring speed is reduced to an appropriate level. According to Stokes' law, the particle size can be stratified by natural sedimentation, with large particles settling to the bottom and small particles suspended in the upper layer. At this time, the solvent is quickly and evenly added to the upper layer, which can effectively dissolve the fine particles generated by secondary nucleation. After dissolution, the fine particles are precipitated at a lower supersaturation. At this time, they are more inclined to grow on the crystal surface rather than nucleate to generate new small particles. The final product has a large particle size and good crystal shape.

[0026] (3) The solvent used for oscillation is kept warm in a jacketed cup connected in series with the crystallization kettle water bath, which can ensure that the temperature fluctuation of the solvent is small during oscillation, and the solvent at a temperature higher than room temperature has a relatively better dissolving power; the pressurized spray feeding method is not only time-saving, but also due to the mixing lag at low stirring speed, it can produce instantaneous local undersaturation of the upper solution to dissolve fine particles. Both measures can achieve better results with limited solvent usage. Compared with other fine particle dissolution technologies, it is simpler and easier to implement while ensuring the effect, and has no impact on batch production time. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Schematic diagram of the IMP+GMP device based on solvent spray oscillation anti-solvent cooling crystallization.

[0028] Figure 2 The Malvern particle size data diagram of the crystal particles of the products obtained in the examples and comparative examples.

[0029] Figure 3 This is an optical microscope image of the crystal particles of the product obtained in Example 1.

[0030] Figure 4 This is an optical microscope image of the crystal particles of the product obtained in Example 2.

[0031] Figure 5 This is an optical microscope image of the crystal particles of the product obtained in Example 3.

[0032] Figure 6 This is an optical microscope image of the crystal particles of the product obtained in Example 4.

[0033] Figure 7This is an optical microscope image of the crystal particles of the product obtained in Comparative Example 1. DETAILED DESCRIPTION

[0034] In order to better understand the present invention, the present invention is further described below in conjunction with embodiments. However, it should be noted that the scope of protection claimed by the present invention is not limited to the scope described in the following embodiments.

[0035] like Figure 1 As shown, the IMP+GMP production device based on solvent spray oscillation anti-solvent cooling crystallization is improved on the basis of the existing crystallizer. The main improvement is that a nozzle 5 is arranged in the crystallization kettle, and the nozzle 5 is connected to one end of the air pressurized atomizer 4; the other end of the air pressurized atomizer 4 is respectively provided with an air inlet 6 and a water inlet 7, the air inlet 6 is connected to the air compressor 8 through an air pipe, and the water inlet 7 is connected to the jacketed thermos cup 11 through a hose, and a metering pump 9 is provided on the hose. The crystallization kettle 1 has a built-in electric thermocouple thermometer 12 and a top-loading stirring paddle 3, and the top-loading stirring paddle 3 is connected to the stirrer 2, and the stirring speed is controlled by the stirrer 2. The crystallization kettle 1 is connected in series with the jacketed thermos cup 11 and the high and low temperature constant temperature tank 10 through an insulation hose.

[0036] Figure 1 The IMP+GMP device based on solvent spray oscillation anti-solvent cooling crystallization mainly adds an air pressurized atomizer 4 to the original basic crystallizer, which is used to add solvent during the crystallization process to realize fine particle dissolution technology. The liquid delivered by the metering pump is pressurized and accelerated by the air delivered by the air compressor 8 in the cavity of the atomizer 4, and is ejected from the nozzle 5 together. At this time, the ejected liquid is fan-shaped and has a certain penetration. Since the stirring speed will be reduced when the solvent is added, large particles will settle. At this time, the solvent that is evenly sprayed and mixed into the upper layer can dissolve the suspended fine particles very well. Conventional metering pumps can only add materials at a single point, and the feeding is relatively uneven and has no penetration, and the mixing depends on the stirring speed. When the stirring speed is fast, it is difficult for the particles to stratify naturally. At this time, the dissolution of large particles will also consume the undersaturation, which is not targeted at the dissolution of fine particles and the effect is relatively poor.

