WO2021104432A1 - L-ornithine composite salt and preparation method therefor and application thereof - Google Patents

Abstract

Provided is a preparation method for an L-ornithine composite salt. The preparation method comprises the following steps: (1) taking an L-ornithine salt solution as a raw material to prepare a free L-ornithine solution by means of a bipolar membrane electrodialysis apparatus; (2) enabling the free L-ornithine solution and substance A to be mixed and reacted to obtain an L-ornithine composite salt solution, the substance A being L-Aspartic acid, α-ketoglutaric acid, or R-(+)-lipoic acid; (3) enabling the L-ornithine composite salt solution to be crystallized to obtain the L-ornithine composite salt. The L-ornithine composite salt prepared by using the preparation method has a water content of less than 2%, no by-product generation, and no waste salt, waste water and other pollution, is green and environmentally friendly, and has an appreciable yield.

Description

L-ornithine compound salt and preparation method and application thereof

This application claims the priority of the PCT application PCT/CN2019/121473 whose filing date is November 28, 2019. This application quotes the full text of the aforementioned PCT patent application.

Technical field

The invention relates to a L-ornithine compound salt and a preparation method and application thereof.

Background technique

Amino acid complex salts are generally formed by combining basic amino acid molecules such as ornithine and arginine with acidic amino acid molecules such as aspartic acid and α-ketoglutarate through ionic bonds to form new compounds. Studies have shown that the amino acid complex salt not only has the pharmacological effects of two amino acids, but also can mutually enhance their physiological activities in the human body, and can be better used in the fields of medicine, food and cosmetics. L-ornithine plays an important role in the excretion of ammonia nitrogen in the human body and the detoxification of ammonia poisoning, while the L-ornithine complex salt exhibits different properties from L-ornithine monomer in the physiological metabolism of the human body. It has special pharmaceutical value, such as L-ornithine-L-aspartate, L-ornithine-α-ketoglutarate and L-ornithine-R-(+)-lipoic acid Salt etc.

L-ornithine-L-aspartate is a white or almost white crystal or powder, odorless, and hygroscopic. The chemical name is (S)-2,5-diaminovaleric acid-(S)-2-aminobutyrate), molecular formula: C ₅ H ₁₉ N ₃ O ₆ , molecular weight: 265.27, and its molecular structure is as follows:

L-ornithine-L-aspartate salt (L-ornithine L-aspartate salt, LOLA) is a stable compound prepared by chemical synthesis of L-ornithine and L-aspartate, in the 20th century Developed in Germany in the 1960s, it was included in the German Pharmacopoeia in 1991 and the Chinese Pharmacopoeia in 2015. It was the first clinically used for the treatment of alcoholism and hepatic encephalopathy. With the accumulation of clinical application experience, L-ornithine-L-aspartate has been more widely used in the treatment of liver diseases, for hepatic encephalopathy, drug-induced liver damage, fatty liver, chronic hepatitis, etc. The disease has achieved definite curative effects and has been widely recognized by clinicians.

L-ornithine-α-ketoglutarate is a white or slightly yellow crystal or powder, chemical name is (2s)-2,5-diaminovaleric acid 2-oxoglutaric acid, molecular formula: C ₁₀ H ₁₈ N ₂ O ₇ , molecular weight: 278.26, molecular structure is as follows:

L-ornithine α-ketoglutarate is a good clinical nutrient, which can promote the recovery of surgical trauma patients, improve chronic malnutrition, improve immune function, and promote growth hormone secretion. In biochemical metabolism, L-ornithine and α-ketoglutarate are key intermediate metabolites of higher organisms, which can enhance cell metabolic activity, improve myocardial energy metabolism, accelerate the metabolism of toxic substances such as ammonia and nitrogen in the body, and have a great impact on the liver. Good protection, while promoting the regeneration and repair of liver cells, L-ornithine α-ketoglutarate can improve the body function without obvious adverse reactions. It is used in the treatment of acute poisoning and reducing chronic cyanide poisoning induced Oxidative stress in the brain can reduce alcohol-induced liver cell damage and increase insulin and growth hormone.

At present, the preparation method of L-ornithine compound salt mainly uses L-ornithine salt (L-ornithine hydrochloride or L-ornithine sulfate, etc.) as the starting material, through ion exchange resin method or Free L-ornithine is obtained by the acid binding agent method, and then organic acids such as L-aspartic acid or lipoic acid are added to form a salt.

Chinese Patent Document CN 108840805A uses L-ornithine hydrochloride as the starting material, passes through an ion exchange resin column, and eluates with ammonia water and concentrates under reduced pressure to obtain free ornithine, and then add aspartic acid to form a salt. This method is a traditional ion exchange resin method, which uses ammonia water for elution, which produces a large amount of waste salt and waste water and causes serious pollution.

