L-isoleucine spherical crystal as well as preparation method and application thereof

Abstract

The invention discloses a preparation method of an L-isoleucine spherical crystal, which comprises the following steps: adding an additive into an L-isoleucine saturated aqueous solution, keeping the temperature at 75-80 DEG C for 30-60 minutes, and then carrying out reduced pressure evaporative crystallization to obtain the L-isoleucine spherical crystal, the additive comprises any one or a combination of at least two of L-amino acid, substituted or unsubstituted C1-C3 alkyl cellulose and substituted or unsubstituted C1-C3 alkyl cellulose salt; the substituted substituent is hydroxyl and / or carboxyl. According to the preparation method, the L-isoleucine spherical crystal is prepared through cooperation of an additive and reduced pressure evaporation crystallization, and the spherical crystal product is good in sphericity degree, uniform in particle, good in fluidity and high in tap density; the preparation method is simple and easy to control, high in yield, green and environment-friendly, and convenient for industrial large-scale production and application.

Description

Technical Field

[0001] This invention belongs to the field of crystallization technology, specifically relating to spherical L-isoleucine crystals, their preparation methods, and applications. Technical Background L-isoleucine, chemically known as α-amino-β-methylvaleric acid, has the molecular formula C6H10H2O. 13 NO2, with a molecular weight of 131.17 g / mol, is a white crystalline powder or prismatic crystals, odorless, with a slightly bitter taste. It is soluble in water, readily soluble in dilute acid and alkali solutions, and sparingly soluble in water, ether, and other organic solvents. As one of the essential branched-chain amino acids for the human body, L-isoleucine cannot be synthesized autonomously and must be obtained through diet or exogenous supplementation. Its deficiency can lead to physiological dysfunctions such as abnormal muscle metabolism, negative nitrogen balance, fatigue accumulation, and delayed wound repair. This amino acid is used in the pharmaceutical field for liver disease treatment and postoperative nutritional support, in the food industry as a sports nutrition fortifier, and is also widely used in feed additives to improve animal protein utilization.

[0002] L-Isoleucine tends to form thin, flaky crystals during conventional crystallization processes. This morphology easily leads to mother liquor encapsulation, crystal agglomeration, and low filtration efficiency, resulting in fluctuations in product purity and increased drying energy consumption. Furthermore, irregular crystals have low tap density and high hygroscopicity, making them prone to moisture absorption and agglomeration during storage and transportation, affecting the uniformity and stability of downstream applications. In recent years, researchers have explored processes for preparing high-density spherical or cubic crystals by controlling crystallization temperature, solvent gradients, and adding crystal-directing agents to improve their flowability and process adaptability, meeting the stringent requirements of industrial production for material properties.

[0003] CN101747217A discloses a crystallization process for L-isoleucine columnar crystals, specifically involving vacuum concentration of an L-isoleucine solution at 45-65 °C and pH 5.5-6.6, followed by the addition of needle-shaped seed crystals to induce crystallization. This method, by controlling the temperature and crystal growth environment, yields columnar crystals with a purity of 99.8%, effectively reducing the problem of mother liquor encapsulation. However, this process requires precise control of the vacuum level and the amount of seed crystals added, placing high demands on equipment stability and operational precision.

[0004] CN109836347A proposes a cyclic crystallization process for L-isoleucine nitrite, which involves reacting L-isoleucine with nitrite at 40-70℃ and pH=1-2, with the mother liquor recycled, achieving a yield of over 98%. While this method simplifies the process and reduces production costs, it requires the use of chemical reagent-grade nitrite, potentially introducing the risk of nitrite residue, and the acidic conditions place strict requirements on the corrosion resistance of the equipment.

[0005] CN115974709A optimizes the bulk density of feed-grade L-isoleucine by employing ceramic membrane impurity removal, activated carbon decolorization, and fluidized bed drying, ultimately controlling particle size through a 5mm sieve to achieve a bulk density of 0.82~0.85 g / mL. While this process significantly improves transport efficiency, it involves multiple separation and drying steps, resulting in high energy consumption. Furthermore, the membrane filtration flux needs to be maintained above 10 m³ / h, potentially leading to membrane fouling issues during industrial scale-up.