[0037] Weigh the required mass of IMP and GMP raw materials with an analytical balance, and measure the required volume of solvent with a measuring cylinder. Open the feeding port on the crystallization reactor 1 and place the feeding funnel. First pour the solid raw materials IMP and GMP from the feeding funnel, then pour the solvent, remove the feeding funnel, close the feeding port, and start the dissolution process; after the dissolution is completed, the anti-solvent is directly input through the feeding port through a metering pump, the anti-solvent is added, the feeding port is closed, and the subsequent steps are started.

[0038] Example 1

[0039] A method for producing IMP+GMP based on solvent spray oscillation anti-solvent cooling crystallization, comprising the following steps:

[0040] Step 1: Weigh 30g of IMP and GMP each on an analytical balance, and measure 200mL of water with a measuring cylinder. Add the two to a 500mL crystallization kettle 1. Control the high and low temperature constant temperature bath 10 to raise the temperature to 65°C and stir at a stirring speed of 180rpm to fully dissolve the solute, and adjust the pH to 7.9. Then keep 80mL of water warm in a jacketed thermos cup 11 connected in series with the crystallizer water bath. Add 100mL of anti-solvent 90% ethanol at a rate of 4mL / min, add 2.8g of IMP+GMP seeds (the mass ratio of IMP and GMP seeds is 1:1), and the seeds are obtained by recrystallization of IMP and GMP. Cultivate the crystal for 20min, start the program to cool down by 5℃ / h, 8℃ / h, 12℃ / h, 14℃ / h, 16℃ / h, and reach the end point in 5 hours.

[0041] Step 2: When the temperature drops to 55°C, adjust the stirring speed of the stirrer 2 to 50rpm, and the particles naturally settle and stratify. First, turn on the air compressor 8, adjust the valve of the air inlet 6 of the air pressurized atomizer 4 to control the air flow rate to 70L / min, and then turn on the metering pump 9 to suck the solvent in the jacketed thermos cup 11 at a speed of 0.8mL / s and transport it to the air pressurized atomizer 4. At this time, it can be seen that the nozzle 5 sprays fan-shaped water mist to the liquid surface of the crystallization kettle. The water mist does not gather into a water column under the help of air and has a certain penetration. When the amount of water sprayed reaches 40mL, turn off the metering pump 9 first, then turn off the air compressor 8, resume stirring at 180rpm, and complete a solvent oscillation. The temperature drops to 35°C, reduce the stirring speed to 70rpm, use 40mL of water, adjust the water flow rate to 1mL / s, and the air flow rate to 90L / min for the second solvent oscillation operation.

[0042] Step 3: Cool down to 10°C, filter, wash and dry to obtain larger crystal particles with narrow particle size distribution. The median particle size d(50) of the Malvern particle size analyzer is 418 μm, which indicates the main particle size value of the whole particle.

[0043] Figure 3 This is an optical microscope image of the crystal particles of the product obtained in Example 1. Figure 3 The IMP+GMP crystals in the solution are coarse rod-shaped crystals with a relatively uniform particle size distribution and less amorphous powder. This indicates that the solvent spray vibration has better controlled the fine particles generated by secondary nucleation during the crystallization process and has a better dissolving effect on amorphous clusters and fine crystal nuclei.

[0044] Example 2

[0045] Step 1: Weigh 30g of IMP and GMP each on an analytical balance, and measure 200mL of water with a measuring cylinder. Add the two to a 500mL crystallization kettle 1, and stir the water bath in a high and low temperature constant temperature bath 10 to 65°C and 180rpm to fully dissolve the solute, and adjust the pH to 7.8. Then keep 105mL of water warm in a jacketed thermos cup 11 connected in series with the crystallizer water bath. Add 100mL of anti-solvent 90% ethanol at a rate of 6mL / min, and add 3.0g of IMP+GMP seeds (the mass ratio of IMP and GMP seeds is 1:2). The seeds are obtained by recrystallization of IMP and GMP, and the crystals are grown for 20min. The program is turned on to cool down by 4℃ / h, 6℃ / h, 8℃ / h, 10℃ / h, 12℃ / h, and 14℃ / h, and the temperature drops to the end point in 6 hours.