The Chinese patent document CN 108440318A method takes L-arginine as the starting material, adds hydrochloric acid and lithium hydroxide dropwise, heats the reaction, cools down and concentrates to prepare ornithine hydrochloride, and then add ornithine hydrochloride to The cation exchange resin is eluted with ammonia water and concentrated under reduced pressure to obtain free ornithine, and then aspartic acid is added to form a salt. This technical method uses the traditional ion exchange resin method, the whole process uses a large amount of acid and alkali, the cycle is long, and the pollution is large.

Chinese patent document CN 106699586B takes L-ornithine acetate and L-aspartic acid as starting materials, adds acid binding agent ammonium carbonate to neutralize the acetate of L-ornithine acetate, and finally prepares pure Ornithine aspartate. This method uses the acid binding agent ammonium carbonate, the residual ammonium ion is difficult to remove, and will produce waste salt ammonium acetate.

Chinese Patent Document CN104387364B discloses the application of preparing L-ornithine lipoate in the preparation of drugs for treating hepatic coma caused by liver diseases, wherein free L-ornithine is obtained by ion exchange resin method, and then added Alcohol solution or powder of lipoic acid is precipitated, and then the precipitate is dissolved and recrystallized to obtain composite salt crystals. This method also produces a large amount of waste salt and waste water.

Therefore, the main technical problems in the preparation method of L-ornithine composite salt in the prior art are as follows: 1) The ion exchange resin method requires a large amount of acid and alkali, produces a large amount of waste salt, and waste water, and has great environmental protection pressure; 2) The acid-binding agent method requires a large amount of reagents and produces a large amount of waste salt, and the residual acid-binding agent is difficult to remove.

In addition, the prior art CN 104058981A also discloses the following preparation method, dissolving ornithine salt in water, adjusting the pH value of 8-11 with lye, using electrodialysis to obtain free ornithine, and then using aspart ammonia The acid adjusts the pH value of the solution to 7-9. After concentration, it is directly added to the methanol solution to crystallize, and the product moisture content is as high as 7%. This method requires a large amount of lye to adjust the pH value of the ornithine salt solution, and after obtaining free ornithine, corresponding waste salts will be produced.

Chinese patent document CN102373245B discloses a method for preparing L-ornithine-α-ketoglutarate, which uses immobilized enzyme to convert arginine substrate, and adjusts the pH value with acetic acid. After the conversion is completed, α-ketoglutarate is added Diacid, then add alcohol to crystallize. Among them, the use of acetic acid to adjust the pH will produce a large amount of waste salts, and the use of alcohols to separate urea and L-ornithine-α-ketoglutarate, the amount of organic solvents is large, the pollution is large, and the production cost is high.

Therefore, an environmentally friendly new process is urgently needed to solve the above technical problems.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the defect that the preparation method of L-ornithine composite salt in the prior art produces a large amount of waste salt and waste water, and to provide a L-ornithine composite salt and its preparation method and application , The preparation method of the present invention has no chemical reagent consumption, no by-product generation, and is green and environmentally friendly.

The present invention solves the above technical problems through the following technical solutions:

The present invention provides a preparation method of L-ornithine composite salt, which comprises the following steps:

(1) Using L-ornithine salt solution as raw material, prepare free L-ornithine solution through a bipolar membrane electrodialysis device;

(2) The free L-ornithine solution is mixed and reacted with substance A to obtain L-ornithine complex salt solution; the substance A is L-aspartic acid, α-ketoglutarate or R- (+)-Lipoic acid;

(3) The L-ornithine composite salt solution can be crystallized to obtain the L-ornithine composite salt.

In the present invention, when the substance A is L-aspartic acid, the prepared L-ornithine complex salt is L-ornithine-L-aspartic acid salt.

In the present invention, when the substance A is α-ketoglutarate, the prepared L-ornithine complex salt is L-ornithine-α-ketoglutarate (molar ratio 1:1 ).

In the present invention, when the substance A is R-(+)-lipoic acid, the prepared L-ornithine complex salt is L-ornithine-R-(+)-lipoic acid.

In step (1), the bipolar membrane electrodialysis device may be a conventional bipolar membrane electrodialysis device in the art.

In step (1), the anode membrane used in the bipolar membrane electrodialysis device may be a cation exchange membrane. The cathode membrane used in the bipolar membrane electrodialysis device may be a cation exchange membrane or an anion exchange membrane.

In step (1), the materials of the cathode and anode electrodes used in the bipolar membrane electrodialysis device can be conventional in the art, and are generally corrosion-resistant materials, such as conventional commercially available alloys of Ti, Pt, and Ir.

In step (1), according to common knowledge in the art, the anode chamber and/or the cathode chamber of the bipolar membrane electrodialysis device contain an electrolyte solution, preferably a strong electrolyte solution.

