A crystallization method for preparing spherical glutathione

Abstract

This invention discloses a method for preparing spherical glutathione crystals, comprising the following steps: (1) raw material dissolution; (2) equipment and solvent pretreatment; (3) crystallization: nucleus induction stage, crystal growth stage, and crystallization termination determination; (4) solid-liquid separation and washing; and (5) vacuum drying. This invention achieves efficient preparation of spherical glutathione crystals through the synergistic effect of specific alcohol-liquid ratios, constant-temperature staged stirring, standardized dissolution, and drying processes. The resulting spherical crystals have regular morphology, fundamentally solving the problem of easy aggregation of traditional needle / plate crystals and significantly reducing the difficulty of separation and purification. Simultaneously, the process parameters of this invention are precisely quantified, highly controllable, easy to operate, and compatible with industrial automation equipment, enabling industrial-scale production and improving the processability and application value of glutathione products.

Description

Technical Field

[0001] This invention relates to the field of crystallization engineering technology, and in particular to a crystallization method for preparing spherical glutathione. Background Technology

[0002] Currently, glutathione crystallization processes mostly employ traditional methods, resulting in needle-like or plate-like crystals. These crystals suffer from several significant technical drawbacks, including: poor flowability, leading to equipment clogging or clumping during subsequent processing and transportation; easy crystal aggregation, increasing the difficulty of separation and purification and requiring additional manpower and equipment costs; and irregular morphology resulting in poor product stability, affecting its application in pharmaceuticals, food, and other fields, and failing to meet the crystal processing performance requirements of industrial production.

[0003] In view of the shortcomings of the existing technology, there is an urgent need to develop a glutathione crystallization process that is easy to operate and highly controllable, to overcome the defects of traditional crystal morphology and performance, and to prepare spherical crystals suitable for industrial production. Summary of the Invention

[0004] To address the shortcomings of existing glutathione crystallization processes, the present invention aims to provide a method for preparing spherical glutathione crystals. This invention solves the problems of irregular crystal morphology, poor fluidity, easy aggregation, difficult separation, and insufficient stability associated with traditional processes by employing temperature- and rate-controlled dissolution, precise alcohol-water ratio, multi-parameter stepwise crystallization control, and synergistic optimization of standardized post-processing. This results in the preparation of high-performance spherical glutathione crystals. Furthermore, the process parameters of this invention are precisely quantified, highly controllable, and easy to operate, adaptable to industrial automation equipment, enabling large-scale industrial production and enhancing the processability and application value of glutathione products.

[0005] Specifically, the technical solution adopted in this invention is as follows: A method for preparing spherical glutathione crystals includes the following steps: (1) Raw material dissolution Pharmaceutical-grade glutathione and ultrapure water were selected as raw materials. Ultrapure water was added to a crystallization reactor and heated to 45℃±0.5℃ through the reactor jacket. A paddle stirrer was started, and the stirring speed was 180-220 r / min. Glutathione was slowly added to the constant-temperature ultrapure water at a constant rate of 5 g / min, and stirring was continued for 30 min until the raw materials were completely dissolved, thus obtaining a glutathione aqueous solution. HPLC analysis showed that the raw material solubility rate was 100%. This dissolution method avoids incomplete dissolution due to excessively low temperatures and slight degradation of glutathione due to excessively high temperatures by controlling temperature, speed, and stirring parameters. At the same time, constant feeding rate and stirring parameters prevent the formation of bubbles in the solution, providing a uniform raw material system for subsequent crystallization.

