Method for preparing L-proline through pressurized temperature oscillation crystallization in water-ethanol system

Abstract

The invention discloses a method for preparing L-proline through pressurized temperature oscillation crystallization in a water-ethanol system. The method comprises the following steps: adding an ethanol solution with the water content of 5-10v% and an L-proline raw material into a jacketed crystallization kettle, starting pressurizing and online particle size detection equipment, heating and stirring until the L-proline raw material is completely dissolved, and enabling the solution to reach a saturated state; performing linear cooling to 60-65 DEG C, closing a pressurizing valve, opening a crystal slurry tank valve, pressing L-proline crystal slurry into a crystallization kettle, growing the crystal, starting a cooling program, and cooling according to a function T2 (t) = T2i-{(t-120) / t2} 2 * (T2i-T2f), tlt; after 240min, cooling is carried out according to a function T3 (t) = T3i-{(t-240) / t3} 2 * (T3i-T3f), and the temperature is reduced according to 240lt; tlt; the time is 450 to 480 minutes; and when the temperature is reduced to the end point, growing crystals, filtering, washing and drying to obtain a crystallized product. The L-proline product prepared by the method is large in particle size, narrow in particle size distribution and relatively high in bulk density.

Description

Technical Field

[0001] The invention relates to a method for preparing L-proline, and in particular to a method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system based on online particle size detection. Background Art

[0002] L-proline (C5H9NO2), also known as L-pyrrolidine-2-carboxylic acid, belongs to the heterocyclic amino acid family and is an α-amino amino acid without free radicals. As one of the non-essential amino acids for the human body, it is widely used in food additives and flavoring agents and is an important animal nutritional additive. In medicine, L-proline is one of the raw materials for large-volume infusion of complex amino acids and can be used for nutritional supplementation after protein deficiency, malnutrition, severe gastrointestinal diseases, burns, and surgery; in agriculture, the introduction of exogenous proline does help to improve the body's ability to resist osmotic stress, thereby increasing the yield of crops; in the food industry, L-proline can be used as a food additive and flavoring agent, and can be heated with sugar to produce amino-carbonyl reactions to generate special flavor substances; in the chemical industry, due to its chiral molecular characteristics, L-proline can be used as a catalyst for some asymmetric catalytic reactions; with the increasing number of studies on L-proline, L-proline will have a wider range of applications, and will also further enhance the value of L-proline. However, compared with amino acid products in Japan and South Korea, my country's crystallization technology is still not perfect. The products obtained by crystallization are mostly needle-shaped, with poor morphology and low bulk density, which seriously affects its quality and subsequent process efficiency, and is at a disadvantage in market competition. Therefore, it is of great significance to optimize the L-proline crystallization process to obtain proline crystal products with good crystal habits.

[0003] At present, there are three ways to prepare L-proline: chemical synthesis, microbial fermentation, and protein hydrolysis. When using the chemical synthesis process to produce L-proline, the process route is long and the cost is high, which is not suitable for large-scale industrial production. When using protein hydrolysis to produce L-proline, the production and purification steps are many, resulting in low final yield and low raw material utilization. In addition, a large amount of toxic chemical raw materials are added during the production process, making it impossible to achieve large-scale production. However, the cost of amino acid microbial fermentation is getting lower and lower, providing strong support for the realization of large-scale industrial production.

[0004] In the production cost structure of L-proline, the downstream processing process of the fermentation product accounts for a considerable proportion and has become a bottleneck problem of the entire production process cost. Therefore, how to separate and purify L-proline from the fermentation broth is also a hot area of ​​research. Chinese invention patent application CN108640865A discloses a method for preparing medicinal proline, wherein the proline fermentation broth is first adsorbed by a strongly acidic cationic resin, and then filtered by a weakly basic anionic resin and a weakly acidic cationic resin in sequence to obtain monohydrate proline, and then dehydrated by ethanol to obtain an anhydrous medicinal proline product. This technology mainly improves the purity of proline by adsorbing impurities in the fermentation broth with an ionic resin, but does not involve crystallization and purification of proline, and the particle size and purity of the obtained proline need to be further improved.

[0005] Chinese invention patent application CN112608266A discloses a method for preparing L-proline, wherein the proline fermentation liquid is filtered through a filter membrane, washed with pure water to obtain a clear liquid, and then the clear liquid is filtered after passing through a weakly basic anion resin and a weakly acidic cationic resin in sequence, and then activated carbon is added to obtain the filtrate for decolorization and filtering, and then the decolorized liquid containing proline is obtained and evaporated and concentrated to obtain a concentrated liquid, and then the concentrated liquid is cooled to 10°C for natural crystallization, and wet crystals are obtained after centrifugation and placed in a vacuum dryer for drying to obtain the L-proline finished product. This technology is to filter, decolorize and concentrate the treated fermentation liquid through anion and cation resins, thereby improving the purity of proline, but the natural cooling crystallization method is adopted, and the early stage of the temperature reduction is too fast, resulting in crystal nucleation, and it is easy to obtain a product with a smaller crystal size.