Wherein, the volume concentration of the strong electrolyte solution is preferably 1 to 3%; for example, 1%, 2% or 3%. The type of the strong electrolyte can be an electrolyte that is almost completely ionized in an aqueous solution in the conventional chemical field, preferably sulfuric acid, hydrochloric acid, nitric acid, sodium hydroxide, sodium chloride, sodium sulfate, sodium nitrate, potassium sulfate, and nitric acid. Potassium, potassium sulfide, or ammonium sulfate, for example, sulfuric acid, hydrochloric acid, nitric acid, or sodium chloride.

In step (1), the bipolar membrane electrodialysis device preferably adopts two compartments or three compartments. Wherein, the two compartments are separated by a bipolar membrane and an "anion exchange membrane or cation exchange membrane". The three-compartment compartment is separated by a bipolar membrane, an anion exchange membrane and a cation exchange membrane.

When the two compartments are separated by a bipolar membrane and an anion exchange membrane, the arrangement of the membrane stacks in the bipolar membrane electrodialysis device is preferably: anode electrode-anode chamber-anode membrane-[acid chamber -Anion exchange membrane-alkali chamber-bipolar membrane] _n -acid chamber-cathode membrane-cathode chamber-cathode electrode, where n is the number of repeating units and the value range is an integer between 1-100, such as 100. Among them, the alkali chambers all contain L-ornithine salt solution. The acid chamber contains reverse osmosis water.

When the two compartments are separated by a bipolar membrane and a cation exchange membrane, the arrangement of the membrane stacks in the bipolar membrane electrodialysis device is preferably: anode electrode-anode chamber-anode membrane-[alkali chamber -Bipolar membrane-acid chamber-cation exchange membrane] _n -alkaline chamber-cathode membrane-cathode chamber-cathode electrode, where n is the number of repeating units and the value range is an integer between 1-100, such as 100. Among them, the alkali chamber contains reverse osmosis water. The acid chambers all contain L-ornithine salt solution.

When the bipolar membrane electrodialysis device adopts the three compartments, and the three compartments are separated by a bipolar membrane, an anion exchange membrane and a cation exchange membrane, the membrane stack in the bipolar membrane electrodialysis device The arrangement is preferably: anode electrode-anode chamber-[bipolar membrane-acid chamber-anion exchange membrane-salt chamber-cation exchange membrane-alkali chamber] _n -bipolar membrane-cathode chamber-cathode electrode; where n It is the number of repeating units and the value range is an integer between 1-100, such as 100. Among them, the salt chamber contains L-ornithine salt solution, and both the acid chamber and the alkali chamber contain reverse osmosis water.

In step (1), those skilled in the art should know that in the bipolar membrane electrodialysis device, the compartment between the membrane and the membrane is lined with grids and gaskets corresponding to the flow channel, wherein the membrane can be a cathode membrane , Anion exchange membrane, cation exchange membrane, bipolar membrane and anode membrane; between alkali chamber and alkali chamber, acid chamber and acid chamber, or salt chamber and salt chamber are generally connected in series through the same flow channel.

In step (1), the two ends of the bipolar membrane electrodialysis device generally have a constant voltage direct current.

Wherein, the parameters of the constant voltage direct current are preferably: the voltage is 220V, and the current density is 10 to 700 A/m ² , for example, 200 A/m ² . The current density is more preferably 100-200 A/m ² .

In step (1), according to common sense, in the bipolar membrane electrodialysis device, each compartment (the compartment can be an acid compartment, an alkali compartment, a salt compartment, a cathode compartment, and an anode compartment) contains a circulating pump, and all compartments are activated. The circulating pump makes the materials and liquids circulate between the compartments. After circulating for 10 minutes to eliminate bubbles, set a flow rate of 2000-6000L/h, and adjust the flow rate of each compartment in a small range to make the pressure of each compartment equal . Generally, after the bubbles are eliminated, the constant voltage direct current power supply is started.

In step (1), the type of L-ornithine salt in the L-ornithine salt solution can be conventional in the art, preferably L-ornithine hydrochloride, L-ornithine sulfate , L-ornithine acetate, L-ornithine nitrate, L-ornithine citrate or L-ornithine malate, such as the L-ornithine sulfate, L-ornithine Amino acid hydrochloride or the L-ornithine acetate, more preferably L-ornithine hydrochloride or L-ornithine acetate.

In step (1), the concentration of L-ornithine salt in the L-ornithine salt solution can be conventional in the art, preferably 0.3 to 3 mol/L, such as 0.3 mol/L, 0.5 mol/L , 1.5mol/L or 3mol/L.

In step (1), in the alkali chamber, the L-ornithine salt solution generates L-ornithine cations and corresponding anions during the ionization process, and the corresponding anions pass through the anion exchange membrane and enter the acid chamber , And then combine with the hydrogen ions ionized by water to generate the corresponding acid. The L-ornithine cation combines with the hydroxide ion ionized by water to generate L-ornithine.

In step (1), the corresponding acid is also generated while preparing the free L-ornithine solution.