[0006] (2) Equipment and solvent pretreatment All experimental / production equipment, including the crystallization reactor, 0.45μm microporous membrane filter, and vacuum drying oven, were sterilized at 121℃ for 30 minutes, and then cooled to room temperature to ensure that the inner walls of the equipment were free of moisture and impurities, thus avoiding contamination by bacteria and heterogeneous crystal nucleation. 93% chromatographic grade anhydrous ethanol was selected and pre-cooled to 6℃±0.5℃ in a low-temperature storage tank for later use. Pre-cooling the ethanol can avoid sudden temperature changes when mixed with hot glutathione aqueous solution, thus preventing morphological distortion caused by rapid crystal nucleation. (3) Crystallization The crystallization process is the core step, and a multi-parameter step-by-step control strategy is adopted, which is divided into a crystal nucleus induction stage and a crystal growth stage. The temperature, stirring speed, feeding rate and cooling rate are precisely controlled throughout the process to achieve uniform induction of crystal nuclei and spherical growth of crystals. ① Crystal nucleus induction stage: Pre-cooled 93% ethanol is pumped into the crystallization reactor. The temperature is precisely controlled by the reactor jacket to maintain the system temperature at 6℃±0.5℃. The stirrer is started at a speed of 200-250r / min. Glutathione aqueous solution is slowly injected into the ethanol system at a rate of 10mL / min through a constant flow pump. After the injection is completed, the constant temperature stirring is continued until spherical precursor crystal nuclei precipitate. ② Crystal growth stage: When the amount of crystal nuclei precipitated reaches 60% of the total solids in the system, determined by visual inspection and weighing, the stirring speed is gradually increased to 380-400 r / min, and the system temperature is maintained at 6-7℃ for 60 min. The cooling rate is controlled to be ≤0.5℃ / h throughout the process (no additional cooling, only constant temperature maintenance by the jacket). Under these parameters, uniform growth of crystal nuclei can be promoted to form regular spherical crystals, while preventing slow crystal growth due to excessively low stirring speed and crystal breakage due to excessively high stirring speed. Controlling the cooling rate avoids agglomeration caused by a large amount of crystal nuclei precipitation. ③ Determination of crystallization termination: After stirring, take a small amount of crystal liquid for observation. If the crystals settle quickly and the supernatant is clear and transparent, and the glutathione content in the supernatant is ≤0.5% by HPLC, the crystallization reaction is determined to be complete, and the operation is stopped. (4) Solid-liquid separation and washing The crystallization system was transferred to a filter and vacuum filtered under a negative pressure of 0.05 MPa. The filter cake crystals were collected and washed three times with 93% ethanol pre-cooled at 2-4℃. During washing, the crystals were gently stirred at a low speed of 100 r / min for 1 min to ensure uniform washing. Then, the crystals were filtered until no filtrate dripped. Pre-cooled ethanol can avoid partial dissolution of crystals caused by room temperature ethanol. Stepwise washing can effectively remove residual glutathione mother liquor on the crystal surface. After washing, the water content of the crystals is ≤5%. (5) Vacuum drying After washing, the crystals are spread evenly on a drying tray with a thickness of ≤1cm to avoid uneven drying and moisture absorption and agglomeration caused by uneven heating between crystal layers; the tray is placed in a vacuum drying oven to ensure uniform drying; after drying, the crystals are cooled to room temperature to obtain spherical glutathione crystals. This drying process, through the coordinated control of constant temperature, vacuum, and material turning, avoids the oxidation and decomposition of glutathione caused by excessively high temperatures and the prolonged drying time and moisture absorption of crystals caused by excessively low temperatures, thus ensuring the purity and stability of the product.

[0007] In step (1), the purity of the pharmaceutical-grade glutathione product is ≥99.5%, and the conductivity of the ultrapure water at 25℃ is ≤0.1μS / cm.

[0008] In step (1), the stirring paddle is submerged to a depth of 80% to ensure that the solution is mixed evenly without local concentration differences.

[0009] In step (1), the concentration of the glutathione aqueous solution is 20.0% or 25.0%.

[0010] In step (3), a precise weight-to-volume ratio is used according to the different concentrations of the glutathione aqueous solution: When the concentration of glutathione aqueous solution is 25.0%, inject the aqueous solution into pre-cooled 93% ethanol at a weight-to-volume ratio of 1:3.0. When the concentration of glutathione aqueous solution is 20.0%, inject the aqueous solution into pre-cooled 93% ethanol at a weight-to-volume ratio of 1:3.2. This ratio is the core basis for the spherical growth of crystals. If it is deviated from, the crystal morphology will be distorted and it will be impossible to form a regular sphere.