[0006] Chinese invention patent CN103265467A discloses a method for refining L-proline by cooling crystallization, wherein crude L-proline is dissolved in an ethanol solution, the temperature is naturally lowered to crystallize, and the temperature is raised to retain large particles as seeds, and then a mixed curve cooling method is adopted for crystallization, and needle-shaped crystal products are obtained after filtration and drying. The patented technology uses large-particle crystals naturally precipitated in the solution as seeds in the early stage, and uses a mixed curve to slowly control the temperature in the early stage to avoid explosive nucleation, and accelerates the cooling rate in the later stage to promote crystal growth, but does not consider the volatilization of ethanol at high temperature and the explosive nucleation phenomenon of crystals, and the mixed cooling curve of the patent is parabolic, which is easy to cause secondary nucleation to obtain products with uneven crystal sizes. Summary of the invention

[0007] The purpose of the present invention is to provide a method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system based on online particle size detection, which has the advantages of suppressing high-temperature volatilization of ethanol and solving the problem of explosive nucleation in the feeding and crystallization processes, being simple and easy to operate and the process being easy to control. The prepared L-proline has the characteristics of narrow particle size distribution, large particle size and high bulk density.

[0008] The purpose of the present invention is achieved through the following technical solutions:

[0009] A method for preparing L-proline by pressure-temperature oscillation crystallization in a water-ethanol system, comprising the following steps:

[0010] 1) Add an ethanol solution with a water content of 5-10 v% and an L-proline raw material to a jacketed crystallization kettle, start the pressure and on-line particle size detection equipment, heat up to 75-80 °C and stir until completely dissolved, the solution reaches a saturated state, and the pressure is controlled according to the function P(t) = P i -(t / t o ) 2 ×P i , where P(t) is the solution pressure at the cooling time t, t = 0 to t0, the total cooling time t0 = 450-480 min, and the initial pressure P i = 0.5-0.8 MPa;

[0011] 2) Reduce the stirring rate to 100-120 r / min, and linearly cool down according to the first cooling function T1(t) = T 1i -(t / t1)×(T 1i -T 1f ), where 0 < t < 90-120 min, T1(t) is the solution temperature at the cooling time t, t = 0 to t1, the total first cooling time t1 = 90-120 min, the initial temperature T 1i = 75-80 °C, T 1f = 60-65 °C. After cooling down to 60-65 °C, close the pressure valve and open the slurry tank valve, and press the L-proline slurry into the crystallization kettle for crystal cultivation for 10-20 min;

[0012] 3) Keep the stirring rate unchanged, and cool down according to the second cooling function T2(t) = T 2i -{(t - 120) / t2} 2 ×(T 2i -T 2f ), where 120 < t < 240 min, the total cooling time t2 = 120 min, the initial temperature T 2i = 60-65 °C, T 2f = 40-45 °C; then according to the third cooling function T3(t) = T 3i -{(t - 240) / t3} 2 ×(T 3i -T 3f ), where 240 < t < 450-480 min, the total third cooling time t3 = 210-240 min, the initial temperature T 3i = 45-50 °C, T 3f = 10-15 °C; T2(t) or T3(t) is the solution temperature at the cooling time t.

[0013] 4) When the temperature drops to the end point temperature of 10-15°C, grow the crystals, filter, wash and dry to obtain a crystalline product.

[0014] To further achieve the purpose of the present invention, preferably, in step 1), the mass of L-proline raw material added per milliliter of ethanol solution is controlled to be 0.4-0.6 g.

[0015] Preferably, in step 1), the online particle size detection is performed by FBRM technology using primary mode detection; the stirring rate is 180-200 r / min.

[0016] Preferably, in step 2), the linear cooling is achieved by starting a high and low temperature constant temperature bath cooling program.

[0017] Preferably, in step 2), the L-proline slurry is obtained by dissolving L-proline in anhydrous ethanol; the amount of L-proline used is 4-6% of the mass of the L-proline raw material, and the particle size is 150-300 μm.

[0018] Preferably, in step 3), the temperature-controlled crystallization is achieved by starting a high-low temperature constant temperature tank cooling program.

[0019] Preferably, in step 4), the crystal growing is carried out while controlling the stirring rate to 80-100 r / min, maintaining the temperature to 10-15° C., and the crystal growing time is 15-30 min.

[0020] Preferably, in step 4), the filtration is performed by vacuum filtration using a Buchner funnel; the washing is performed by washing the filtered crystals with anhydrous ethanol for 2 to 3 times; and the drying is performed by drying the washed crystals in an oven at 35 to 40° C. for 8 to 12 hours.

[0021] Preferably, the method is implemented by a device for preparing L-proline by temperature oscillation crystallization in a water-ethanol system, the device comprising a jacketed crystallization kettle, a stirring paddle, an FBRM probe, and a pressure gauge are provided on the jacketed crystallization kettle, the stirring paddle is connected to the stirrer, a high and low temperature constant temperature bath is connected to the jacketed crystallization kettle, the FBRM probe is connected to the Particle Track G400 and a computer, and the pressure gauge is connected to the pressure reducing valve and a compressed air bottle.

[0022] Preferably, the FBRM probe is a focused beam total reflection meter.

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

[0024] 1) The pressure control function and temperature control function discovered in the present invention increase the particle size and bulk density of the crystalline product, and at the same time have the advantages of low production cost, simple and easy process, and easy process control.