[0046] Step 2: When the temperature drops to 55°C, adjust the stirring speed of the stirrer 2 to 50rpm, and the particles naturally settle and stratify. First, turn on the air compressor 8, adjust the valve of the air inlet 6 of the air pressurized atomizer 4 to control the air flow rate to 30L / min, and then turn on the metering pump 9 to suck the solvent in the jacketed thermos cup 11 at a speed of 0.5mL / s and transport it to the air pressurized atomizer 4. At this time, it can be seen that the nozzle 5 sprays fan-shaped water mist to the liquid surface of the crystallization kettle. The water mist does not gather into a water column under the help of air and has a certain penetration. When the amount of water sprayed reaches 30mL, turn off the metering pump 9 first, then turn off the air compressor 8, resume stirring at 180rpm, and complete a solvent oscillation. When the temperature drops to 45°C and 30°C, the stirring speed is reduced to 60rpm and 80rpm respectively, and 35mL and 40mL of water are used, and the flow rate is adjusted to 0.7mL / s and the air flow rate is 60L / min for the second and third solvent oscillation operations.

[0047] Step 3: Cool down to 11°C, filter, wash and dry to obtain larger crystal particles with narrow particle size distribution. The median particle size d(50) of the Malvern particle size analyzer is 480 μm, which represents the main particle size value of the whole particle.

[0048] Figure 4 This is an optical microscope image of the crystal particles of the product obtained in Example 2. Figure 4 The IMP+GMP crystals in the solution are coarse rod-shaped crystals, with a more uniform particle size distribution, fewer needle-shaped fine particles, and less amorphous powder than in Example 1. This indicates that the solvent spray oscillation can better control the fine particles generated by secondary nucleation during the crystallization process when the solvent amount is gradually increased, and has a better dissolving effect on amorphous clusters and fine crystal nuclei.

[0049] Example 3

[0050] Step 1: Weigh 30g of IMP and GMP on an analytical balance, and 220mL of water in a measuring cylinder. Add the two to the crystallization kettle 1. Heat the water bath in the high and low temperature constant temperature bath 10 to 63°C, stir at a stirring speed of 200rpm to fully dissolve the solute, and adjust the pH to 7.6. Then keep 100mL of water warm in a jacketed thermos cup 11 connected in series with the crystallizer water bath. Add 110mL of anti-solvent 90% ethanol at an addition rate of 6mL / min, and add 4.0g of IMP+GMP seeds (the mass ratio of IMP and GMP seeds is 2:1). The seeds are obtained by recrystallization of IMP and GMP. Cultivate the crystal for 20min, start the program to cool down by 5℃ / h, 7℃ / h, 10℃ / h, 14℃ / h, 15℃ / h, and reach the end point in 5 hours.

[0051] Step 2: When the temperature drops to 53°C, adjust the stirring speed of the stirrer 2 to 60rpm, and the particles naturally settle and stratify. First, turn on the air compressor 8, adjust the valve of the air inlet 6 of the air pressurized atomizer 4 to control the air flow rate to 60L / min, and then turn on the metering pump 9 to absorb the solvent in the jacketed thermos cup 11 at a speed of 0.5mL / s and transport it to the air pressurized atomizer 4. At this time, it can be seen that the nozzle 5 sprays fan-shaped water mist to the liquid surface of the crystallization kettle. The water mist does not gather into a water column under the help of air and has a certain penetration. When the amount of water sprayed reaches 25mL, turn off the metering pump 9 first, then turn off the air compressor 8, resume stirring at 200rpm, and complete a solvent shock. When the temperature drops to 43°C, 34°C, and 25°C, the stirring speed is reduced to 70rpm, 80rpm, and 90rpm respectively, and 25mL of water is used, the flow rate is adjusted to 0.5mL / s, and the air flow rate is 60L / min for the second, third, and fourth solvent shock operations.

[0052] Step 3: Cool down to 12°C, filter, wash and dry to obtain larger crystal particles with narrow particle size distribution. The median particle size d(50) of the Malvern particle size analyzer is 405 μm, which represents the main particle size value of the whole particle.