[0011] In the nucleus induction stage of step (3), crystal nuclei are precipitated by stirring a 25.0% concentration aqueous solution for 20 min, with a nucleus particle size of 5-10 μm and an induction rate of ≥98%; crystal nuclei are precipitated by stirring a 20.0% concentration aqueous solution for 30 min, with a nucleus particle size of 4-8 μm and an induction rate of ≥98.5%.

[0012] In step (4), a 0.45μm microporous filter membrane is used for vacuum filtration to avoid the loss of fine crystals and ensure product yield.

[0013] In step (4), the amount of ethanol used for each wash is 200 mL / 500 g of mother liquor.

[0014] In step (5), the drying parameters are a temperature of 45℃±0.5℃ and a vacuum of 0.09MPa, and the material is turned over once every 1 hour.

[0015] In step (5), the crystals prepared with a 25.0% concentration aqueous solution are dried for 4 hours, and the crystals prepared with a 20.0% concentration aqueous solution are dried for 3.5 hours.

[0016] Compared with the prior art, the outstanding effect of the present invention is as follows: (1) By optimizing the raw material ratio, crystallization temperature, stirring conditions and post-processing, the present invention successfully prepared spherical crystals of glutathione. The resulting spherical crystals have regular morphology, which fundamentally solves the problem of easy agglomeration of traditional needle / plate crystals and greatly reduces the difficulty of separation and purification.

[0017] (2) The fluidity of spherical crystals is significantly improved, which effectively avoids equipment blockage and clumping problems in subsequent processing and transportation, and reduces production and logistics costs.

[0018] (3) The separation and purification process is simpler, without the need for additional complex purification steps, reducing production energy consumption and manpower and equipment investment.

[0019] (4) Spherical crystals have higher stability and can better meet the application requirements of glutathione products in the fields of medicine and food.

[0020] (5) The entire process is simple to operate and highly controllable, with no complex equipment or operational requirements, making it suitable for large-scale industrial production. All process parameters can be controlled by industrial automation. In industrial production, a 5L crystallization reactor can be replaced with a 50L-1000L intelligent temperature-controlled crystallization reactor, equipped with an industrial-grade constant flow pump, frequency conversion stirring system, continuous vacuum filtration equipment, and fully automatic vacuum drying oven to achieve continuous production of raw material dissolution, crystallization, separation, and drying. At the same time, the amount of raw materials and process parameters can be scaled up proportionally according to the production scale without additional adjustment of the core process. The production efficiency is high, the unit product cost is low, and it is suitable for large-scale industrial production of glutathione spherical crystals.

[0021] (6) The spherical crystals of glutathione prepared by the present invention can be widely used in pharmaceutical preparations (such as glutathione for injection, glutathione tablets), food additives (such as antioxidants, nutritional fortifiers) and other fields. The products have excellent uniformity and stability, and have extremely high industrial application value and market prospects.

[0022] The crystallization method for preparing spherical glutathione according to the present invention will be further described below with reference to the accompanying drawings and specific embodiments. Attached Figure Description

[0023] Figure 1 The image shows a scanning electron microscope (SEM) image of the spherical glutathione crystals prepared in Example 1.

[0024] Figure 2 The image shows a scanning electron microscope (SEM) image of the spherical glutathione crystals prepared in Example 2.

[0025] Figure 3 Scanning electron microscope image of needle-like glutathione crystals prepared by traditional process.

[0026] Figure 4 The XRD pattern of glutathione prepared in Example 1. Detailed Implementation

[0027] The experimental materials used in the following examples and comparative examples are: glutathione finished product (purity 99.6%, pharmaceutical grade); ultrapure water (conductivity 0.08 μS / cm, 25℃); 93% ethanol (chromatographic grade); cold ethanol (2-4℃, 93% volume fraction).

[0028] Experimental equipment used: 5L intelligent temperature-controlled crystallization reactor (accuracy ±0.5℃, with frequency conversion stirring system); 0.45μm microporous membrane filter; vacuum drying oven (temperature control accuracy ±0.5℃, vacuum degree 0.08-0.1MPa); laser particle size analyzer; scanning electron microscope; powder flowability tester; high performance liquid chromatograph (HPLC); electronic analytical balance (accuracy 0.0001g); X-ray powder diffractometer (XRD); dynamic vapor adsorption analyzer (DVS); Karl Fischer moisture analyzer; dissolution tester; ultraviolet-visible spectrophotometer; constant temperature and humidity chamber; centrifuge; powder density meter.