[0025] 2) Through the pressurizing device, the present invention can effectively inhibit the volatilization of ethanol during the high-temperature dissolution process, thereby avoiding the initial burst nucleation phenomenon of L-proline, ensuring that the solution system is in a saturated state during the dissolution stage, and the pressure during the crystallization process follows the function P(t) = P i -(t / t o ) 2 ×P i to proceed, which can effectively inhibit the volatilization of ethanol during the crystallization process, thereby avoiding the phenomenon of crystal agglomeration on the stirring paddle blades and the wall of the crystallizer.

[0026] 3) The present invention adopts the method of temperature oscillation - cooling crystallization. During the cooling process, by controlling the oscillation temperature point, cooling rate, etc., the specific function expression of the cooling segmented function is determined, that is, the first cooling function T1(t) = T 1i -(t / t1)×(T 1i -T 1f ), where 0 < t < 90 - 120 min, the second cooling function T2(t) = T 2i -{(t - 120) / t2} 2 ×(T 2i -T 2f ), where 120 < t < 240 min, the third cooling function T3(t) = T 3i -{(t - 240) / t3} 2 ×(T 3i -T 3f ), where 240 < t < 450 - 480 min. Furthermore, by strictly controlling the supersaturation, the secondary nucleation can be significantly reduced, and larger-sized L-proline crystal products can be obtained.

[0027] 4) In the initial stage of crystallization, the present invention adds a certain amount of crystal slurry through pressure in the pressurizing device to consume a high supersaturation and avoid burst nucleation. The addition of crystal slurry can provide a larger growth surface area, promote crystal growth, and obtain larger-sized crystalline products.

[0028] 5) The invention adopts an on-line particle size monitoring device, which can monitor the dynamic changes in the number of particles with different chord lengths during the crystallization process. By the particle changes in the solution system, the experimental conditions are optimized to achieve precise control of the crystal particle size. Brief Description of the Drawings

[0029] Figure 1 Schematic diagram of the device for preparing L-proline by temperature oscillation crystallization in a water - ethanol system.

[0030] Figure 2 The figure is a data diagram of the particle size of the crystal particles of the products obtained in the examples and comparative examples.

[0031] Figure 3 This is an optical microscope image of the crystal particles of the product obtained in Example 1.

[0032] Figure 4 This is an optical microscope image of the crystal particles of the product obtained in Example 2.

[0033] Figure 5 This is an optical microscope image of the crystal particles of the product obtained in Example 3.

[0034] Figure 6 This is an optical microscope image of the crystal particles of the product obtained in Example 4.

[0035] Figure 7 This is an optical microscope image of the crystal particles of the product obtained in Comparative Example 1.

[0036] Figure 8 This is an optical microscope image of the crystal particles of the commercially available product. DETAILED DESCRIPTION

[0037] 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.

[0038] Crystallization is the last step in the purification of L-proline, which plays a decisive role in the quality of proline products. Therefore, it is necessary to develop a new crystallization process and optimize the process in combination with equipment. This is not only of great practical significance and application value for improving product quality and grade and reducing production costs, but also can greatly improve the competitiveness of L-proline in the international market.

[0039] Common recrystallization methods include cooling, vacuum evaporation, adding anti-solvents, etc. When the solubility of the solute is greatly affected by temperature, the cooling crystallization method is usually used, generally using a parabolic cooling or linear cooling mode. In addition, the cooling crystallization equipment is low in cost and easy to scale up. At present, the ethanol-water system is generally used in China to cool and crystallize L-proline. The volatilization of high-temperature feed ethanol leads to explosive nucleation. The temperature control method during the crystallization process is relatively rough, and no precise temperature and pressure control means are used, resulting in high ethanol residues in the obtained product, small particle size, low bulk density, low process production efficiency, and increased production costs.

[0040] like Figure 1As shown in the figure, the device for preparing L-proline by pressure-temperature oscillation crystallization in a water-ethanol system according to the present invention is based on the existing jacketed crystallization kettle 2. A stirring paddle 4, a pressure gauge 6, and an FBRM probe 3 are provided on the jacketed crystallization kettle 2. The stirring paddle 4 is connected to a stirrer 5, and the stirring speed is controlled by the stirrer 5. The high and low temperature constant temperature bath 7 is connected in parallel with the jacketed crystallization kettle 2. The temperature of the jacketed crystallization kettle 2 is controlled by the high and low temperature constant temperature bath 7 and is connected by a heat preservation hose. The FBRM probe 3 is connected to the on-line particle size detector 1. The pressure gauge 6 is connected to a pressure reducing valve 8 through a pressure-resistant pipeline, and a pressure increasing valve 10 is provided on the pipeline. The crystal slurry tank 12 is connected to the pressure reducing valve 8 through a pressure-resistant pipeline, and a crystal slurry valve 11 is provided on the pipeline. The pressure in the system is controlled by adjusting the pressure reducing valve 8 connected to the air bottle 9.

