A method for purifying and crystallizing L-histidine
A membrane filtration and controlled crystallization process addresses yield and purity issues in L-histidine production, achieving high purity and stable crystal form without organic solvents, suitable for pharmaceutical use.
Patent Information
- Application Number
- CN202211482752.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-11-24
- Publication Date
- 2024-12-27
- Estimated Expiration
- 2042-11-24
AI Technical Summary
Current methods for producing pharmaceutical-grade L-histidine face challenges such as low yield, high wastewater generation, impurity removal inefficiencies, and the use of organic solvents, which are environmentally unfriendly and difficult to control, leading to unsuitable crystal forms and low purity.
A method involving pH adjustment, membrane filtration, addition of specific salts and acids, decolorization with activated carbon and medicinal charcoal, and controlled crystallization to achieve high purity and stable crystal form L-histidine, using inorganic and organic membranes to filter out impurities without organic solvents.
The method achieves high purity L-histidine with ≥99.0% light transmittance and stable crystal form A, reducing wastewater and operational complexity, meeting pharmaceutical standards with improved yield and environmental friendliness.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of bioengineering fermentation, and specifically relates to a method for purifying and crystallizing L-histidine. Background Art
[0002] L-histidine, also known as α-amino-β-imidazolyl propionic acid, is a basic amino acid containing an imidazole nucleus in its molecule. It is an important natural amino acid. Its solid state characteristics are colorless or white crystalline powder. It is an important amino acid API and is widely used in food, health care products and pharmaceuticals. In medical applications, it is the main component of amino acid infusion and comprehensive amino acid preparations. It is used in medicine to treat gastric ulcers, anemia, allergies, etc.
[0003] At present, the production methods of L-histidine in China mainly include chemical synthesis, protein hydrolysis and direct fermentation. The first method is to produce histidine by chemical synthesis, which is easy to produce a racemic mixture, and the process is complicated, and its product quality is difficult to meet the quality requirements of pharmaceutical-grade APIs. The second method is protein hydrolysis, which mainly uses pig blood powder or pig hair as raw materials, and is separated and refined by acid hydrolysis. Since animal-derived materials are used as raw materials, the impurities used to prepare pharmaceutical-grade APIs are complex and there is a risk of introducing viruses. Moreover, the raw materials of this method are not easy to obtain and the quality is difficult to control. With the improvement of the quality requirements of pharmaceutical APIs, this method is not suitable for pharmaceutical-grade requirements. The third method is direct fermentation, which is prepared by microbial fermentation and extraction and purification. The risk of introducing viruses is controllable, the quality is controllable, and it is suitable for preparing pharmaceutical APIs. However, the current application of fermentation to produce L-histidine is less. Due to the low content of histidine in the fermentation broth and the presence of other amino acid impurities, ion exchange resins are generally used for separation. The disadvantage of this process is that the amount of wastewater is large, and large-scale production is not environmentally friendly. The quality standard of pharmaceutical-grade L-histidine has a requirement for light transmittance. The current process requires multiple re-refining to obtain a qualified light transmittance, which will result in a too low yield in the production process. At the same time, pharmaceutical-grade L-histidine has a crystal form requirement. According to current literature reports, an organic solvent must be added to obtain a single stable crystal form. However, pharmaceutical-grade APIs have strict limits on organic solvents, and adding organic solvents for crystallization is not the best choice in drug production.
[0004] Chinese patent application CN114133354A discloses an industrial preparation method for L-histidine, comprising the following steps: step 1, adding L-histidine hydrochloride to purified water, stirring and dissolving at room temperature, and then adjusting the pH of the solution to neutral with alkali solution to prepare a salt solution of L-histidine for standby use; step 2, electrodialysis treatment of the salt solution of L-histidine with an electrodialysis desalting water tank until the conductivity of the desalted solution is less than or equal to 1000ms / cm, stopping the electrodialysis, and obtaining an L-histidine aqueous solution; during the electrodialysis treatment, controlling the pH of the desalted solution to be neutral; step 3, condensing the desalted L-histidine aqueous solution at high temperature and reduced pressure to 0.25-0.3 times the original volume, adding a composite organic solvent to the concentrated solution, and then cooling and crystallizing, centrifugal filtering, and drying under reduced pressure to obtain L-histidine. This method uses a composite organic solvent, which is difficult to purify, difficult to control the process, and unfriendly to the production environment. Summary of the invention
[0005] In view of the above technical defects, the present invention provides a method for purifying and crystallizing L-histidine with high purity, light transmittance ≥ 99.0% and stable crystal form.