[0029] Example 1: Preparation of spherical crystals from a 25.0% glutathione aqueous solution (1) Raw material dissolution: Take 375.000g of ultrapure water and add it to a 5L crystallization reactor. Heat it to 45℃±0.5℃ and start the paddle stirring (200r / min, immersion depth 80%). Accurately weigh 125.000g of glutathione product and add it at a rate of 5g / min. Continue stirring for 30min until completely dissolved to obtain a 25.0% (w / w) glutathione aqueous solution with a total mass of 500.000g. The dissolution rate was 100% as detected by HPLC.

[0030] (2) Equipment and solvent pretreatment: The equipment was sterilized at 121℃ for 30 min and then cooled; 1500 mL of 93% ethanol was pre-cooled to 6℃±0.5℃ and kept for later use.

[0031] (3) Crystallization: Pre-cooled ethanol was pumped into the reactor and the temperature was controlled at 6℃±0.1℃. The mixture was stirred at 250r / min. Glutathione aqueous solution was injected at a rate of 10mL / min and stirred for 20min to precipitate crystal nuclei (particle size 5-10μm, induction rate 98.2%). When the amount of crystal nuclei precipitated reached 60%, the stirring speed was increased to 380r / min and the mixture was stirred at a constant temperature of 6-7℃ for 60min. The cooling rate was 0.5℃ / h. HPLC analysis showed that the glutathione content in the supernatant was 0.48%, indicating complete crystallization.

[0032] (4) Solid-liquid separation and washing: 0.05MPa vacuum filtration, and 200mL of 93% ethanol at 2-4℃ were used to wash the crystals three times. The water content of the crystals after washing was 4.8%.

[0033] (5) Vacuum drying: The crystals are laid flat with a thickness of 0.8cm, and vacuum dried at 45℃±0.5℃ and 0.09MPa for 4h. The material is turned over once every 1h and cooled to room temperature to obtain the finished product.

[0034] (6) Complete test data: The finished product weighs 118.25g, with a yield of 94.60%. The crystal morphology is regular spherical, without needle-like / plate-like crystals. The crystal nucleus size is 7.5μm, D50=8.2μm, D90=15.8μm, and D90 / D50=1.93. The angle of repose is 28.5° (excellent flowability), the agglomeration rate is 1.2%, and the loose packing density is 0.62g / cm³. 3 Tap density: 0.78 g / cm³ 3 Compression ratio 20.5%; crystal purity 98.6% (matching standard crystal form); moisture absorption 1.8% at RH 75%; purity 99.75%; moisture content 0.42%; accelerated test 30-day content change rate 0.3%; after 90 days of stockpiling, angle of repose 30.1°; agglomeration rate 1.6% (increase of 0.4%); dissolution rate T90 = 12.5 min.

[0035] Example 2: Preparation of spherical crystals from a 20.0% glutathione aqueous solution (1) Raw material dissolution: Take 400.000g of ultrapure water and add it to a 5L crystallization reactor. Heat it to 45℃±0.5℃ and start the paddle stirring (200r / min, immersion depth 80%). Accurately weigh 100.000g of glutathione product and add it at a rate of 5g / min. Continue stirring for 30min until completely dissolved to obtain a 20.0% (w / w) glutathione aqueous solution with a total mass of 500.000g. The dissolution rate was 100% as detected by HPLC.

[0036] (2) Equipment and solvent pretreatment: Same as in Example 1; take 1600mL of 93% ethanol and precool it to 6℃±0.5℃ for later use.

[0037] (3) Crystallization: Pre-cooled ethanol was pumped into the reactor and the temperature was controlled at 6℃±0.5℃. The mixture was stirred at 250r / min. Glutathione aqueous solution was injected at a rate of 10mL / min and stirred for 30min to precipitate crystal nuclei (particle size 4-8μm, induction rate 98.6%). When the amount of crystal nuclei precipitated reached 60%, the stirring speed was increased to 400r / min and the mixture was stirred at a constant temperature of 6-7℃ for 60min. The cooling rate was 0.5℃ / h. HPLC analysis showed that the glutathione content in the supernatant was 0.39%, indicating complete crystallization.