[0006] CN106699587A improves the isoleucine water washing crystallization process by controlling the concentration vacuum degree, temperature, and purified water immersion washing, increasing the yield from less than 50% to 70%, while avoiding the flammability risk of alcohol washing. However, isoleucine partially dissolves during the water washing process, requiring precise control of washing time and water volume to balance purity and yield, and the long drying time may affect production efficiency.

[0007] Therefore, it is essential to develop a novel L-isoleucine. Summary of the Invention

[0008] To overcome the shortcomings of existing methods for preparing L-isoleucine products, this invention provides a novel method for preparing spherical L-isoleucine crystals. This method utilizes additives and vacuum evaporation crystallization to prepare spherical L-isoleucine crystals. These spherical crystals exhibit good sphericity, uniform particle size, good flowability, and high tap density. The preparation method is simple, easy to control, has a high yield, is environmentally friendly, and is suitable for large-scale industrial production.

[0009] To achieve this objective, the technical solution of this invention is as follows: One objective of this invention is to provide a method for preparing L-isoleucine spherical crystals, the method comprising the following steps: Additives were added to a saturated aqueous solution of L-isoleucine, and the solution was kept at 75-80℃ for 30-60 min. Then, the solution was evaporated under reduced pressure to crystallize and obtain spherical crystals of L-isoleucine. The additives include any one or a combination of at least two of L-amino acids, substituted or unsubstituted C1-C3 alkyl cellulose, and substituted or unsubstituted C1-C3 alkyl cellulose salts. The substituents are hydroxyl and / or carboxyl groups.

[0010] In this application, L-isoleucine spherical crystals are prepared by using additives and vacuum evaporation crystallization. The spherical crystals have good sphericity, uniform particle size, good flowability, and high tap density. The preparation method is simple and easy to control, has a high yield, is environmentally friendly, and is suitable for large-scale industrial production.

[0011] In the vacuum evaporation crystallization process, a controllable evaporation rate and lower operating temperature are achieved by reducing the system pressure, significantly reducing energy consumption and improving process efficiency. In the initial stage, under vacuum evaporation control, the concentration of the L-isoleucine solution rises to supersaturation, triggering primary nucleation and forming tiny two-dimensional plate-like crystals. Under this environment, additive molecules selectively adsorb onto the hydrophilic dominant crystal faces of the nascent L-isoleucine plate-like crystals through intermolecular interactions. Under the influence of additive adsorption, secondary nucleation occurs on the dominant crystal faces of these primary L-isoleucine plate-like crystals, roughening the crystal face and promoting the growth of non-crystalline plate-like branches. As growth progresses, the stepwise growth of the dominant crystal faces of the plate-like crystals becomes more pronounced, and the plate-like branches gradually converge towards the center. The continuous stacking of these plate-like structures further increases the convergence of the plate-like branches towards the center, transforming the morphology from a two-dimensional plate-like structure to a three-dimensional petal-like structure. Finally, the continuous growth of the plate-like structure in the central region of the petal drives the spheroidization process, resulting in complete and dense spherulites. The structural evolution process is shown in the attached figure. Figure 1 As shown.

[0012] The core advantage of this synergistic mechanism lies in the following: the additive selectively adsorbs onto the dominant crystal facet of L-isoleucine through intermolecular interactions, altering its growth pattern; while the reduced-pressure evaporation technology significantly reduces energy consumption by lowering the operating temperature, and the controllable evaporation rate both suppresses explosive nucleation and provides a stable kinetic environment for the directional assembly of layered structures. This combination of molecular engineering and process intensification techniques ultimately enables the efficient preparation of high-density L-isoleucine spherical crystals.

[0013] Preferably, the small molecule amino acid additive includes any one or a combination of at least two of L-alanine, L-phenylalanine, L-serine, L-valine, L-lysine, or L-tyrosine.

[0014] In this application, when the additive is L-alanine, L-phenylalanine, L-serine, L-valine, L-lysine or L-tyrosine, the strong hydrophilicity and large molecular volume of the additive are conducive to adsorption on the dominant crystal face of L-isoleucine and roughen the crystal face, generating amorphous branches to form L-isoleucine spherical crystals.