[0006] To solve the above technical problems, the technical solution provided by the present invention is: a method for purifying and crystallizing L-histidine, the steps are: S1: pre-treating the histidine solution, adjusting the pH to 6.5-7.5 with acid, first filtering the microfiltrate with an inorganic membrane to obtain a microfiltrate, and then filtering the microfiltrate with an organic membrane to obtain a nanofiltrate, and the filtration temperature is controlled below 90°C; the filtration pore size of the inorganic membrane is 10nm-200nm; the pore size of the organic membrane is 100-200 Daltons;
[0007] S2: adding an acid or salt solution to the filtrate of step S1, heating to 60-80°C, concentrating under vacuum until the L-histidine content in the filtrate of step S1 is 20-35%, stopping the concentration, cooling and precipitating a solid to obtain a crude salt; the amount of the acid added is 1.0-1.2 of the equivalent of histidine; the amount of the salt solution added is 5-25% by weight of the L-histidine;
[0008] S3: Take the crude salt product of step S2, add pure water and heat to 60-90°C until it is completely dissolved, add activated carbon for decolorization and filter, collect the decolorized solution, add salt solution to adjust the pH to 7.4-7.7, add a crystalline antioxidant, stir the decolorized solution and cool it down for crystallization, the cooling rate is 10-20°C / h, cool it down to 2-15°C, separate and obtain the secondary crude L-histidine, the amount of pure water added is 8-12 times the weight of the secondary crude L-histidine; the amount of activated carbon added is 5-12% of the weight of the secondary crude L-histidine;
[0009] S4: taking the L-histidine secondary crude product of step S3, adding pure water and heating at 70-85° C. until completely dissolved, adding medicinal charcoal for decolorization, filtering while hot, collecting the decolorized liquid, stirring, cooling and crystallizing, separating and drying to obtain the L-histidine finished product; the amount of pure water added is 8-12 times the weight of the L-histidine secondary crude product; the amount of medicinal charcoal for decolorization added is 2-6% of the weight of the L-histidine secondary crude product.
[0010] Further: In the above-mentioned method for purifying and crystallizing L-histidine, the inorganic membrane in step S1 is a ceramic membrane or a silicon carbide membrane, and the filtration pore size specification is 20nm; the organic membrane in step S1 is a polyamide nanofiltration membrane, and the specification is 150 or 200 Daltons. The nanofiltration membrane is an organic membrane, such as polyamide, polyethersulfone (PES), polytetrafluoroethylene (PVDF), sulfonated polyethersulfone, etc., and the specification is preferably 200 Daltons. The nanofiltration temperature is room temperature, generally between 20 and 40°C, preferably 30°C. The microfiltrate is nanofiltered to further remove particles, colloids, impurity proteins and high-valent metal ions (Ca2+, Mg2+ and Mn2+, etc.).
[0011] The acid used to adjust the pH in step S1 is at least one of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid. The histidine solution in step S1 is derived from microbial fermentation and needs to be heated to 80° C. for sterilization.
[0012] The acid added in step S2 is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, malic acid, citric acid and organic sulfonic acid; the amount of the acid solution added is 1.05 of the equivalent of histidine. The salt added in step S2 is at least one of ammonium chloride, sodium chloride, potassium chloride, ammonium sulfate and ammonium acetate, and the amount of the salt added is 10% of the weight of L-histidine. The mass concentration is preferably 10%, depending on the solubility of the salt in the solvent.
[0013] The heating and dissolving temperature in the step S3 is 70-75° C. The alkaline solution in the step S3 is one of potassium hydroxide solution, sodium hydroxide solution, and ammonia solution; the acidic solution is one of acetic acid solution, sulfuric acid solution, and hydrochloric acid solution. The antioxidant in the step S3 is one or more of ascorbic acid, uric acid, tea polyphenols, sulfite, or dithionite, and the added amount is 0.1-0.5% of the weight of histidine.