[0038] (4) Solid-liquid separation and washing: Same as in Example 1, the water content of the crystals after washing is 4.2%.

[0039] (5) Vacuum drying: The crystals are laid flat with a thickness of 0.8cm, and vacuum dried at 45℃±0.5℃ and 0.09MPa for 3.5h. The material is turned over once every 1h and cooled to room temperature to obtain the finished product.

[0040] (6) Complete test data: The finished product weighs 97.80g, with a yield of 97.80%. The crystal morphology is regular spherical, without needle-like / plate-like crystals. The crystal nucleus size is 6.1μm, D50=7.3μm, D90=13.8μm, and D90 / D50=1.89. The angle of repose is 27.2° (excellent flowability), the agglomeration rate is 0.9%, and the loose packing density is 0.65g / cm³. 3 Tap density: 0.82 g / cm³ 3 Compression ratio 20.7%; crystal purity 99.1% (matching standard crystal form); moisture absorption 1.5% at RH 75%; purity 99.82%; moisture content 0.38%; accelerated test 30-day content change rate 0.25%; after 90 days of stockpiling, angle of repose 29.8°; agglomeration rate 1.3% (increase of 0.4%); dissolution rate T90 = 11.8 min.

[0041] Comparative example of glutathione crystal preparation using traditional crystallization processes Using a traditional room-temperature natural crystallization process, the same batch of glutathione product was prepared into a 25.0% aqueous solution. After being dissolved by stirring at room temperature, it was directly allowed to crystallize at room temperature for 48 hours. After undergoing the same separation, washing, and drying processes, crystals were obtained and subjected to the same tests. The key test data are as follows: The crystal morphology is needle-like, with irregular crystal nucleus size (10-30 μm), D90 / D50=3.85; angle of repose 45.2° (poor fluidity); agglomeration rate 8.5%; compressibility 38.6%; moisture absorption at RH 75% 4.2%; purity 99.21%; accelerated reaction 30-day content change rate 1.2%; dissolution rate T90=28.6 min; crystallization yield 82.5%.

[0042] Experimental data verification and analysis 1. Morphology and Powder Properties: The spherical glutathione prepared in Examples 1 and 2 has a uniform particle size distribution (D90 / D50≤1.93), an angle of repose of <30°, an agglomeration rate of ≤1.2%, and a compressibility of <21%, which is far superior to the needle-like crystals of the comparative example, and solves the core problems of poor fluidity and easy agglomeration of traditional crystals.

[0043] 2. Purity and impurity control: The purity of the products in the examples is ≥99.75%, which is better than that of the comparative examples and meets the purity requirements of the pharmaceutical and food industries, proving that the separation and purification effect of this process is superior.

[0044] 3. Stability: The accelerated test of the product in the example showed a content change rate of ≤0.3% after 30 days, no significant performance degradation after 90 days of stockpiling, and a moisture absorption of <2% at 75% RH. Compared with the comparative example, the stability was greatly improved, which improved the product's shelf life and application adaptability.

[0045] 4. Application performance: The dissolution rate T90 of the product in the example is ≤12.5 min, which is much faster than that of the comparative example. It is more suitable for the rapid dissolution requirements of pharmaceutical preparations. The antioxidant activity retention rate is high, which ensures its functional effectiveness in the food and pharmaceutical fields.

[0046] 5. Process yield: The yields of Examples 1 and 2 reached 94.60% and 97.80% respectively, which were significantly improved compared with the 82.5% of the comparative example. In addition, the raw material dissolution rate was 100%, the crystal nucleus induction rate was ≥98.2%, and the glutathione content in the supernatant was ≤0.48% during the process, which proved that the material utilization rate of this process is higher and more suitable for industrial production.

[0047] In summary, the glutathione spherical crystals prepared by this invention exhibit excellent performance in all detection indicators, demonstrating significant performance advantages compared to traditional crystallization processes. Furthermore, the process parameters are controllable, the detection system is comprehensive, and industrial-scale production can be achieved.