[0041] A method for preparing L-proline by pressure-temperature oscillation crystallization in a water-ethanol system according to the present invention specifically includes the following steps:

[0042] 1) Add the ethanol solution and the L-proline raw material into the jacketed crystallization kettle 2. The volume percentage of water in the ethanol solution is 5-10%, and the mass of the L-proline raw material added to each milliliter of the ethanol solution is controlled to be 0.6-0.8 g. Put the FBRM probe 3 in, and turn on the on-line particle size detector 1. After the crystallizer is in a closed state, open the compressed air bottle 9 and then the pressure reducing valve 8. The pressure is carried out according to the function P(t)=P i -(t / t o ) 2 ×P i . P(t) is the solution pressure at the cooling time t, t = 0-t0, the total cooling time t0 = 450-480 min, and the initial pressure P i = 0.5-0.8 MPa. Heat the solution to 75-80 °C, and the stirring rate is 180-200 r / min. Stir until completely dissolved until the solution reaches a saturated state;

[0043] 2) Add crystal slurry: Reduce the stirring rate to 100-120 r / min, start the cooling program of the high and low temperature constant temperature bath 7, and the cooling is carried out according to the first cooling function T1(t)=T 1i -(t / t1)×(T 1i -T 1f ), where 0<t<90-120 min. T1(t) is the solution temperature at the cooling time t, t = 0-t1, the total cooling time t1 = 90-120 min, the initial temperature T 1i = 75-80 °C, T 1f= 60 - 65 °C. After cooling down to 60 °C, close the pressure valve 10 and open the valve 11 of the crystal slurry tank, then press the L-proline crystal slurry in the crystal slurry tank 12 into the jacketed crystallization kettle 2 for crystal growth for 10 - 20 minutes. The crystal slurry is the L-proline crystal seeds dissolved in absolute ethanol. The particle size of the crystal seeds is 150 - 300 μm, and the amount of crystal seeds is 4 - 6% of the mass of the L-proline raw material.

[0044] 3) Curve-controlled temperature crystallization: Keep the stirring rate unchanged. First, cool down according to the second cooling function T2(t) = T 2i -{(t - 120) / t2} 2 ×(T 2i -T 2f ), where T2(t) is the temperature of the solution at the cooling time t, 120 < t < 240 min, the total second cooling time t2 = 120 min, the initial temperature T 2i = 60 - 65 °C, T 2f = 40 - 45 °C; then according to the third cooling function T3(t) = T 3i -{(t - 240) / t3} 2 ×(T 3i -T 3f ), where 240 < t < 450 - 480 min, T3(t) is the temperature of the solution at the cooling time t; the total cooling time t3 = 210 - 240 min, the initial temperature T 3i = 45 - 50 °C, T 3f = 10 - 15 °C.

[0045] 4) When the temperature drops to the end temperature of 10 - 15 °C, control the stirring rate to 80 - 100 r / min, keep this temperature for crystal growth for 15 - 30 minutes, then filter, wash, and dry to obtain the crystalline product.

[0046] The characteristics of the method of the present invention are that in the water-ethanol system, pressure-temperature oscillation crystallization is used to prepare the L-proline system, and the relationship between the pressure control function and the temperature control function of temperature and pressure control in the crystallization process is discovered. Specifically, it is mainly reflected in the following aspects: In the dissolution stage, the ethanol volatilization is controlled by pressure to inhibit the initial burst nucleation during feeding; in the initial stage of crystallization, by adding a certain amount of crystal slurry, the high supersaturation is consumed to avoid primary burst nucleation and stabilize the crystallization process. During the crystallization process, the pressure is carried out according to the pressure function P(t) = P i -(t / t o ) 2 ×P i which can effectively inhibit the volatilization of ethanol during the crystallization process, thus avoiding the phenomenon that crystals agglomerate on the stirring paddle blades and the wall of the crystallizer. In the early stage of cooling, according to the first cooling function T1(t) = T 1i -(t / t1)×(T 1i-T 1f ), where it is carried out when 0 < t < 90 - 120 min to provide supersaturation for subsequent crystal nucleation and growth; after adding the crystal slurry, the oscillation temperature point and cooling rate are optimized through the particle changes in the solution system; according to the second cooling function T2(t) = T 2i -{(t - 120) / t2} 2 ×(T 2i -T 2f ), cool down the temperature, where 120 < t < 240 min, and then according to the third cooling function T3(t) = T 3i -{(t - 240) / t3} 2 ×(T 3i -T 3f ), cool down the temperature, where 240 < t < 450 - 480 min. In the present invention, the crystal is first cooled slowly according to the function so that the crystal grows with the slow increase of supersaturation, and then the interval with relatively serious secondary nucleation is selected, and the small particle crystals generated by secondary nucleation are dissolved by raising the temperature according to the function, and finally a crystalline product with large crystal size, narrow particle size distribution and high bulk density is obtained. In addition to the definition of the cooling function, the specific parameters of the addition amount of ethanol solution, stirring rate, preparation process of L-proline crystal slurry, and crystal cultivation process can be defined according to the invention purpose and the method of the present invention. The temperature control crystallization, filtration, washing, and drying of the present invention can be obtained by combining conventional practices according to the invention purpose; the device for preparing L-proline by temperature oscillation crystallization in the water-ethanol system of the present invention can be obtained by the above method.

[0047] The cooling crystallization method of the present invention is applicable to substances whose solubility decreases significantly with the decrease of temperature, and has the advantages of simple equipment and easy operation. The principle is that as the temperature decreases, the supersaturation of the solution gradually increases, so as to promote the solute in the solution to precipitate in the form of crystals.