Wherein, preferably, the amount of the corresponding acid substance is equivalent to the amount of the corresponding anion substance in the L-ornithine salt solution. In the acid chamber, the concentration of the corresponding acid is preferably 0 to 3.0 mol/L, such as 1.05 mol/L, 1.2 mol/L, 1.3 mol/L, 1.36 mol/L, 1.1 mol/L, 1.57mol/L, 2.3mol/L, 2.51mol/L or 1.82mol/L.

In step (1), preferably, the amount of L-ornithine in the free L-ornithine solution is equal to the amount of the L-ornithine cation in the L-ornithine salt solution The amount is comparable. In the free L-ornithine solution, the concentration of free L-ornithine is preferably 0.3-3.1 mol/L, such as 0.3 mol/L, 0.61 mol/L, 0.96 mol/L, 1.0 mol /L, 1.03mol/L, 1.2mol/L, 1.5mol/L, 2.88mol/L or 3.01mol/L.

In step (1), when the bipolar membrane electrodialysis device uses two compartments, and the two compartments are separated by a bipolar membrane and an anion exchange membrane, the reaction is generally controlled by detecting the conductivity and current of the alkali compartment process. Preferably, the reaction in step (1) is stopped when the conductivity of the alkali chamber drops to 0.1-3.0 ms/cm, for example, the reaction in step (1) is stopped when the conductivity is below 3.0 ms/cm.

In step (1), when the bipolar membrane electrodialysis device adopts two compartments, and the two compartments are separated by a bipolar membrane and a cation exchange membrane, the pH value and current of the acid chamber are generally detected. And the conductivity controls the reaction process. Preferably, the reaction in step (1) is stopped when the pH value of the acid chamber no longer decreases and the conductivity no longer changes.

In step (1), when the bipolar membrane electrodialysis device adopts three compartments, and the three compartments are separated by a bipolar membrane, a cation exchange membrane, and an anion exchange membrane, the salt chamber is generally detected The conductivity and current control the reaction process. Preferably, the reaction in step (1) is stopped when the conductivity of the salt chamber drops to 0.1-3.0 ms/cm, for example, the reaction in step (1) is stopped when the conductivity drops below 0.1 ms/cm.

In step (2), the dosage of the substance A can be conventional in the art. Preferably, the molar ratio of the substance A to the L-ornithine in the free L-ornithine solution is 1:1 ~ 1:1.3.

In step (2), when the substance A is L-aspartic acid, the L-aspartic acid can also be used to adjust the pH value of the L-ornithine complex salt solution, and the pH value Preferably it is 6-7. The L-aspartic acid is commercially available, for example, it can be purchased from Japan Ajinomoto.

In step (3), before the crystallization operation step, the L-ornithine composite salt solution is preferably decolorized, filtered and concentrated in sequence.

Wherein, the decolorization operations and steps can be conventional in the art, and the decolorization is generally performed by adding activated carbon. The amount of the activated carbon can be conventional in the art. Preferably, the ratio of the activated carbon to the L-ornithine composite salt is 0.1-10% by weight, such as 0.5% by weight or 1% by weight. The time for the decolorization can be conventional in the art, such as 0 to 2 hours for decolorization, and for example 30 minutes.

Wherein, the filtering method can be conventional in the field, and is generally realized by plate and frame filtering.

Wherein, the operating conditions for the concentration can be conventional in the art, for example, it can be carried out under vacuum conditions.

Wherein, preferably, the concentration of the L-ornithine complex salt in the concentrated solution after concentration is 1.00-3.4 mol/L, for example, 1.00 mol/L, 1.25 mol/L, 2 mol/L, 2.5 mol/L L or 3.4mol/L.

In step (3), the crystallization method can be conventional in the art. For example, the conventional addition method of the eluent in the crystallization process includes forward flow addition or reverse flow addition.

Those skilled in the art know that the positive flow is to gradually add the eluent to the solution, so that the supersaturation is slowly generated. For the present invention, the positive flow addition crystallization process is adopted. With the gradual increase of supersaturation, the oil phase will be generated in the solution first. After a period of time, the oil phase will be transformed into a solid phase on the container wall, which is easy to cause agglomeration. Phenomenon, the final product is hydrate.

Those skilled in the art know that counter-current addition is to add the solution to the eluent to make the solution supersaturate instantaneously, and directly pass the oil phase step to precipitate solid phase crystals, but the crystals produced before the solid phase crystals are precipitated are still There is agglomeration.

In step (3), the crystallization method is preferably carried out as follows: the L-ornithine composite salt solution, the eluent and the seed crystals of the L-ornithine composite salt are mixed.

It is more preferable to proceed as follows: adding the L-ornithine composite salt solution to the mixed solution of "the seed crystal of the L-ornithine composite salt and the eluent".

The inventor found through creative work that on the basis of the prior art counter-current addition process, by adding seed crystals, adding the solution to the mixed solution of "seed crystal + eluent" can not only eliminate the above-mentioned agglomeration phenomenon, but also The crystal shape of the obtained crystal is more uniform and regular, and the moisture content is also lower.