[0053] Figure 5 This is an optical microscope image of the crystal particles of the product obtained in Example 3. This example uses four equal spray solvent oscillations. Figure 5 The IMP+GMP crystals in the sample are relatively large rod-shaped crystals, but the particle size distribution is slightly uneven, with a certain amount of needle-shaped fine particles and less amorphous powder. It is possible that the amount of solvent water used in each spray is relatively small, and the dissolution effect of fine particles in the later stage is not good. Compared with the comparative example 1, the crystal quality is still greatly improved, indicating that the solvent spray vibration has a very high control efficiency on the crystallization process.

[0054] Example 4

[0055] Step 1: Weigh 30g of IMP and GMP on an analytical balance, and 250mL of water in a measuring cylinder. Add the two to the crystallization kettle 1. Heat the water bath in the high and low temperature constant temperature bath 10 to 63°C, stir at a stirring speed of 200rpm to fully dissolve the solute, and adjust the pH to 8.0. Then keep 75mL of water warm in a jacketed thermos cup 11 connected in series with the crystallizer water bath. Add 120mL of 90% ethanol, an anti-solvent, at an addition rate of 6mL / min, and add 5.0g of IMP+GMP seeds (the mass ratio of IMP and GMP seeds is 1:1). The seeds are obtained by recrystallization of IMP and GMP. Cultivate the crystal for 20min, start the program to cool down by 5℃ / h, 8℃ / h, 11℃ / h, 14℃ / h, 15℃ / h, and reach the end point in 5 hours.

[0056] Step 2: When the temperature drops to 50°C, adjust the stirring speed of the stirrer 2 to 60rpm, and the particles naturally settle and stratify. First, turn on the air compressor 8, adjust the valve of the air inlet 6 of the air pressurized atomizer 4 to control the air flow rate to 40L / min, and then turn on the metering pump 9 to absorb the solvent in the jacketed thermos cup 11 at a speed of 0.5mL / s and transport it to the air pressurized atomizer 4. At this time, it can be seen that the nozzle 5 sprays fan-shaped water mist onto the crystallization kettle page. The water mist does not gather into a water column under the help of air and has a certain penetration. When the amount of water sprayed reaches 30mL, turn off the metering pump 9 first, then turn off the air compressor 8, resume stirring at 200rpm, and complete a solvent oscillation. When the temperature drops to 35°C, the stirring speed drops to 70rpm, use 45mL of water, adjust the water flow rate to 0.7mL / s, and the air flow rate to 60L / min, and perform the second solvent oscillation operation.

[0057] Step 3: Cool down to 10°C, filter, wash and dry to obtain larger crystal particles with narrow particle size distribution. The median particle size d(50) of the Malvern particle size analyzer is 451 μm, which represents the main particle size value of the whole particle.

[0058] Figure 6 The optical microscope image of the crystal particles of the product obtained in Example 4. Example 4 uses two solvent spray oscillations with increasing solvent volume gradients, showing that the IMP+GMP crystals are coarse rod-shaped crystals with a relatively uniform particle size distribution, less amorphous powder, and the crystal quality is similar to that of Example 2.

[0059] Comparative Example 1

[0060] Weigh 30g of IMP and GMP each on an analytical balance, measure 300mL of water with a measuring cylinder, add the two to a 500mL crystallization kettle 1, control the high and low temperature constant temperature bath 10 to heat up to 50°C in a water bath, stir at a stirring speed of 200rpm to fully dissolve the solute, and adjust the pH to 7.9. Add 120mL of anti-solvent 90% ethanol at an addition rate of 5mL / min, add 6.0g of IMP+GMP seeds (the mass ratio of IMP and GMP seeds is 1:1), which are obtained by mixing IMP and GMP for recrystallization, grow the crystal for 20min, and start the program to cool down. Cool to 12°C, filter, wash, and dry to obtain crystal particles with significantly smaller particle size. The median particle size d(50) of the Malvern particle size analyzer test result is 192μm, which represents the main particle size value of the entire particle.