[0048] Example 1

[0049] 1) Weigh 120 g of L-proline crude product raw material, measure 300 ml of ethanol solution with a water content of 5 v% and add it to the jacketed crystallization kettle 2. Heat the solution in the jacketed crystallization kettle to 75 °C through the high and low temperature constant temperature bath 7, put the FBRM probe 3 in, and turn on the online particle size detector 1; after the crystallizer is in a closed state, open the compressed air bottle 9, and then open the pressure reducing valve 8. The pressure gauge reading is carried out according to the function P(t) = P i -(t / t o ) 2 ×P i , P(t) is the solution pressure at the cooling time t, t = 0 - t0, the total cooling time t0 = 480 min, and the initial pressure P i = 0.5 MPa. The stirring rate is 180 r / min, stir until completely dissolved, and the solution reaches a saturated state;

[0050] 2) Reduce the stirring rate to 100 r / min, start the cooling program of the high and low temperature constant temperature bath 7, and cool down according to the first cooling function T1(t) = T 1i -(t / t1)×(T 1i -T 1f ), where 0 < t < 120 min, T1(t) is the solution temperature at the cooling time t, t = 0 to t1, the total cooling time t1 = 120 min, the initial temperature T 1i = 75 °C, T 1f = 60 °C. After cooling to 60 °C, close the pressure valve 10 and open the valve 11 of the crystal slurry tank, and press the L-proline crystal slurry in the crystal slurry tank 12 into the jacketed crystallization kettle 2 for crystal cultivation for 10 min. The crystal slurry is the L-proline crystal seeds dissolved in absolute ethanol, the particle size of the crystal seeds is 150 - 300 μm, and the amount of crystal seeds is 4% of the mass of the L-proline raw material;

[0051] 3) Keep the stirring rate unchanged. First, cool down according to the second cooling function T2(t) = T 2i -{(t - 120) / t2} 2 ×(T 2i -T 2f ), where 120 < t < 240 min, T2(t) is the solution temperature at the cooling time t, the total cooling time t2 = 120 min, the initial temperature T 2i = 60 °C, T 2f = 40 °C; then cool down according to the third cooling function T3(t) = T 3i -{(t - 240) / t3} 2 ×(T 3i -T 3f ), where T3(t) is the solution temperature at the cooling time t, 240 < t < 480 min, the total cooling time t3 = 240 min, the initial temperature T 3i = 45 °C, T 3f = 15 °C.

[0052] 4) When the temperature drops to the end temperature of 15 °C, control the stirring rate to 100 r / min, keep this temperature for crystal cultivation for 15 min, filter, wash, and dry to obtain the crystalline product. Filtration is carried out by vacuum filtration with a Buchner funnel; washing is to wash the filtered crystals with absolute ethanol; drying is to dry the washed crystals in an oven. Figure 3 This is the optical microscope image of the product crystal particles obtained in Example 1. The result of the online particle size detector shows that the average chord length is 123.05 μm and the bulk density is 0.446 g / mL.

[0053] Example 2

[0054] 1) Weigh 120 g of the crude L - proline raw material, measure 300 ml of an ethanol solution with a water content of 10 v% and add it to the jacketed crystallization kettle 2. Heat the solution in the jacketed crystallization kettle to 80 °C through the high - low temperature constant temperature bath 7, put in the FBRM probe 3, and turn on the online particle size detector 1; after the crystallizer is in a closed state, open the compressed air bottle 9 and then the pressure reducing valve 8. The pressure gauge reading follows the function P(t) = P i -(t / t o ) 2 ×P i proceeds, where P(t) is the pressure of the solution at the cooling time t, t = 0 - t0, the total cooling time t0 = 480 min, and the initial pressure P i = 0.8 MPa. The stirring rate is 200 r / min. Stir until completely dissolved until the solution reaches a saturated state;

[0055] 2) Reduce the stirring rate to 120 r / min, start the cooling program of the high - low temperature constant temperature bath 7. The cooling is carried out according to the first cooling function T1(t) = T 1i -(t / t1)×(T 1i -T 1f ), where 0 < t < 120 min. T1(t) is the temperature of the solution at the cooling time t, t = 0 - t1, the total cooling time t1 = 120 min, the initial temperature T 1i = 80 °C, T 1f = 60 °C. After cooling to 60 °C, close the pressure - adding valve 10 and open the valve of the crystal slurry tank 11, and press the L - proline crystal slurry in the crystal slurry tank 12 into the jacketed crystallization kettle 2 for 20 min of crystal growth. The crystal slurry is L - proline crystal seeds dissolved in absolute ethanol, the particle size of the crystal seeds is 150 - 300 μm, and the amount of crystal seeds is 6% of the mass of the L - proline raw material;

[0056] 3) Keep the stirring rate unchanged. First, cool according to the second cooling function T2(t) = T 2i -{(t - 120) / t2} 2 ×(T 2i -T 2f ), where 120 < t < 240 min, T2(t) is the temperature of the solution at the cooling time t, the total cooling time t2 = 120 min, the initial temperature T 2i = 60 °C, T 2f = 40 °C; then cool according to the third cooling function T3(t) = T 3i -{(t - 240) / t3} 2 ×(T 3i -T 3f ), where T3(t) is the temperature of the solution at the cooling time t, 240 < t < 480 min, the total cooling time t3 = 240 min, and the initial temperature T 3i= 45 °C, T 3f = 10 °C.