[0048] Scanning electron micrographs of the glutathione spherical crystals prepared in Examples 1 and 2 are shown below. Figure 1 , 2 As shown, it can be clearly observed that the crystals prepared by this invention are regular spherical with uniform particle size distribution and no obvious agglomeration.

[0049] Figure 3 The crystals obtained by traditional processes are irregular mixed morphologies of needle-like and plate-like shapes, with large differences in the aspect ratio of the crystals. The length of needle-like crystals can reach more than 50 μm, while the thickness of plate-like crystals is uneven and the edges are irregular. At the same time, there is a serious crystal agglomeration phenomenon, with needle-like and plate-like crystals intertwined and stacked to form aggregates of different sizes, with aggregate particle sizes reaching hundreds of micrometers.

[0050] Figure 4 A series of sharp, symmetrical, and high-intensity characteristic diffraction peaks can be observed, with no impurity peaks or broadened peaks, indicating that the spherical crystals prepared by this invention have a pure crystal structure, high crystallinity, complete crystal form, and no amorphous regions. The position and intensity of the characteristic diffraction peaks are highly reproducible.

[0051] In summary, the key to the crystallization method of this invention lies in: (1) The precise weight-volume ratio of glutathione aqueous solution to 93% ethanol: 25.0% glutathione aqueous solution corresponds to 1:3.0 (w:v), 20.0% glutathione aqueous solution corresponds to 1:3.2 (w:v), and ethanol needs to be pre-cooled to 6℃±0.5℃. This ratio is the core basis for the growth of crystal spherical shape. If it is deviated, the crystal morphology will be distorted and it will be impossible to form a regular spherical shape.

[0052] (2) Multi-parameter coordinated control of the crystallization process: constant temperature control of 6-7℃ (accuracy ±0.5℃), staged stirring speed adjustment of 200-250r / min during the nucleus induction period and 380-400r / min during the crystal growth period, and cooling rate of ≤0.5℃ / h. The three parameters work together to achieve uniform nucleus induction and spherical crystal growth. Any deviation of any parameter will lead to crystal agglomeration, breakage or irregular shape.

[0053] (3) Standardized temperature and rate controlled dissolution process: constant temperature water addition at 45℃±0.5℃, feeding rate of 5g / min, and stirring at 180-220r / min to ensure 100% dissolution of glutathione without degradation, providing a uniform raw material system for subsequent crystallization.

[0054] (4) Vacuum drying process at 45℃±0.5℃ and 0.09MPa: Combined with the operation of turning the material once every 1 hour and spreading the material with a thickness of ≤1cm, the crystals are dried evenly, avoiding oxidation decomposition and moisture absorption and agglomeration; at the same time, the drying time is set according to the concentration of the aqueous solution to ensure the drying effect while improving production efficiency.

[0055] (5) Stepwise washing process of 93% ethanol pre-cooled at 2-4℃: wash 3 times, each time 200mL / 500g mother liquor, to remove residual mother liquor while avoiding crystal dissolution loss, and to ensure high product yield and high purity.