[0014] In step S4, the stirring is performed to cool down, the stirring rate is preferably slow, the cooling rate is 10-20°C / h, and the temperature is cooled to 2-15°C. The drying condition of step S4 is vacuum drying at 70-75°C. The product crystal form in step 4 is type A, and the quality index meets the pharmaceutical standards. The finished product yield in step 4 is 50-66%.
[0015] Compared with the prior art, the present invention solves the problems that the amount of wastewater extracted from L-histidine is large and environmentally unfriendly, the extraction yield is low, the purity is low, and the transmittance is difficult to meet the requirements of pharmaceutical grade. The beneficial effects of the present invention are: the present invention improves the purity of the crude L-histidine by adding a specific salt solution to prepare the crude salt, removes most of the impurities for preparing pharmaceutical grade products, and shortens the production cycle. The method is simple to operate, does not use organic solvents, and greatly reduces the amount of wastewater in the production process, which is suitable for industrial production. At the same time, the method adds a small amount of auxiliary agent during the crystallization process, which can solve the problem that L-histidine is easily oxidized, improve the purity of the crystal form, and obtain a single stable crystal form. Compared with traditional extraction and crystallization techniques, the present invention can obtain L-histidine with high process purity, the transmittance is ≥99.0%, and other indicators meet the pharmaceutical grade standards. At the same time, a single crystal form with high purity and more stability, crystal form A, can be obtained. The method has the advantages of being environmentally friendly, easy to operate, and controllable quality. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1-17 This is a crystal form image of the finished product obtained in Example 1-17 under a microscope;
[0017] Fig.18 This is a crystal diagram of the finished product obtained in the comparative example under a microscope.
[0018] Fig.19 is the spectrum obtained by differential scanning calorimetry (DSC) of Example 1;
[0019] Fig. 20 is the spectrum obtained by differential scanning calorimetry (DSC) of Example 17;
[0020] Fig.21 is the spectrum obtained by differential scanning calorimetry (DSC) of the comparative example; DETAILED DESCRIPTION
[0021] The technical solution of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, any obvious changes made by ordinary technicians in the field without departing from the principles and spirit of the present invention should be considered to be included in the scope of protection of the claims of the present invention.
[0022] The raw material used in the present invention comes from a factory laboratory or production line, and is a histidine solution obtained by synthesis, enzyme engineering conversion or microbial fermentation, and is particularly suitable for extraction and purification of fermentation broth produced by fermentation.
[0023] Example 1:
[0024] S1, 36L of fermentation broth (content of about 3.5%, about 1.3kg) was heated to 80°C, pH was adjusted to 7.0 with concentrated hydrochloric acid, passed through a 20nm ceramic membrane, and the pressure was controlled at 0.25-0.3Mpa. When 30L was filtered out, 30L of pure water was added for washing in batches, and the filtrate and 60L of filtrate washing water were collected as microfiltrate. The microfiltrate was washed with a 200D nanofiltration membrane, and when 5L of nanofiltration was left, it was washed with 40L of pure water each time, and the filtrate and washing filtrate were collected as a total of 100L of nanofiltrate (content of about 1.25%).
[0025] S2, take 2000mL of nanofiltrate (containing about 25g of L-histidine), add 5.0g of potassium chloride (20% of the weight of L-histidine), heat to 70°C and concentrate to 80mL (content about 30%) under vacuum conditions, clarify the solution, cool to 10°C for crystallization, and separate 29g of crude salt.
[0026] S3, take the crude salt, add 250mL pure water and heat to dissolve, adjust the pH to 7.6 with potassium hydroxide, add 2.0g activated carbon, decolorize for 30 minutes, filter while hot, add 0.1g ascorbic acid to the decolorized solution, stir at 75rpm and cool at 15℃ / h in a 500mL reaction bottle to crystallize. When a large amount of crystallization occurs, adjust the stirring speed to 110rpm, continue to cool to 5℃, stand for 2 hours to crystallize, and separate 14g of secondary crude L-histidine with a yield of about 55%.
[0027] S4, take 14g of L-histidine secondary crude product, add 120mL of pure water to dissolve, add 0.7g of medicinal charcoal to decolorize for 20 minutes, add 0.1g of ascorbic acid to the decolorizing solution, cool at a rate of 15°C / h, stir at 75rpm to cool and crystallize, when a large amount of crystallization occurs, adjust the stirring speed to 100rpm, cool the decolorizing solution to 10°C and stir for 2h, separate, and dry in vacuum at 70°C to obtain 8.5g of finished L-histidine with a yield of 60%.