[0057] 4) When the temperature drops to the final temperature of 10 °C, control the stirring rate to 80 r / min, keep the temperature for crystal growth for 30 min, filter, wash, and dry to obtain the crystalline product. Filtration is carried out by vacuum filtration with a Buchner funnel; washing is to wash the crystals after filtration with absolute ethanol; drying is to dry the washed crystals in an oven. Figure 4 It is the optical microscope image of the product crystal particles obtained in Example 2. The result of the online particle size detector shows that the average chord length is 85.95 μm and the bulk density is 0.372 g / mL.

[0058] Example 3

[0059] 1) Weigh 180 g of the crude L-proline raw material, measure 300 ml of an ethanol solution with a water content of 5 v% and add it to the jacketed crystallization kettle 2. Heat the solution in the jacketed crystallization kettle to 75 °C through the high and low temperature constant temperature bath 7, put in the FBRM probe 3, and turn on the online particle size detector 1; after the crystallizer is in a closed state, open the compressed air bottle 9, then open the pressure reducing valve 8, and the pressure gauge reading follows the function P(t) = P i -(t / t o ) 2 ×P i proceeds, P(t) is the solution pressure at the cooling time t, t = 0 - t0, the total cooling time t0 = 450 min, and the initial pressure P i = 0.5 MPa. The stirring rate is 180 r / min, stir until completely dissolved, and the solution reaches a saturated state;

[0060] 2) Reduce the stirring rate to 100 r / min, start the cooling program of the high and low temperature constant temperature bath 7, and cool according to the first cooling function T1(t) = T 1i -(t / t1)×(T 1i -T 1f ), where 0 < t < 90 min, T(t) is the solution temperature at the cooling time t, t = 0 - t1, the total first cooling time t1 = 90 min, the initial temperature T 1i = 75 °C, T 1f = 60 °C. After cooling to 60 °C, close the pressure valve 10 and open the valve 11 of the slurry tank, and press the L-proline slurry in the slurry tank 12 into the jacketed crystallization kettle 2 for crystal growth for 10 min. The slurry is the L-proline crystal seeds dissolved in absolute ethanol, the particle size of the crystal seeds is 150 - 300 μm, and the amount of crystal seeds is 6% of the mass of the L-proline raw material;

[0061] 3) Keep the stirring rate unchanged, and cool according to the second cooling function T2(t) = T 2i -{(t - 120) / t2} 2×(T 2i -T 2f ), where 90 < t < 210 min, T2(t) is the temperature of the solution at the cooling time t, the total cooling time t2 = 120 min, the initial temperature T 2i = 60 °C, T 2f = 40 °C; then cool down according to the third cooling function T3(t) = T 3i -{(t - 240) / t3} 2 ×(T 3i -T 3f ), where 210 < t < 450 min, T3(t) is the temperature of the solution at the cooling time t, the total cooling time t3 = 240 min, the initial temperature T 3i = 45 °C, T 3f = 15 °C.

[0062] 4) When the temperature drops to the end temperature of 15 °C, control the stirring rate to 100 r / min, keep this temperature for crystal cultivation for 15 min, filter, wash, and dry to obtain the crystalline product. Filtration is carried out by vacuum filtration with a Buchner funnel; washing is to wash the crystals after filtration with anhydrous ethanol; drying is to dry the washed crystals in an oven. Figure 5 Figure for the optical microscope of the product crystal particles obtained in Example 3. The average chord length measured by the online particle size analyzer is 92.54 μm, and the bulk density is 0.426 g / mL.

[0063] Example 4

[0064] 1) Weigh 180 g of the L-proline crude product raw material, measure 300 ml of an ethanol solution with a water content of 10 v% and add it to the jacketed crystallization kettle 2. Heat the solution in the jacketed crystallization kettle to 80 °C through the high and low temperature constant temperature bath 7, put in the FBRM probe 3, and turn on the online particle size analyzer 1; after the crystallizer is in a closed state, open the compressed air bottle 9, then open the pressure reducing valve 8, and the pressure gauge reading changes according to the function P(t) = P i -(t / t o ) 2 ×P i , P(t) is the pressure of the solution at the cooling time t, t = 0 to t0, the total cooling time t0 = 450 min, and the initial pressure P i = 0.8 MPa. The stirring rate is 200 r / min, stir until completely dissolved, and the solution reaches a saturated state;

[0065] 2) Reduce the stirring rate to 120 r / min, start the cooling program of the high and low temperature constant temperature bath 7, and cool down according to the first cooling function T1(t) = T 1i -(t / t1)×(T 1i -T 1f), which is carried out when 0 < t < 90 min, T(t) is the temperature of the solution at the cooling time t, t = 0 to t1, the total cooling time t1 = 90 min, and the initial temperature T 1i = 80 °C, T 1f = 65 °C. After cooling to 65 °C, close the pressure valve 10 and open the valve 11 of the crystal slurry tank, and press the L-proline crystal slurry in the crystal slurry tank 12 into the jacketed crystallization kettle 2 for 20 min of crystal cultivation. The crystal slurry is the L-proline crystal seed dissolved in absolute ethanol, the particle size of the crystal seed is 150 - 300 μm, and the amount of crystal seed is 4% of the mass of the L-proline raw material;

[0066] 3) Keep the stirring rate unchanged, and cool down according to the second cooling function T2(t) = T 2i -{(t - 120) / t2} 2 ×(T 2i -T 2f ), where 90 < t < 210 min, T2(t) is the temperature of the solution at the cooling time t, the total second cooling time t2 = 120 min, the initial temperature T 2i = 65 °C, T 2f = 45 °C; then cool down according to the third cooling function T3(t) = T 3i -{(t - 240) / t3} 2 ×(T 3i -T 3f ), T3(t) is the temperature of the solution at the cooling time t, where 210 < t < 450 min, the total cooling time t3 = 240 min, the initial temperature T 3i = 50 °C, T 3f = 10 °C.