[0056] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. They should not be construed as limitations on the present invention. Various modifications and improvements to the technical solutions of the present invention made by those skilled in the art without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for preparing spherical glutathione crystals, characterized in that, Includes the following steps: (1) Dissolving raw materials Pharmaceutical-grade glutathione and ultrapure water were selected as raw materials. Ultrapure water was added to a crystallization reactor and heated to 45℃±0.5℃ through the reactor jacket. A paddle stirrer was started, and the stirring speed was 180-220 r / min. Glutathione was slowly added to the constant-temperature ultrapure water at a constant rate of 5 g / min, and stirring was continued for 30 min until the raw materials were completely dissolved, thus obtaining a glutathione aqueous solution. HPLC analysis showed that the raw material solubility rate was 100%. (2) Equipment and solvent pretreatment All production equipment was sterilized at 121℃ for 30 minutes, and then cooled to room temperature to ensure that the inner walls of the equipment were free of moisture and impurities, thus avoiding contamination by bacteria and heterogeneous crystal nucleation. 93% chromatographic grade anhydrous ethanol was selected and pre-cooled to 6℃±0.5℃ in a low-temperature storage tank for later use. (3) Crystallization ① Crystal nucleus induction stage: Pre-cooled 93% ethanol is pumped into the crystallization reactor. The temperature is precisely controlled by the reactor jacket to maintain the system temperature at 6℃±0.5℃. The stirrer is started at a speed of 200-250r / min. Glutathione aqueous solution is slowly injected into the ethanol system at a rate of 10mL / min through a constant flow pump. After the injection is completed, the constant temperature stirring is continued until spherical precursor crystal nuclei precipitate. ② Crystal growth stage: When the amount of crystal nuclei precipitated reaches 60% of the total solids in the system by visual inspection and weighing, the stirring speed is increased stepwise to 380-400 r / min, and the system temperature is maintained at 6-7℃ for 60 min. The cooling rate is controlled to be ≤0.5℃ / h throughout the process. ③ Determination of crystallization termination: After stirring, take a small amount of crystal liquid for observation. If the crystals settle quickly and the supernatant is clear and transparent, and the glutathione content in the supernatant is ≤0.5% by HPLC, the crystallization reaction is determined to be complete, and the operation is stopped. (4) Solid-liquid separation and washing The crystallization system was transferred to a filter and vacuum filtered under a negative pressure of 0.05 MPa. The filter cake crystals were collected and washed three times with 93% ethanol pre-cooled at 2-4℃. During washing, the crystals were gently stirred at a low speed of 100 r / min for 1 min to ensure uniform washing. Then, the crystals were filtered until no filtrate dripped. The water content of the washed crystals was ≤5%. (5) Vacuum drying The washed crystals were spread evenly on a drying tray with a thickness of ≤1cm. The tray was then placed in a vacuum drying oven to ensure uniform drying. After drying, the crystals were cooled to room temperature to obtain spherical glutathione crystals.

2. The method for preparing spherical glutathione crystallization according to claim 1, characterized in that: In step (1), the purity of the pharmaceutical-grade glutathione product is ≥99.5%, and the conductivity of the ultrapure water at 25℃ is ≤0.1μS / cm.

3. The method for preparing spherical glutathione crystallization according to claim 1, characterized in that: In step (1), the stirring paddle is submerged to a depth of 80% to ensure that the solution is mixed evenly without local concentration differences.

4. The method for preparing spherical glutathione crystallization according to claim 1, characterized in that: In step (1), the concentration of the glutathione aqueous solution is 20.0% or 25.0%.

5. The method for preparing spherical glutathione crystallization according to claim 4, characterized in that: In step (3), when the concentration of the glutathione aqueous solution is 25.0%, the aqueous solution is injected into pre-cooled 93% ethanol at a weight-to-volume ratio of 1:3.

0. When the concentration of glutathione aqueous solution is 20.0%, the aqueous solution is injected into pre-cooled 93% ethanol at a weight-to-volume ratio of 1:3.

2.

6. The method for preparing spherical glutathione crystallization according to claim 5, characterized in that: In the nucleus induction stage of step (3), crystal nuclei are precipitated by stirring a 25.0% concentration aqueous solution for 20 min, with a nucleus particle size of 5-10 μm and an induction rate of ≥98%; crystal nuclei are precipitated by stirring a 20.0% concentration aqueous solution for 30 min, with a nucleus particle size of 4-8 μm and an induction rate of ≥98.5%.

7. The method for preparing spherical glutathione crystallization according to claim 1, characterized in that: In step (4), a 0.45μm microporous filter membrane is used for vacuum filtration.

8. The method for preparing spherical glutathione crystallization according to claim 1, characterized in that: In step (4), the amount of ethanol used for each wash is 200 mL / 500 g of mother liquor.

9. The method for preparing spherical glutathione crystallization according to claim 1, characterized in that: In step (5), the drying parameters are a temperature of 45℃±0.5℃ and a vacuum of 0.09MPa, and the material is turned over once every 1 hour.

10. The method for preparing spherical glutathione crystallization according to claim 1, characterized in that: In step (5), the crystals prepared with a 25.0% concentration aqueous solution are dried for 4 hours, and the crystals prepared with a 20.0% concentration aqueous solution are dried for 3.5 hours.

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