Wherein, preferably, before the seed crystals of the L-ornithine composite salt are mixed with the eluent, the eluent is preheated to 40-60°C, such as 40°C, 50°C, 55°C or 60°C.

Wherein, the adding rate of the L-ornithine composite salt solution can be conventional in the art, for example, 50 L/min.

According to common knowledge in the art, after the seed crystal and the eluent are mixed, the stirring is started.

According to common knowledge in the art, after the L-ornithine composite salt solution is added to the mixed solution, the mixture is kept warm and quickly stirred for 30 minutes, cooled to normal temperature, centrifuged, and dried to obtain the L-ornithine composite salt.

According to common knowledge in the field, the cooling is achieved by using ice brine.

Wherein, the type of the eluent can be conventional in the art, preferably any one of methanol, ethanol, acetone and their aqueous solutions, such as methanol or ethanol.

Wherein, the amount of the eluent can be conventional in the art. Preferably, the mass ratio of the eluent to the L-ornithine complex salt is 3-6:1, for example, 6:1, 3:1, 3.3:1 or 4.5:1.

Wherein, preferably, the amount of the seed crystal of the L-ornithine composite salt accounts for 1 to 4% by weight of the eluent, for example, 1% by weight, 1.5% by weight, 2% by weight or 4% by weight.

The present invention also provides a L-ornithine compound salt, the L-ornithine compound salt is L-ornithine-L-aspartate, L-ornithine-α-ketoglutarate Either one of salt (1:1) and L-ornithine-R-(+)-lipoic acid;

In the powder X-ray diffraction spectrum of the L-ornithine-L-aspartate salt using Cu-Kα as the radiation source, the diffraction angle 2θ=7.263, 8.24, 19.321, 19.844, 21.764, 22.474, 24.075, There are main peaks at 24.573, 27.148, 27.565, 28.877, 31.349, 36.18, 37.809, 38.122, 39.23 and 41.091 degrees. Preferably, the water content of the L-ornithine-L-aspartate salt is less than 2% .

Wherein, the diffraction peak of the crystal form of the L-ornithine-L-aspartate salt is preferably shown in FIG. 7.

Wherein, the total impurity content in the L-ornithine-L-aspartate salt is preferably not more than 0.097%.

The present invention also provides an application of a bipolar membrane electrodialysis device in the preparation of L-ornithine composite salt. During the application process, the raw materials are L-ornithine salt and substance A, and the substance A is L -Aspartic acid, α-ketoglutarate or R-(+)-lipoic acid.

Among them, the type of L-ornithine salt is preferably L-ornithine hydrochloride, L-ornithine sulfate, L-ornithine acetate, L-ornithine nitrate, L-ornithine citrate or L-ornithine malate, such as the L-ornithine sulfate or the L-ornithine acetate.

The bipolar membrane used in the present invention is commercially available in the field.

In the present invention, when the bipolar membrane electrodialysis device adopts two compartments, and the two compartments are separated by a bipolar membrane and an anion exchange membrane, the principle in step (1) is as follows: Pass the L-ornithine salt solution, pass the reverse osmosis water into the acid chamber; pass the strong electrolyte solution into the anode chamber and the cathode chamber of the bipolar membrane electrodialysis device, and start each compartment (acid Chamber, alkali chamber, anode chamber and cathode chamber) to make each material liquid circulate between the corresponding compartments, start the power supply at both ends of the bipolar membrane electrodialysis device, under the action of the electric field, the bipolar The water in the catalytic layer of the membrane is ionized, the generated H ⁺ enters the acid chamber through the cation exchange membrane, OH ^- enters the alkali chamber through the anion exchange membrane, and the anions of the L-ornithine salt in the alkali chamber permeate The anion exchange membrane migrates to the acid chamber and ^{combines with the H +} entering the acid chamber to generate the corresponding acid. The acid chamber obtains an acid solution; the L-ornithine cation remaining in the alkali chamber combines with ^{the OH-entering the alkali chamber to form free} The free L-ornithine solution is obtained in the alkali chamber.

In the present invention, when the bipolar membrane electrodialysis device adopts two compartments, and the two compartments are separated by a bipolar membrane and a cation exchange membrane, the principle in step (1) is as follows: Pass reverse osmosis water, pass the L-ornithine salt solution into the acid chamber; pass the strong electrolyte solution into the anode and cathode chambers of the bipolar membrane electrodialysis device, and start each compartment (acid Chamber, alkali chamber, anode chamber and cathode chamber) to make each material liquid circulate between the corresponding compartments, start the power supply at both ends of the bipolar membrane electrodialysis device, under the action of the electric field, the bipolar The water in the catalytic layer of the membrane is dissociated, the generated H ⁺ enters the acid chamber through the cation exchange membrane, and the OH ^- enters the alkali chamber through the anion exchange membrane. At the same time, the L- of L-ornithine in the acid chamber Ornithine cations migrate through the cation exchange membrane to the alkali compartment, and ^{combine with the OH-} entering the alkali compartment to form free L-ornithine, and free L-ornithine solution is obtained in the alkali compartment; the anions remaining in the acid compartment are ^{Combines with H +} entering the acid chamber to produce an acid solution.