[0028] After testing, the product is a uniform and stable L-histidine A crystal form, with a purity of 99.9% measured by an amino acid analyzer, a transmittance of 99.5% measured by the method of the 2020 edition of the Chinese Pharmacopoeia, a chloride content of less than 0.02%, and no other amino acids were detected. It meets the requirements for pharmaceutical use. This product is L-histidine in a single crystal form A. The typical crystal form under an optical digital microscope is shown in the figure below: Figure 1 The differential scanning calorimeter (DSC) spectrum is shown in Fig.19 As shown, there are no impurity peaks and the crystal form is single.
[0029] Examples 2 to 11:
[0030] S2, take the histidine nanofiltrate obtained by the preparation process of Example 1, take 2000 mL each, add 5.0 g of ammonium chloride, sodium chloride, potassium chloride, ammonium sulfate, potassium sulfate, ammonium acetate, potassium acetate, sodium acetate, ammonium dihydrogen phosphate, and potassium dihydrogen phosphate respectively, concentrate to 80 mL (content 30%) under vacuum conditions at 70°C, cool and crystallize, and separate the crude salt.
[0031] S3, dissolve the above crude salt in 250mL of water, adjust the pH to 7.6 with sodium hydroxide, add 2.0g of carbon for decolorization for 30 minutes, filter while hot to obtain a decolorized solution, add 0.1g of ascorbic acid, and stir at a speed of 15°C / h and 75rpm to cool and crystallize. When a large amount of crystallization occurs, adjust the stirring speed to 110rpm, continue to cool to 5°C, let stand for 2 hours, and separate to obtain a secondary crude L-histidine product.
[0032] S4, dissolving the crude L-histidine in 120 mL of water, and obtaining a finished product after crystallization and purification according to Example 1. The test results of the finished product are shown in Table 1.
[0033] The test results of adding different salts are shown in Table 1 below:
[0034]
[0035]
[0036] The tested products are all uniform and stable L-histidine crystal form A, with a light transmittance of >99.5%, and impurities and various indicators meet the requirements of drug standards. The typical crystal form under an optical digital microscope is shown below: Figure 2-11 Differential scanning calorimeter (DSC) spectrum and Fig.19 The results are similar, indicating that there are no impurity peaks and the crystal form is single.
[0037] Examples 12-16
[0038] S2: Take 2000 mL of histidine nanofiltrate prepared by the preparation process of Example 1, adjust the solution pH to 2.0 with hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and benzenesulfonic acid, concentrate to 30% content under vacuum conditions at 70°C, cool and crystallize to separate the crude salt.
[0039] S3: Dissolve the crude salt in 250 mL, add ammonia water to adjust the pH to 7.6, add carbon to decolorize for 30 minutes, filter while hot to obtain the decolorized solution, and cool and crystallize at a speed of 15°C / h and 75 rpm. When a large amount of crystallization occurs, adjust the stirring speed to 110 rpm, continue to cool to 5°C, let stand for 2 hours, and separate the secondary crude L-histidine.
[0040] S4: Take the L-histidine secondary crude product of step S3, add pure water and heat to 70-85°C until completely dissolved, add medicinal charcoal for decolorization, filter while hot, collect the decolorized liquid, stir, cool and crystallize, separate and dry to obtain the L-histidine finished product. The test results of the finished product are shown in Table 2; the amount of pure water added is 8-12 times the weight of the L-histidine secondary crude product; the amount of medicinal charcoal for decolorization is 2-6% of the weight of the L-histidine secondary crude product.
[0041] Add different acids, the test results are shown in Table 2:
[0042]
[0043] The tested products are all uniform and stable L-histidine crystal form A, with a light transmittance of >99.5%, and impurities and various indicators meet the requirements of drug standards. The typical crystal form under an optical digital microscope is shown below: Figure 12-16 Differential scanning calorimeter (DSC) spectrum and Fig.19 The results are similar, indicating that there are no impurity peaks and the crystal form is single.