[0015] Preferably, the additive includes any one or a combination of at least two of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, or hydroxypropylmethylcellulose.

[0016] In this application, when the additive is methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose or hydroxypropylmethylcellulose, the strong hydrophilicity of the additive is conducive to adsorption onto the dominant crystal face of L-isoleucine and roughening the crystal face, generating amorphous branches to form L-isoleucine spherical crystals.

[0017] Preferably, the method for preparing the L-isoleucine saturated aqueous solution includes: adding L-isoleucine to water under stirring conditions, dissolving it at 80~85℃, and then cooling it to 70~75℃ to obtain the L-isoleucine saturated aqueous solution.

[0018] Preferably, the stirring rate is 200-400 rpm and the stirring time is 30-60 min.

[0019] Preferably, the cooling rate is 0.5~1.2 ℃ / min.

[0020] Preferably, the amount of the additive added is 0.25 to 2% of the mass of L-isoleucine in the saturated aqueous solution of L-isoleucine.

[0021] Preferably, the vacuum degree of the reduced pressure evaporation crystallization is 0.07~0.085 MPa, and the evaporation temperature is 70~75℃.

[0022] Preferably, the reduced pressure evaporation crystallization is carried out at an evaporation rate of 0.33 to 1% of the initial solution volume per minute, and the evaporation amount is 50 to 80% of the initial solution volume.

[0023] Preferably, in the reduced pressure evaporation crystallization in step (2), the evaporation rate is 0.33~1% of the volume of the L-isoleucine saturated solution per minute, evaporating to 50%~80% of the initial solution volume.

[0024] Preferably, the preparation method further includes sequentially performing solid-liquid separation, washing, and drying on the mixture obtained after vacuum evaporation and crystallization.

[0025] Preferably, the solid-liquid separation method is filtration.

[0026] Preferably, the cleaning solvent is water, and the cleaning is performed 3 to 5 times.

[0027] Preferably, the drying temperature is 50~70 ℃ and the drying time is 12~24 h.

[0028] The second objective of this invention is to prepare L-isoleucine spherical crystals according to the preparation method described in the first objective.

[0029] Preferably, the L-isoleucine spherical crystals have a particle size of 400-1400 µm and a main particle size of 600-1200 µm.

[0030] Preferably, the bulk density of the L-isoleucine spherical crystals is 0.41-0.59 g / cm³. 3 .

[0031] Preferably, the tap density of the L-isoleucine spherical crystals is 0.42-0.62 g / cm³. 3 .

[0032] Preferably, the repose angle of the L-isoleucine spherical crystals is 25.7°-37.8°.

[0033] In this invention, the L-isoleucine crystals exhibit intact morphology, good flowability, high bulk density, non-agglomeration, and low deliquescence, facilitating industrial application. Furthermore, compared to the method for preparing columnar L-isoleucine crystals disclosed in CN101747217A, this invention uses less additive and eliminates the need for seed crystals during crystallization, reducing process steps and operation time while yielding high-quality spherical products. Moreover, compared to the method disclosed in CN115974709A, which employs ceramic membrane impurity removal, activated carbon decolorization, and fluidized bed drying, ultimately controlling particle size through a 5mm sieve to increase bulk density, this method reduces process steps and operation time, and is green, safe, and environmentally friendly.

[0034] The inventiveness of this invention compared to existing technologies lies in: (1) The additives used in this method can be adsorbed on the L-isoleucine crystal surface through hydrophilic interaction and steric hindrance effect, increasing the crystal surface roughness and inducing the formation of amorphous branches, thereby preparing spherical L-isoleucine crystals.

[0035] (2) This method uses evaporation crystallization combined with the addition of additives to effectively create an environment for the nucleation, growth and aggregation of L-isoleucine. The process is simple, the production cycle is short, the efficiency is high and the yield is high.

[0036] (3) This method can produce particles with uniform size, main particle size of 600-1200 µm, and high tap density (0.62 g / cm³) by adding additives. 3 The method produces spherical crystals with good fluidity (angle of repose 25.7°) and a sphericity of 0.894. The spherical products obtained by this method have superior filling properties and stability, and are easy to store and transport.