In the present invention, when the bipolar membrane electrodialysis device adopts three compartments, and the three compartments are separated by a bipolar membrane, a cation exchange membrane and an anion exchange membrane, the principle in step (1) is as follows: Pass the L-ornithine salt solution into the salt chamber, and pass reverse osmosis water into both the acid chamber and the alkali chamber; pass the strong electrolyte solution into the anode chamber and the cathode chamber respectively, and start each compartment (salt chamber, acid chamber) , Alkali chamber, anode chamber and cathode chamber) to make each material liquid circulate between the corresponding compartments, start the power supply of the bipolar membrane electrodialysis device, under the action of the electric field, the bipolar membrane The water in the catalytic layer dissociates, the generated H ⁺ enters the acid chamber through the cation exchange membrane, OH ^- enters the alkali chamber through the anion exchange membrane, and the anions of the L-ornithine salt in the salt chamber pass through the anion exchange acid film migrate to the chamber, and the chamber into the acid H ⁺ bound acid to form the corresponding acid to give an acid solution chamber; L- ornithine L- ornithine salt cationic salts chamber proceeds base chamber, and OH ^- The combination produces free L-ornithine, and the free L-ornithine solution is obtained in the alkali chamber. The ions in the salt chamber migrate outward, leaving behind uncharged impurities over time.

On the basis of conforming to common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive and progressive effects of the present invention are:

1) For the first time, the bipolar membrane electrodialysis method is used to prepare L-ornithine composite salt. There are no special requirements for the starting material L-ornithine salt, no additional reagents are required, and free L-ornithine is generated in one step. The acid and the corresponding acid, the acid can be recycled as the raw material for preparing L-ornithine salt, no by-products are generated, no waste salt and waste water pollution, green and environmentally friendly;

2) The removal rate of anions in the free L-ornithine prepared by the electrodialysis method of the present invention is almost 100%, and the yield of the final L-ornithine composite salt is as low as 87.7%, and the highest can be Reach 95.25%;

3) The crystallization method of the present invention has low requirements on the eluent and does not require a refining process, and the product in the preferred embodiment is a needle-columnar crystal form with uniform and regular crystal form, and a moisture content of less than 2%, which is stable Good performance, long shelf life, up to 18 months.

Description of the drawings

FIG. 1 is a schematic diagram of the arrangement of the two-compartment membrane stacks separated by a bipolar membrane and an anion exchange membrane in Example 1 and Example 3. FIG.

FIG. 2 is a schematic diagram of the arrangement of the two-compartment membrane stack formed by the bipolar membrane and the anion exchange membrane in Example 2 and Example 4. FIG.

3 is a schematic diagram of the arrangement of the two-compartment membrane stack formed by the bipolar membrane and the cation exchange membrane in Example 5. FIG.

Fig. 4 is a schematic diagram of the arrangement of the membrane stacks of the three compartments in Examples 6-8.

Figure 5 is an SEM image of the products of Examples 1 to 6.

Figure 6 is a high performance liquid chromatogram of L-ornithine-L-aspartate in Example 3

Figure 7 is the XRD pattern of L-ornithine-L-aspartate in Example 3.

Detailed ways

The present invention will be further described by way of examples below, but the present invention is not limited to the scope of the described examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions, or according to the product specification.

The "acid storage tank" in Figures 1 and 2 of the following embodiments is the "acid chamber".

Example 1

(1) Use the bipolar membrane electrodialysis device with two compartments as shown in Figure 1, the arrangement of the membrane stack is anode electrode-anode chamber-anode membrane-[acid chamber-anion exchange membrane-alkali chamber-bipolar membrane] ₁₀₀ -acid chamber-cathode membrane-cathode chamber-cathode electrode, 100 is the number of repeating units, in which both the anode membrane and the cathode membrane are cation exchange membranes. The anode and cathode electrodes are all corrosion-resistant Ti, Pt and Ir alloy materials. The compartment between the membrane and the membrane is lined with grids and gaskets corresponding to the flow channel, and all the alkali chambers or acid chambers are connected in series through the same flow channel. Install the membrane stack to the electrodialysis equipment, connect the anode plate to the positive power supply, the cathode plate to the negative power supply, connect each compartment to the corresponding storage barrel and circulation pump, and fill the storage barrel with a certain amount of reverse osmosis water. Start the circulating pump to make the reverse osmosis water flow between the storage barrels and the corresponding compartments. After circulating for 10 minutes to eliminate bubbles, set the flow rate to 2000L/h. After checking that the membrane stack has no leakage, the installation of the membrane stack is completed;