[0061] Figure 7 The optical microscope image of the crystal particles of the product obtained in Comparative Example 1. Since the number of fine particles in the crystallization process was not controlled in the comparative example, the crystal particle product was an elongated needle-shaped crystal with some amorphous formation, and the particles were seriously agglomerated. Combined with the test results of the particle size analyzer, it is shown that by using the spray solvent oscillation technology, the fine particles generated in the crystallization process are effectively dissolved, which promotes the crystal growth in the crystallization process, so that the final product has a larger particle size and better morphology quality.

[0062] d(50) refers to the particle size at which the cumulative distribution of particles is 50%. Also called the median particle size or median particle size, this is a typical value that represents the particle size. This value accurately divides the population into two equal parts, that is, 50% of the particles exceed this value and 50% of the particles are below this value. This value is most often used to represent the main particle size of the entire particle.

[0063] The quality of crystal products, such as crystal morphology, particle size and particle size distribution, will affect the crystallization process route and downstream process flows such as filtration, washing, drying, grinding, packaging and storage, and thus affect equipment design and processing, investment costs, process operations, etc. High-quality flavor enhancers usually have the advantages of good grain morphology, large particle size, and good fluidity. The crystals of monosodium glutamate, salt, sugar, etc. sold on the market are mostly rod-shaped or block-shaped, and the main particle size is relatively large (above 200μm). As the main component of super-fresh monosodium glutamate, chicken essence and other seasonings, I+G should meet the requirements of good crystal morphology, large particle size, and good fluidity, so that the composite flavor enhancer obtained after mixing with monosodium glutamate still has the characteristics of uniform particle size and good fluidity, and a high-quality flavor enhancer is prepared. The IMP+GMP crystal particle product produced by the present invention is in the shape of a coarse rod, with very little amorphous precipitation, and the main particle size reaches 360-480μm, which not only effectively improves the downstream process efficiency and saves production costs, but also meets the requirements of high-quality flavor enhancers.

[0064] The present invention controls primary nucleation by adding seed crystals, introduces spray solvent vibration to eliminate secondary nucleation fine particles, and the final product particles are observed to be thick rod-shaped with very little amorphous formation under polarizing microscope. The main particle size detected by Malvern particle size analyzer is increased from 192μm to 360-480μm. Although the process adds the spray solvent vibration step, each time it takes a short time (within 2 minutes) and it is carried out during the cooling process, which has no effect on the batch production time, and the additional energy consumption is extremely low.

[0065] Chinese invention patent 201210214154.1 dissolves fine particles by heating the solution that has been cooled and crystallized to a certain degree (temperature increase range 25-45°C). Since the crystallization kettle is based on the jacket convection heat transfer principle, the energy loss is large, and the temperature increase range is large. It takes a long time and the energy consumption is high, which increases the batch production time and production energy consumption. In addition, the crystallization process is only controlled once, the dissolution is not targeted, and the control effect is poor. The final product particles are flaky crystals with a main particle size of only 40-60μm.

[0066] Chinese invention patent CN105031963A evacuates the solution that has been cooled and crystallized to a certain extent (pressure drops to 20-60 kPa), and utilizes the volatility difference between the anti-solvent and the solvent to make the anti-solvent evaporate more than the solvent evaporates, thereby reducing the anti-solvent ratio in the solution, increasing solubility, and dissolving particles. Anti-solvents are mostly organic alcohol reagents. This measure will cause waste of additional reagents, increase recovery costs, increase pollution risks, and make the implementation process more difficult to control. In addition, the evaporation solution has a small amplitude and many times, and the dissolution of large and small particles is not distinguished. The lack of pertinence increases the batch production time, and the final main particle size increase of each embodiment product is limited (increase of 20-40 μm), and the control effect is poor.

[0067] Chinese invention patent CN201921832883.7 mentions a spray crystallization device and a production device for sugar alcohols. The essence of this technology is melt spray crystallization, which uses compressed air to break up the molten raw material slurry, disperse it and attach it to the surface of the seed particles in the crystallizer, and then cool it to solidify and crystallize. This technology has requirements for the properties of the raw materials. The melting point of the raw materials is not high and the properties are stable at high temperatures. It is often used to produce small-particle spherical crystal products. However, this patented technology is in the category of solution crystallization. During the solution crystallization process, compressed air and atomizing nozzles are used to increase the penetration and uniformity of the solvent when it is added, and the stirring speed is reduced to distinguish the crystal particles by size, which effectively eliminates the undesirable fine particles produced during the solution crystallization process and produces coarse rod-shaped crystal particle products.