[0037] (4) This method uses only water as a solvent throughout the entire process, which is green and environmentally friendly, simple, industrializable and economically low. Attached Figure Description

[0038] Figure 1 A scanning electron microscope image of the spherical evolution process of the L-isoleucine product obtained in Example 1; Figure 2 A scanning electron microscope image of the L-isoleucine product obtained in Example 1; Figure 3 The particle size distribution curve of the L-isoleucine product obtained in Example 1 is shown. Figure 4 Comparison of the XRD pattern of the spherulite obtained in Example 1 with that of the pure product; Figure 5 A scanning electron microscope image of the L-isoleucine product obtained in Comparative Example 1; Figure 6 The particle size distribution curve of the L-isoleucine product obtained in Comparative Example 1 is shown. Figure 7 An atomic force microscope image of the L-isoleucine product obtained in Comparative Example 2; Figure 8 An atomic force microscope image of the L-isoleucine product obtained in Comparative Example 1. Detailed Implementation

[0039] Terminology Definitions: In this invention, the term "angle of repose" refers to the angle between the free surface of a powder aggregate formed from granular material (such as crystalline L-isolenic acid in this invention) and the horizontal plane when the free surface is in a state of equilibrium under gravitational force. A smaller angle of repose indicates better powder flowability. The method used in this patent to measure the angle of repose is the injection method. Furthermore, the term "tap density" in this invention refers to the ratio of the mass of powder formed from granular material (such as crystalline L-isolenic acid in this invention) measured when it is placed in a container to its volume (e.g., the actual volume after tapping). The specific tap density can be measured using a powder tap density meter.

[0040] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0041] Example 1: (1) Prepare 300 mL of saturated aqueous solution of L-isoleucine at 75 °C with a stirring rate of 300 rpm; (2) After keeping warm for 30 min, the solution was cooled to 70 ℃ at a cooling rate of 0.5 ℃ / min, 2% L-tyrosine was added, and the mixture was stirred and equilibrated for 60 min. (3) Evaporate 150 mL of solvent at an evaporation rate of 0.416 mL / min. As the evaporation process continues, L-isoleucine crystallizes out continuously, aggregates and grows, and a spherical product is obtained. (4) The above spherical product was vacuum filtered, washed with water, and dried at 60 °C under normal pressure for 12 h to obtain L-isoleucine spherical crystals.

[0042] Electron microscope image of the L-isoleucine spherical crystals prepared in Example 1 is shown below. Figure 2 As shown, the particle size distribution is as follows Figure 3 As shown, through Figure 2 and Figure 3 It is known that L-isoleucine crystals are dense spherical crystals with a main particle size of 600-1200 µm and no fine crystals smaller than 100 μm, which can avoid dust explosion.

[0043] Figure 3 A comparison of the XRD pattern of the spherulite obtained in Example 1 with that of the pure product, through... Figure 4 It can be seen that the additive did not change the crystal structure of L-isoleucine, and the resulting spherulites were dense with no additive residue.

[0044] Example 2: (1) Prepare 300 mL of saturated aqueous solution of L-isoleucine at 80 ℃ with a stirring rate of 300 rpm; (2) After keeping warm for 60 min, the solution was cooled to 70 ℃ at a cooling rate of 0.5 ℃ / min, 2% L-tyrosine was added, and the mixture was stirred and equilibrated for 60 min. (3) Evaporate 150 mL of solvent at an evaporation rate of 0.5 mL / min. As the evaporation process continues, L-isoleucine crystallizes out continuously, aggregates and grows, and a spherical product is obtained. (4) The above spherical product was vacuum filtered, washed with water, and dried at 60 °C under normal pressure for 12 h to obtain L-isoleucine crystals.

[0045] The L-isoleucine crystals prepared in Example 2 were tested using the same testing method as in Example 1. It was found that the L-isoleucine crystals were dense spherulites with a main particle size of 600-1200 µm and no fine crystals with a particle size of less than 100 μm.