[0067] 4) When the temperature drops to the end temperature of 10 °C, control the stirring rate to 80 r / min, keep this temperature for 30 min of crystal cultivation, filter, wash, and dry to obtain the crystalline product. Filtration is carried out by vacuum filtration with a Buchner funnel; washing is to wash the filtered crystals with absolute ethanol; drying is to dry the washed crystals in an oven. Figure 6 is the optical microscope image of the crystal particles of the product obtained in Example 4. The average chord length measured by the online particle size detector is 90.15 μm, and the bulk density is 0.428 g / mL.

[0068] Comparative Example 1

[0069] 1) Weigh 120 g of L-proline crude product raw material, measure 300 ml of ethanol solution with a water content of 5 v% and add it to the jacketed crystallization kettle 2. Heat the solution in the jacketed crystallization kettle to 75 °C through the high and low temperature constant temperature bath 7, put in the FBRM probe 3, and turn on the online particle size detector 1; stir at a speed of 180 r / min until completely dissolved, and the solution reaches a saturated state.

[0070] 2) Reduce the stirring rate to 100 r / min, start the cooling program of the high and low temperature constant temperature bath 7, and control the cooling rate to cool down to 15°C at 10°C / h.

[0071] 3) When the temperature drops to the end point temperature of 15°C, control the stirring rate to 100 r / min, maintain the temperature for 15 minutes, filter, wash and dry to obtain a crystalline product. Figure 7 This is an optical microscope image of the crystal particles of the product obtained in Comparative Example 1. The online particle size detector results show that the average chord length is 37.15 μm and the bulk density is 0.342 g / mL.

[0072] The operating parameters and results of each embodiment and comparative example 1 are compared in Table 1. It can be seen that the crystallization product prepared by the crystallization method of the present invention has obvious advantages in terms of quality and yield.

[0073] Table 1. Comparison of operating parameters and results of examples and comparative examples

[0074]

[0075] Figure 2 The chord length data of the crystal particles of the products obtained in the examples and comparative examples are obtained by an online particle size detector. Figure 2 It can be seen that compared with the products of the comparative examples, the chord length distribution of the embodiments is narrower, indicating that the particle size range of the crystal product is more concentrated and the particle size is more uniform; the average chord length reaches about 120 μm, and the bulk density reaches about 0.446 g / mL, indicating that the obtained crystal product meets the basic requirements of high-quality amino acids. Figure 3-7 They are optical microscope images of the crystal particles of the products obtained in Examples 1-4 and Comparative Example 1. It can be seen from the images that, compared with Comparative Example 1, the crystal particle size of the products of Examples 1-4 is significantly larger, and the particle size distribution is more uniform, with less crystal aggregation and fewer fine particles.

[0076] In summary, the effect of the pressurization and temperature oscillation method is obvious, and the final product has a larger particle size and better morphology quality. The present invention controls the volatilization of ethanol by pressurization during the dissolution stage to inhibit the initial nucleation of the feed. The pressure is calculated according to the pressure function P(t) = P i -(t / t o ) 2 ×P i It can effectively inhibit the volatilization of ethanol during the crystallization process, thereby avoiding the phenomenon of crystals agglomerating on the stirring blades and the wall of the crystallizer; in the initial stage of crystallization, by adding a certain amount of crystal slurry, a higher supersaturation is consumed to avoid primary burst nucleation and stabilize the crystallization process. During the crystallization process, the temperature is lowered according to the function T1(t)=T 1i -(t / t1)×(T1i -T 1f ), where 0 < t < 90 - 120 min, T2(t) = T 2i -{(t - 120) / t2} 2 ×(T 2i -T 2f ), where 120 < t < 240 min, T3(t) = T 3i -{(t - 240) / t3} 2 ×(T 3i -T 3f ), which is carried out when 240 < t < 450 - 480 min. By using a method combining function-controlled crystallization and temperature oscillation, the function-controlled crystallization provides a stable supersaturation for crystal nucleation and growth, raises the temperature to dissolve the small particle crystals generated by secondary nucleation, and reduces the generation of fine crystal nuclei and crystal aggregation phenomena. The average chord length of the L-proline crystal particle product prepared by the present invention reaches about 120 μm, the bulk density reaches about 0.446 g / mL, the crystals are non-aggregated thick rod-shaped, the particle size is uniform and the distribution is narrow, and the bulk density is relatively high.

[0077] The object of the present invention is to provide a method for preparing L-proline by pressure-controlled temperature oscillation crystallization in a water-ethanol system based on online particle size detection, which can inhibit the high-temperature volatilization of ethanol, solve the problem of explosive nucleation during the feeding and crystallization processes, is simple and easy to operate, and the process is easy to control. The prepared L-proline has the characteristics of narrow particle size distribution, large particle size, and high bulk density.