[0068] The implementation methods of the present invention are not limited to the above-mentioned embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principles of the present invention shall be equivalent replacement methods and shall be included in the protection scope of the present invention.

Claims

1. A method for producing IMP+GMP based on solvent spray oscillation anti-solvent cooling crystallization, characterized in that The steps include: Step 1: Weigh 30g of IMP and GMP, measure 200mL of water, add the two into a 500mL crystallization kettle, control the high and low temperature constant temperature water bath to heat up to 65°C, stir at a stirring speed of 180rpm to fully dissolve the solute, and adjust the pH to 7.9; then keep 80mL of water warm in a jacketed thermos cup connected in series with the crystallization kettle water bath; add 100mL of anti-solvent 90% ethanol at a rate of 4mL / min, add 2.8g of IMP+GMP seed crystals, the mass ratio of IMP to GMP seed crystals is 1:1, the seed crystals are obtained by recrystallization of IMP and GMP, grow the crystal for 20min, start the program to cool down by 5℃ / h, 8℃ / h, 12℃ / h, 14℃ / h, 16℃ / h, and reach the end point in 5 hours; Step 2: When the temperature drops to 55°C, adjust the stirring speed of the stirrer to 50rpm, and the particles naturally settle and stratify. First, turn on the air compressor, adjust the air pressure atomizer air inlet valve to control the air flow rate to 70L / min, and then turn on the metering pump to suck the solvent in the jacketed thermos cup at a speed of 0.8mL / s and transport it to the air pressure atomizer. The nozzle sprays fan-shaped water mist to the liquid surface of the crystallization kettle. The water mist does not gather into a water column under the help of air and has a certain penetrating power. The sprayed water volume reaches 40mL. First turn off the metering pump, then turn off the air compressor, and resume stirring at 180rpm to complete a solvent oscillation; the temperature drops to 35°C, reduce the stirring speed to 70rpm, use 40mL of water, adjust the water flow rate to 1mL / s, and the air flow rate to 90L / min for the second solvent oscillation operation; Step 3: Cool down to 10°C, filter, wash and dry to obtain crystal particles.

2. A method for producing IMP+GMP based on solvent spray oscillation anti-solvent cooling crystallization, characterized in that The steps include: Step 1: Weigh 30g of IMP and GMP, measure 200mL of water, add the two to a 500mL crystallization kettle, control the high and low temperature constant temperature water bath to heat up to 65°C, stir at a stirring speed of 180rpm to fully dissolve the solute, and adjust the pH to 7.8; then keep 105mL of water warm in a jacketed thermos cup connected in series with the crystallization kettle water bath; add 100mL of anti-solvent 90% ethanol at a rate of 6mL / min, add 3.0g of IMP+GMP seed crystals, the mass ratio of IMP to GMP seed crystals is 1:2, the seed crystals are obtained by recrystallization of IMP and GMP, grow the crystal for 20min, start the program to cool down by 4℃ / h, 6℃ / h, 8℃ / h, 10℃ / h, 12℃ / h, 14℃ / h, and reach the end point in 6 hours; Step 2: When the temperature drops to 55°C, adjust the stirring speed of the stirrer to 50rpm, and the particles naturally settle and stratify. First, turn on the air compressor, adjust the air pressure atomizer air inlet valve to control the air flow rate to 30L / min, and then turn on the metering pump to absorb the solvent in the jacketed thermos cup at a speed of 0.5mL / s and transport it to the air pressure atomizer. The nozzle sprays fan-shaped water mist to the liquid surface of the crystallization kettle. The water mist does not gather into a water column under the help of air and has a certain penetrating power. The amount of water sprayed reaches 30mL. First turn off the metering pump, then turn off the air compressor, and resume stirring at 180rpm to complete a solvent oscillation; when the temperature drops to 45°C and 30°C, reduce the stirring speed to 60rpm and 80rpm respectively, use 35mL and 40mL of water, adjust the flow rate to 0.7mL / s, and the air flow rate to 60L / min for the second and third solvent oscillation operations; Step 3: Cool down to 11°C, filter, wash and dry to obtain crystal particles.