[0046] Example 3: (1) Prepare 300 mL of saturated aqueous solution of L-isoleucine at 75 °C with a stirring rate of 300 rpm; (2) After keeping warm for 45 min, the solution was cooled to 70 ℃ at a cooling rate of 0.5 ℃ / min, 2% L-tyrosine was added, and the mixture was stirred and equilibrated for 45 min. (3) Evaporate 150 mL of solvent at an evaporation rate of 0.416 mL / min. As the evaporation process continues, L-isoleucine crystallizes out continuously, aggregates and grows, and a spherical product is obtained. (4) The above spherical product was vacuum filtered, washed with water, and dried at 60 °C under normal pressure for 12 h to obtain L-isoleucine crystals.

[0047] The L-isoleucine crystals prepared in Example 3 were tested using the same testing method as in Example 1. It was found that the L-isoleucine crystals were dense spherulites with a main particle size of 600-1200 µm and no fine crystals with a particle size of less than 100 μm.

[0048] Example 4: (1) Prepare 300 mL of saturated aqueous solution of L-isoleucine at 75 °C with a stirring rate of 300 rpm; (2) After keeping warm for 30 min, the solution was cooled to 70 ℃ at a cooling rate of 0.5 ℃ / min, 2% L-lysine was added, and the mixture was stirred and equilibrated for 60 min. (3) Evaporate 150 mL of solvent at an evaporation rate of 0.416 mL / min. As the evaporation process continues, L-isoleucine crystallizes out continuously and aggregates to grow, resulting in a spherical product. (4) The above spherical product was vacuum filtered and washed with water, and dried at 60 °C under normal pressure for 12 h to obtain L-isoleucine crystals.

[0049] The L-isoleucine crystals prepared in Example 4 were tested using the same testing method as in Example 1. It was found that the L-isoleucine crystals were dense spherulites with a main particle size of 600-1200 µm and no fine crystals with a particle size of less than 100 μm.

[0050] Example 5: (1) Prepare 300 mL of saturated aqueous solution of L-isoleucine at 75 °C with a stirring rate of 300 rpm.

[0051] (2) After keeping warm for 30 min, the solution was cooled to 70 ℃ at a cooling rate of 0.5 ℃ / min, 2% L-phenylalanine was added, and the mixture was stirred and equilibrated for 60 min. (3) Evaporate 150 mL of solvent at an evaporation rate of 0.416 mL / min. As the evaporation process continues, L-isoleucine crystallizes out continuously, aggregates and grows, and a spherical product is obtained. (4) The above spherical product was vacuum filtered, washed with water, and dried at 60 °C under normal pressure for 12 h to obtain L-isoleucine crystals.

[0052] The L-isoleucine crystals prepared in Example 5 were tested using the same testing method as in Example 1. It was found that the L-isoleucine crystals were dense spherulites with a main particle size of 600-1200 µm and no fine crystals with a particle size of less than 100 μm.

[0053] Example 6: (1) Prepare 300 mL of saturated aqueous solution of L-isoleucine at 75 °C with a stirring rate of 300 rpm.

[0054] (2) After keeping the solution warm for 30 min, cool the solution to 70 ℃ at a cooling rate of 0.5 ℃ / min, add 0.5% sodium carboxymethyl cellulose (viscosity specification 1200-1500 mPa·s), and stir to balance for 60 min; (3) Evaporate 150 mL of solvent at an evaporation rate of 0.416 mL / min. As the evaporation process continues, L-isoleucine crystallizes out continuously, aggregates and grows, and a spherical product is obtained. (4) The above spherical product was vacuum filtered, washed with water, and dried at 60 °C under normal pressure for 12 h to obtain L-isoleucine crystals.

[0055] The L-isoleucine crystals prepared in Example 6 were tested using the same testing method as in Example 1. It was found that the L-isoleucine crystals were dense spherulites with a main particle size of 600-1200 µm and no fine crystals with a particle size of less than 100 μm.

[0056] Example 7: (1) Prepare 300 mL of saturated aqueous solution of L-isoleucine at 75 °C with a stirring rate of 300 rpm.