[0044] Example 17: Implementation on a large production scale
[0045] S1, fermentation is carried out in a 60m3 fermentation tank to prepare histidine. After the fermentation is completed, the fermentation liquid is heated to 80°C, and the pH is adjusted to 7.2 with concentrated hydrochloric acid. About 50m3 of the fermentation liquid (content of about 3.8%, about 1900kg) is passed through a 20nm silicon carbide membrane, and the filtrate and washing water are combined to obtain 80m3 of microfiltrate, which is passed through a 200D nanofiltration membrane;
[0046] S2, about 140m3 of nanofiltrate and nanofiltration washing water are mixed and concentrated to 13% content at 70°C in vacuum, 190kg of sodium chloride is added, and the mixture is concentrated to 6.5m3 (about 30%), cooled to 5°C, and centrifuged to obtain 2000kg of crude salt.
[0047] S3, take the crude salt, add 12M3 water, heat to completely dissolve, adjust the pH to 7.59 with sodium hydroxide solution, add activated carbon for decolorization for 30 minutes, add 259g of sodium bisulfite, cool the crystallization solution to 10°C at a rate of 10°C / h, keep warm for crystallization for 2h, and centrifuge to obtain 1294kg of secondary crude L-histidine with a yield of 58.5%.
[0048] S4. Take the secondary crude L-histidine, add 10M3 pure water, heat to completely dissolve, add activated carbon for decolorization for 30 minutes, add 200g sodium bisulfite to the decolorized filtrate, stir and cool to 10°C at a speed of 10°C / h, centrifuge and dry to obtain 780kg of finished product with a yield of 60%.
[0049] After testing, the product is a uniform and stable L-histidine A crystal form, with a purity of 99.8% measured by an amino acid analyzer, a transmittance of 99.6% measured by the method of the 2020 edition of the Chinese Pharmacopoeia, chloride less than 0.02%, and no other amino acids were detected. It meets the requirements of the 2020 edition of the Chinese Pharmacopoeia. This product is L-histidine A crystal form, a single crystal form, and a typical crystal form under an optical digital microscope is shown below. Fig.17 The differential scanning calorimeter (DSC) spectrum is shown in Fig. 20 , indicating that there is no impurity peak and the crystal form is single.
[0050] In the above-mentioned embodiments 1-17, the antioxidant in S3 is one or more of ascorbic acid, uric acid, tea polyphenols, sulfite or dithionite, and the amount added is 0.1-0.5% of the weight of histidine. In step S4, the temperature is cooled by stirring at a cooling rate of 10-20°C / h to 2-15°C. The drying temperature in step S4 is 70-75°C vacuum drying.
[0051] All products are uniform and stable crystal form A, with light transmittance >99.5%, and impurities and various indicators meet the requirements of pharmaceutical standards.
[0052] Comparative Example
[0053] Take 2000 mL of the histidine nanofiltrate prepared in Example 1, heat to 70°C and concentrate under vacuum until it becomes turbid at about 200 mL. Continue to concentrate to 80 mL (content of about 30%) and solid precipitate. Stop concentrating, cool to 10°C for crystallization, and separate 25 g of a crude product.
[0054] Take 25 g of crude salt, add 250 mL of pure water and heat to dissolve, adjust the pH to 7.6 with potassium hydroxide, add 2.0 g of activated carbon, decolorize for 30 minutes, filter while hot, add 0.1 g of ascorbic acid to the decolorized solution, stir at 75 rpm and cool at 15 ° C / h in a 500 mL reaction bottle to crystallize. When a large amount of crystallization occurs, adjust the stirring speed to 110 rpm, continue to cool to 5 ° C, let stand for 2 hours to crystallize, and separate 13 g of crude product with a yield of about 52%.
[0055] Take 13g of the crude product, add 120mL of pure water to dissolve, add 0.7g of medicinal charcoal to decolorize for 20 minutes, add 0.1g of ascorbic acid to the decolorizing solution, cool at a rate of 15°C / h, stir at 75rpm to cool and crystallize, when a large amount of crystallization occurs, adjust the stirring speed to 100rpm, cool the decolorizing solution to 10°C and stir for 2h, separate, and dry in a vacuum oven at 70°C to obtain 7.6g of finished L-histidine with a yield of 58.5%.