(2) Dissolve 228kg of L-ornithine sulfate monohydrate in 2000L of water to prepare a solution with a concentration of 0.3mol/L, add the L-ornithine sulfate solution to the caustic compartment storage tank, and add 200L of reverse osmosis Add water to the acid chamber storage barrel, add 2000L of sulfuric acid solution with a concentration of 1% to the anode and cathode chamber storage barrels respectively, start the circulation pump corresponding to each compartment, and make each material liquid circulate between the storage barrel and the corresponding compartment After flowing, circulating flow for 10 minutes to eliminate bubbles, set a flow rate of 2000L/h, and adjust the flow rate of each compartment in a small range to make the pressure of each compartment equal;

(3) After the compartment liquid circulates in the bipolar membrane electrodialysis device for 10 minutes, start the power supply of the bipolar membrane electrodialysis device, set the voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the liquid level of the alkali chamber and the conductivity. If the pH value of the acid chamber no longer drops, add 100L of reverse osmosis water to the acid chamber to reduce the acid concentration of the acid chamber; if the liquid level of the alkali chamber drops, replenish 100L reverse osmosis water makes the liquid level equal to the beginning of the experiment. The experiment runs until the conductivity of the alkali chamber drops below 3.0ms/cm and stops. At this time, the SO4 ^2- in the alkali compartment drops below 10 ppm, the sulfuric acid concentration in the acid compartment reaches 1.05 mol/L, and the free L-ornithine (orn) solution concentration in the alkali compartment is 0.61 mol/L.

(4) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 140～160kg L-aspartic acid to adjust the pH to 6.0～7.0, add 1.6kg activated carbon to decolorize for 30min, filter the plate and frame until the filtrate is clear , The filtrate was concentrated under reduced pressure to 1200L with a concentration of 1.00mol/L; 1908kg of ethanol (6:1) was added to the concentrate at a rate of 50L/min. With the addition of ethanol, an oil phase was generated in the solution, and the oil phase was After a period of time, it transforms into a solid phase on the container wall, causing agglomeration. Collect the agglomerated solids, centrifuge the material, and dry to obtain 279.01 kg of L-ornithine-L-aspartate salt. The yield is 87.7%.

^{Effect data: SO4 2- in the} free L-ornithine solution in the alkali compartment is reduced to below 10 ppm; the yield of L-ornithine-L-aspartate is 87.7%.

Example 2

(1) Use the bipolar membrane electrodialysis device with two compartments as shown in Figure 2, the arrangement of the membrane stack is anode electrode-anode chamber-anode membrane-[acid chamber-anion exchange membrane-alkali chamber-bipolar membrane] ₁₀₀ -acid chamber-cathode membrane-cathode chamber-cathode electrode, 100 is the number of repeating units, wherein the anode membrane is a cation exchange membrane and the cathode membrane is an anion exchange membrane. The anode and cathode electrodes are all corrosion-resistant Ti, Pt and Ir alloy materials. The compartment between the membrane and the membrane is lined with grids and gaskets corresponding to the flow channel, and all the alkali chambers or acid chambers are connected in series through the same flow channel. Install the membrane stack to the electrodialysis equipment, connect the anode plate to the positive power supply, the cathode plate to the negative power supply, connect each compartment to the corresponding storage barrel and circulation pump, and fill the storage barrel with a certain amount of reverse osmosis water. Start the circulating pump to make the reverse osmosis water flow between the storage barrels and the corresponding compartments. After circulating for 10 minutes to eliminate bubbles, set the flow rate to 2000L/h. After checking that the membrane stack has no leakage, the installation of the membrane stack is completed;

(2) Dissolve 228kg of L-ornithine sulfate monohydrate in 2000L of water to prepare a solution with a concentration of 0.3mol/L, add the L-ornithine sulfate solution to the caustic compartment storage tank, and add 200L of reverse osmosis Add water to the acid chamber storage tank, add 2000L of 1% sulfuric acid solution to the anode and cathode chamber storage tanks, add 200L of 2% sodium hydroxide solution to the cathode chamber storage tank, and activate the corresponding compartments Circulating pump to make each material and liquid circulate between the storage barrel and the corresponding compartment. After circulating for 10 minutes to remove the bubbles, set the flow rate to 2000L/h, and adjust the flow rate of each compartment in a small range to make the pressure of each compartment equal;

(3) After the compartment liquid circulates in the bipolar membrane electrodialysis device for 10 minutes, start the power supply of the bipolar membrane electrodialysis device, set the voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the liquid level of the alkali chamber and the conductivity. If the pH value of the acid chamber no longer drops, add 100L of reverse osmosis water to the acid chamber to reduce the acid concentration of the acid chamber; if the liquid level of the alkali chamber drops, replenish 100L reverse osmosis water makes the liquid level equal to the beginning of the experiment. The experiment runs until the conductivity of the alkali chamber drops below 3.0ms/cm and stops. At this time, the base chamber ^- SO4 ^2- reduced to 10ppm or less, the concentration of sulfuric acid chamber reaches 1.05mol / L, the free base of the chamber L- ornithine (Orn) solution at a concentration of 0.61mol / L.