[0057] (2) After keeping the solution warm for 30 min, cool the solution to 70 ℃ at a cooling rate of 0.5 ℃ / min, add 0.5% hydroxypropyl methylcellulose (viscosity specification 150-400 mPa·s), and stir to equilibrate for 60 min; (3) Evaporate 150 mL of solvent at an evaporation rate of 0.416 mL / min. As the evaporation process continues, L-isoleucine crystallizes out continuously, aggregates and grows, and a spherical product is obtained. (4) The above spherical product was vacuum filtered, washed with water, and dried at 60 °C under normal pressure for 12 h to obtain L-isoleucine crystals.

[0058] The L-isoleucine crystals prepared in Example 7 were tested using the same testing method as in Example 1. It was found that the L-isoleucine crystals were dense spherulites with a main particle size of 600-1200 µm and no fine crystals with a particle size of less than 100 μm.

[0059] Example 8: (1) Prepare 300 mL of saturated aqueous solution of L-isoleucine at 75 °C with a stirring rate of 300 rpm.

[0060] (2) After keeping the solution warm for 30 min, cool the solution to 70 ℃ at a cooling rate of 0.5 ℃ / min, add 0.5 % hydroxyethyl cellulose (viscosity specification of 1000-1500 mPa·s), and stir to equilibrate for 60 min; (3) Evaporate 150 mL of solvent at an evaporation rate of 0.416 mL / min. As the evaporation process continues, L-isoleucine crystallizes out continuously, aggregates and grows, and a spherical product is obtained. (4) The above spherical product was vacuum filtered, washed with water, and dried at 60 °C under normal pressure for 12 h to obtain L-isoleucine crystals.

[0061] The L-isoleucine crystals prepared in Example 8 were tested using the same testing method as in Example 1. It was found that the L-isoleucine crystals were dense spherulites with a main particle size of 600-1200 µm and no fine crystals with a particle size of less than 100 μm.

[0062] Comparative Example 1: The difference from Example 1 is that no additives are added, but the other preparation methods are the same as in Example 1.

[0063] The L-isoleucine crystals prepared in Comparative Example 1 were tested using the same testing method as in Example 1. The results showed that the scanning electron microscope image of the obtained L-isoleucine crystals was as follows: Figure 5 As shown, these are plate-like crystals, not spherical crystals; the grain size distribution is as follows. Figure 6 As shown, the main particle size is mainly in the range of 10-200 µm.

[0064] The comparison between Example 1 and Comparative Example 1 shows that the absence of additives during the crystallization process will affect the overall crystallization process, thus hindering the acquisition of high-quality products.

[0065] The crystallization process is monitored using atomic force microscopy, such as Figure 8As shown, it was found that secondary nucleation occurred on the dominant crystal plane of L-isoleucine plate crystals without the addition of additives. The roughness of this crystal plane did not change much, which is not conducive to the growth of non-crystalline plate branches, and thus not conducive to the growth of spherical crystals.

[0066] The product morphology of the products obtained in Example 1 and Comparative Example 1 was tested using a Malvern-3000 particle size analyzer. The test results are shown in Table 1. Table 1 As can be seen from Table 1, the L-isoleucine crystals prepared by the method of this application are spherical crystals with uniform particle size distribution.

[0067] Comparative Example 2: The difference from Example 1 is that the amount of L-tyrosine added is 0.5%, while the other preparation methods are the same as in Example 1.

[0068] The L-isoleucine crystals prepared in Comparative Example 2 were tested using the same testing method as in Example 1. It was found that the obtained L-isoleucine crystals were plate-like crystals rather than spherical crystals; in addition, the average particle size of the product was also low.

[0069] The comparison between Example 1 and Comparative Example 2 shows that the amount of additives added during the crystallization process can affect the overall crystallization process, which is not conducive to obtaining high-quality products.

[0070] The crystallization process is monitored using atomic force microscopy, such as Figure 7 As shown, secondary nucleation occurred on the dominant crystal plane of L-isoleucine plate-like crystals under the action of key additives. The roughness of this crystal plane increased, which was conducive to the growth of non-crystalline plate-like branches, thus facilitating the growth of spherical crystals. However, if the amount of additive was too low, L-isoleucine spherical crystals could not be prepared.

[0071] Comparative Example 3: The difference from Example 1 is that the additive L-tyrosine is replaced with an equal mass of polyacrylamide (viscosity specification MW=80000000), while the rest of the preparation method is the same as in Example 1.