[0056] The conventional method of preparing histidine, after testing, L-histidine is an amorphous powder with a purity of 97.5% and a transmittance of 93.6%. The other amino acids 2.5% do not meet the requirements for pharmaceutical use. The typical crystal form under an optical digital microscope is shown in the figure below. Fig.18 The differential scanning calorimeter (DSC) spectrum is shown in Fig.21 As shown, there are two L-histidine crystal forms and impurities.
[0057] Obviously, the embodiments of the present invention are only examples for clearly explaining the present invention, and are not intended to limit the implementation methods of the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention shall be included in the protection scope of the claims of the present invention.
Claims
1. A method for purifying and crystallizing L-histidine, comprising the steps of: S1: pretreating the histidine solution, adjusting the pH to 6.5-7.5 with acid, first filtering the solution with an inorganic membrane to obtain a microfiltrate, and then filtering the microfiltrate with an organic membrane to obtain a nanofiltrate, and the filtration temperature is controlled below 90°C; the filtration pore size of the inorganic membrane is 10nm-200nm; the pore size of the organic membrane is 100-200 Daltons; S2: adding an acid or salt solution to the nanofiltrate of step S1, heating to 60-80° C., concentrating under vacuum until the L-histidine content is 20-35%, stopping the concentration, cooling to precipitate a solid, and obtaining a crude salt; the amount of the acid added is 1.0-1.2 of the histidine equivalent; the amount of the salt solution added is 5-25% by weight of the L-histidine; S3: Take the crude salt product of step S2, add pure water and heat to 60-90°C until it is completely dissolved, add activated carbon for decolorization and filter, collect the decolorized solution, add alkaline solution to adjust the pH to 7.4-7.7, add a crystalline antioxidant, stir the decolorized solution and cool it down to crystallize, the cooling rate is 10-20°C / h, cool it down to 2-15°C, separate and obtain the secondary crude L-histidine, the amount of pure water added is 8-12 times the weight of the crude L-histidine salt; the amount of activated carbon added is 5-12% of the weight of the crude L-histidine salt; S4: Take the L-histidine secondary crude product of step S3, add pure water and heat to 70-85°C until completely dissolved, add medicinal charcoal for decolorization, filter while hot, collect the decolorized liquid, stir, cool and crystallize, separate and dry to obtain the L-histidine finished product; the amount of pure water added is 8-12 times the weight of the L-histidine secondary crude product; the amount of medicinal charcoal for decolorization is 2-6% of the weight of the L-histidine secondary crude product: The acid added in step S2 is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and benzenesulfonic acid; the amount of the acid solution added is 1.0 to 1.2 of the histidine equivalent; The salt solution added in step S2 is at least one of ammonium chloride, sodium chloride, potassium chloride, ammonium sulfate, potassium sulfate, ammonium acetate, potassium acetate, ammonium dihydrogen phosphate, and potassium dihydrogen phosphate, and the amount added is 5 to 25% of the weight of L-histidine; The antioxidant in S3 is one or both of ascorbic acid and sodium bisulfite, and the added amount is 0.1-0.5% of the weight of histidine.
2. The method for purifying and crystallizing L-histidine according to claim 1, characterized in that: The inorganic membrane in step S1 is a ceramic membrane or a silicon carbide membrane, and the filtration pore size specification is 20 nm; the organic membrane in step S1 is a polyamide nanofiltration membrane, and the specification is 150 or 200 Daltons.
3. The method for purifying and crystallizing L-histidine according to claim 1, characterized in that: The acid used to adjust the pH in step S1 is at least one of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid.
4. The method for purifying and crystallizing L-histidine according to claim 1, characterized in that: The heating and dissolving temperature in the step S3 is 78-85°C.
5. The method for purifying and crystallizing L-histidine according to claim 1, characterized in that: The alkaline solution in S3 is one of potassium hydroxide solution, sodium hydroxide solution and ammonia water.
6. The method for purifying and crystallizing L-histidine according to claim 1, characterized in that: In step S4, the temperature is cooled by stirring at a rate of 10 to 20°C / h to a temperature of 2 to 15°C.
7. The method for purifying and crystallizing L-histidine according to claim 1, characterized in that: The drying temperature of step S4 is 70-75° C. vacuum drying.