3. A method for producing IMP+GMP based on solvent spray oscillation anti-solvent cooling crystallization, characterized in that The steps include: Step 1: Weigh 30g of IMP and GMP, measure 220mL of water, add the two to the crystallization kettle, control the high and low temperature constant temperature water bath to heat up to 63°C, stir at a stirring speed of 200rpm to fully dissolve the solute, and adjust the pH to 7.6; then keep 100mL of water warm in a jacketed thermos cup connected in series with the crystallization kettle water bath; add 110mL of anti-solvent 90% ethanol at an addition rate of 6mL / min, add 4.0g of IMP+GMP seed crystals, the mass ratio of IMP and GMP seed crystals is 2:1, the seed crystals are obtained by recrystallization of IMP and GMP, grow the crystal for 20min, start the program to cool down by 5℃ / h, 7℃ / h, 10℃ / h, 14℃ / h, 15℃ / h, and it takes 5 hours to reach the end point; Step 2: When the temperature drops to 53°C, adjust the stirring speed of the stirrer to 60rpm, and the particles naturally settle and stratify. First, turn on the air compressor, adjust the air pressure atomizer air inlet valve to control the air flow rate to 60L / min, and then turn on the metering pump to absorb the solvent in the jacketed thermos cup at a speed of 0.5mL / s and transport it to the air pressure atomizer. The nozzle sprays fan-shaped water mist to the liquid surface of the crystallization kettle. The water mist does not gather into a water column under the help of air and has a certain penetrating power. The amount of water sprayed reaches 25mL. First turn off the metering pump, then turn off the air compressor, and resume stirring at 200rpm to complete a solvent oscillation; when the temperature drops to 43°C, 34°C, and 25°C, respectively, reduce the stirring speed to 70rpm, 80rpm, and 90rpm, use 25mL of water, adjust the flow rate to 0.5mL / s, and the air flow rate to 60L / min for the second, third, and fourth solvent oscillation operations; Step 3: Cool down to 12°C, filter, wash and dry to obtain crystal particles.

4. A method for producing IMP+GMP based on solvent spray oscillation anti-solvent cooling crystallization, characterized in that The steps include: Step 1: Weigh 30g of IMP and GMP, measure 250mL of water, add the two to the crystallization kettle, control the high and low temperature constant temperature water bath to heat up to 63°C, stir at a stirring speed of 200rpm to fully dissolve the solute, and adjust the pH to 8.0; then keep 75mL of water warm in a jacketed thermos cup connected in series with the crystallization kettle water bath; add 120mL of anti-solvent 90% ethanol at a rate of 6mL / min, add 5.0g of IMP+GMP seed crystals, the mass ratio of IMP and GMP seed crystals is 1:1, the seed crystals are obtained by recrystallization of IMP and GMP, grow the crystal for 20min, start the program to cool down by 5℃ / h, 8℃ / h, 11℃ / h, 14℃ / h, 15℃ / h, and it takes 5 hours to reach the end point; Step 2: When the temperature drops to 50°C, adjust the stirring speed of the stirrer to 60rpm, and the particles naturally settle and stratify. First, turn on the air compressor, adjust the air pressure atomizer air inlet valve to control the air flow rate to 40L / min, and then turn on the metering pump to absorb the solvent in the jacketed thermos cup at a speed of 0.5mL / s and transport it to the air pressure atomizer. The nozzle sprays fan-shaped water mist to the liquid surface of the crystallization kettle. The water mist does not gather into a water column under the help of air and has a certain penetrating power. The sprayed water volume reaches 30mL. First turn off the metering pump, then turn off the air compressor, and resume stirring at 200rpm to complete a solvent oscillation; when the temperature drops to 35°C, the stirring speed is reduced to 70rpm, 45mL of water is used, the water flow rate is adjusted to 0.7mL / s, and the air flow rate is 60L / min, and the second solvent oscillation operation is performed; Step 3: Cool down to 10°C, filter, wash and dry to obtain crystal particles.

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