[0072] The L-isoleucine crystals prepared in Comparative Example 2 were tested using the same testing method as in Example 1. It was found that the obtained L-isoleucine crystals were plate-like crystals rather than spherical crystals.

[0073] Comparative Example 4: The difference from Example 1 is that the additive L-tyrosine is replaced with an equal mass of polyvinyl alcohol (viscosity specification 1788 low viscosity type), and the rest of the preparation method is the same as in Example 1.

[0074] The L-isoleucine crystals prepared in Comparative Example 3 were tested using the same testing method as in Example 1. It was found that the obtained L-isoleucine crystals were plate-like crystals rather than spherical crystals.

[0075] The angle of repose and tap density of the products obtained in Examples 1-8, Comparative Examples 1 and 2-3 were tested using the aforementioned method. The measurement results are shown in Table 2. Table 2 As shown in Table 2, L-isoleucine spherical crystals were prepared by combining additives and vacuum evaporation crystallization. These spherical crystals have good sphericity, uniform particle size, good flowability, and high tap density.

[0076] A comparison of Example 1 and Comparative Examples 1-4 shows that when no additives are included or the additives specified in this application are not used, the resulting product is a flaky granule with poor flowability and tap density.

[0077] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A method for preparing L-isoleucine spherical crystals, characterized in that, The preparation method includes: Additives were added to a saturated aqueous solution of L-isoleucine, and the solution was kept at 70-75°C for 30-60 min. Then, the solution was evaporated under reduced pressure to crystallize and obtain spherical crystals of L-isoleucine. The additives include any one or a combination of at least two of L-amino acids, substituted or unsubstituted C1-C3 alkyl cellulose, and substituted or unsubstituted C1-C3 alkyl cellulose salts. The substituents are hydroxyl and / or carboxyl groups.

2. The preparation method according to claim 1, characterized in that, The additives include any one or a combination of at least two of L-alanine, L-phenylalanine, L-serine, L-valine, L-lysine, or L-tyrosine.

3. The preparation method according to claim 1, characterized in that, The additives include any one or a combination of at least two of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, or hydroxypropylmethylcellulose.

4. The preparation method according to claim 1, characterized in that, The method for preparing the L-isoleucine saturated aqueous solution includes: adding L-isoleucine to water under stirring conditions, dissolving it at 80~85℃, and then cooling it to 70~75℃ to obtain an L-isoleucine saturated aqueous solution; Preferably, the stirring rate is 200-400 rpm and the stirring time is 30-60 min; Preferably, the cooling rate is 0.5~1.2℃ / min.

5. The preparation method according to claim 1, characterized in that, The amount of the additive added is 0.25-2% of the mass of L-isoleucine in the saturated aqueous solution of L-isoleucine.

6. The preparation method according to claim 1, characterized in that, The vacuum degree of the reduced pressure evaporation crystallization is 0.07~0.085 MPa, and the evaporation temperature is 70~75℃; Preferably, the reduced pressure evaporation crystallization is carried out at an evaporation rate of 0.33 to 1% of the initial solution volume per minute, and the evaporation amount is 50 to 80% of the initial solution volume.

7. The preparation method according to claim 1, characterized in that, The preparation method further includes sequentially performing solid-liquid separation, washing, and drying on the mixture obtained after vacuum evaporation and crystallization.

8. The preparation method according to claim 7, characterized in that, The solid-liquid separation method is filtration; Preferably, the cleaning solvent is water, and the cleaning is performed 3 to 5 times; Preferably, the drying temperature is 50~70℃ and the drying time is 12~24 h.

9. L-Isoleucine spherical crystals are prepared by the preparation method according to any one of claims 1-8.

10. The L-isoleucine spherical crystals according to claim 9, characterized in that, The L-isoleucine spherical crystals have a particle size of 400-1400 µm, of which the main particle size is 600-1200 µm; The bulk density of the L-isoleucine spherical crystals is 0.41-0.59 g / cm³. 3 The tap density is 0.42-0.62 g / cm³. 3 The angle of repose is 25.7°-37.8°.

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