[0078] The prior art generally adopts the method of cooling crystallization to produce L-proline in a single water solvent or a water-ethanol mixed solvent system. Since L-proline has a very high solubility in water, it is difficult to control the problem of explosive nucleation during the cooling crystallization process. The amount of pure water used is large and it is not easy to recycle, increasing the production cost. While the production cost is reduced in the water-ethanol system, the ethanol solution flashes at high temperature, and the solution concentration in the crystallization tank changes, resulting in explosive nucleation of crystals. The obtained product has poor quality and serious ethanol residue, which is not conducive to the subsequent process treatment.

[0079] The production technology of existing commercially available products usually obtains L-proline through fermentation, adjusts the acidity, decolors, filters, obtains a concentrated solution through an ion exchange column, and then directly cools and crystallizes after decoloring, filtering, and dissolving in alcohol to obtain the L-proline crystal product. The average chord length of existing commercially available products is about 34.77 μm, and the bulk density is 0.332 g / mL. The microscope image of the product is as Figure 8 shown. The crystals are severely broken and aggregated, and the particle size of the product is small. In contrast, the pressure control function and temperature control function discovered by the present invention increase the particle size and bulk density of the crystallization product, and at the same time have the advantages of low production cost, simple and easy to operate process, and easy to control process.

[0080] 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 preparing L-proline by pressure temperature oscillation crystallization in a water-ethanol system, characterized in that The steps include: 1) Add 5-10v% ethanol solution and L-proline raw material into the jacketed crystallization kettle, start pressurization and online particle size detection equipment, heat to 75-80°C and stir until completely dissolved, the solution reaches saturation, and the pressure is calculated according to the function P(t)=P i -(t / t o ) 2 ×P i Control, P(t) is the solution pressure at the cooling time t, t = 0 ~ t0, the total cooling time t0 = 450 ~ 480min, the initial pressure P i =0.5~0.8MPa; 2) Reduce the stirring rate to 100 - 120 r / min, and linearly cool down according to the first cooling function T1(t) = T 1i -(t / t1)×(T 1i -T 1f ), where it is carried out for 0 < t < 90 - 120 min, t = 0 - t1, the first cooling time t1 = 90 - 120 min, the initial temperature T 1i = 75 - 80 °C, T 1f = 60 - 65 °C. After cooling down to 60 - 65 °C, close the pressure valve and open the valve of the crystal slurry tank, and press the L - proline crystal slurry into the crystallization kettle for crystal growth for 10 - 20 min; 3) Keep the stirring rate constant. First, cool down according to the second cooling function \(T2(t)=T\) 2i -\(\{(t - 120) / t2\}\) 2 \(\times(T\) 2i -T 2f ) where \(120\lt t\lt240\) min, the second cooling time \(t2 = 120\) min, the initial temperature \(T\) 2i \(= 60 - 65^{\circ}C\), \(T\) 2f \(= 40 - 45^{\circ}C\); Then cool down according to the third cooling function \(T3(t)=T\) 3i -\(\{(t - 240) / t3\}\) 2 \(\times(T\) 3i -T 3f ) where \(240\lt t\lt450 - 480\) min, the third cooling time \(t3 = 210 - 240\) min, the initial temperature \(T\) 3i \(= 45 - 50^{\circ}C\), \(T\) 3f \(= 10 - 15^{\circ}C\); 4) When the temperature drops to the end point temperature of 10-15°C, grow the crystals, filter, wash and dry to obtain a crystalline product.

2. The method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system according to claim 1, characterized in that: In step 1), the mass of L-proline raw material added per milliliter of ethanol solution is controlled to be 0.4-0.6 g.

3. The method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system according to claim 1, characterized in that: In step 1), the online particle size detection is performed by FBRM technology using primary mode detection; the stirring rate is 180-200 r / min.

4. The method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system according to claim 1, characterized in that: In step 2), the linear cooling is achieved by starting the high and low temperature constant temperature bath cooling program.

5. The method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system according to claim 1, characterized in that: In step 2), the L-proline slurry is obtained by dissolving L-proline in anhydrous ethanol; the amount of L-proline used is 4-6% of the mass of the L-proline raw material, and the particle size is 150-300 μm.

6. The method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system according to claim 1, characterized in that: In step 3), the temperature-controlled crystallization is achieved by starting a high-low temperature constant temperature tank cooling program.

7. The method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system according to claim 1, characterized in that: In step 4), the crystal growing is carried out by controlling the stirring rate to 80-100 r / min, maintaining the temperature to 10-15° C., and the crystal growing time is 15-30 min.

8. The method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system according to claim 1, characterized in that: In step 4), the filtering is to filter under reduced pressure using a Buchner funnel; the washing is to wash the filtered crystals with anhydrous ethanol; and the drying is to dry the washed crystals in an oven.

9. The method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system according to claim 1, characterized in that: The method is realized by a device for preparing L-proline by temperature oscillation crystallization in a water-ethanol system, the device comprising a jacketed crystallization kettle, a stirring paddle, an FBRM probe, and a pressure gauge are arranged on the jacketed crystallization kettle, the stirring paddle is connected to the stirrer, a high and low temperature constant temperature bath is connected to the jacketed crystallization kettle in parallel, the FBRM probe is connected to the Particle Track G400 and a computer, and the pressure gauge is connected to the pressure reducing valve and a compressed air bottle.

10. The method for preparing L-proline by pressurized temperature oscillation crystallization in a water-ethanol system according to claim 9, characterized in that: The FBRM probe is a focused beam total reflection measuring instrument.

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