(4) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 140～160kg L-aspartic acid to adjust the pH to 6.0～7.0, add 1.6kg activated carbon to decolorize for 30min, filter the plate and frame until the filtrate is clear , The filtrate was concentrated under reduced pressure to 1200L, the concentration was 1.00mol/L; 1908kg ethanol (6:1) was added to the crystallization tank, the stirring was started, and the concentrated solution of L-ornithine-L-aspartate was added to 50L The flow rate per minute is added to the crystallization tank. The moment the concentrated solution is mixed with the ethanol solution, crystallization and adhesion will produce agglomerated solids. After the flow is completed, the agglomerated solids are collected, centrifuged and dried to obtain L-ornithine -283.02 kg of L-aspartate salt, with a yield of 89%.

^{Effect data: SO4 2- in the} free L-ornithine solution in the alkali compartment is reduced to below 10 ppm; the yield of L-ornithine-L-aspartate is 89%.

Example 3

(1) Use the bipolar membrane electrodialysis device with two compartments as shown in Figure 1, the arrangement of the membrane stack is anode electrode-anode chamber-anode membrane-[acid chamber-anion exchange membrane-alkali chamber-bipolar membrane] ₁₀₀ -acid chamber-cathode membrane-cathode chamber-cathode electrode, 100 is the number of repeating units. The anode and cathode electrodes are all corrosion-resistant Ti, Pt and Ir alloy materials. The compartment between the membrane and the membrane is lined with grids and gaskets corresponding to the flow channel, and all the alkali chambers or acid chambers are connected in series through the same flow channel. Install the membrane stack to the electrodialysis equipment, connect the anode plate to the positive power supply, the cathode plate to the negative power supply, connect each compartment to the corresponding storage barrel and circulation pump, and fill the storage barrel with a certain amount of reverse osmosis water. Start the circulating pump to make the reverse osmosis water flow between the storage barrels and the corresponding compartments. After circulating for 10 minutes to eliminate bubbles, set the flow rate to 2000L/h. After checking that the membrane stack has no leakage, the installation of the membrane stack is completed;

(2) Dissolve 228kg of L-ornithine sulfate monohydrate in 2000L of water to prepare a solution with a concentration of 0.3mol/L, add the L-ornithine sulfate solution to the caustic compartment storage tank, and add 200L of reverse osmosis Add water to the acid chamber storage barrel, add 2000L of sulfuric acid solution with a concentration of 1% to the anode and cathode chamber storage barrels respectively, start the circulation pump corresponding to each compartment, and make each material liquid circulate between the storage barrel and the corresponding compartment After flowing, circulating flow for 10 minutes to eliminate bubbles, set a flow rate of 2000L/h, and adjust the flow rate of each compartment in a small range to make the pressure of each compartment equal;

(3) After the compartment liquid circulates in the bipolar membrane electrodialysis device for 10 minutes, start the power supply of the bipolar membrane electrodialysis device, set the voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the liquid level of the alkali chamber and the conductivity. If the pH value of the acid chamber no longer drops, add 100L of reverse osmosis water to the acid chamber to reduce the acid concentration of the acid chamber; if the liquid level of the alkali chamber drops, replenish 100L reverse osmosis water makes the liquid level equal to the beginning of the experiment. The experiment runs until the conductivity of the alkali chamber drops below 3.0ms/cm and stops. At this time, the SO4 ^2- in the alkali compartment drops below 10 ppm, the sulfuric acid concentration in the acid compartment reaches 1.05 mol/L, and the free L-ornithine (orn) solution concentration in the alkali compartment is 0.61 mol/L.

(4) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 140～160kg L-aspartic acid to adjust the pH to 6.0～7.0, add 1.6kg activated carbon to decolorize for 30min, filter the plate and frame until the filtrate is clear , The filtrate was concentrated under reduced pressure to 1200L, the concentration was 1.00mol/L, and the temperature was maintained at 40℃; 1908kg of ethanol (6:1) was added to the crystallization tank, stirring was started, the temperature was raised to 40℃, and the amount of ethanol was 1% L -19 kg of ornithine-L-aspartate seed crystals, stir for more than 30 minutes, add the concentrated solution of L-ornithine-L-aspartate salt into the crystallization tank at a flow rate of 50L/min, and flow After the addition is completed, heat preservation and rapid stirring for 30 minutes, the ice salt water is cooled to normal temperature, centrifuged, and dried to obtain 321.89 kg of L-ornithine-L-aspartate salt (including 19 kg of seed crystals), with a yield of 95.25%.

^{Effect data: SO4 2- in the} free L-ornithine solution in the alkali chamber is reduced to below 10 ppm; the yield of L-ornithine-L-aspartate is 95.25%.

Example 4

(1) Use the bipolar membrane electrodialysis device with two compartments as shown in Figure 2, the arrangement of the membrane stack is anode electrode-anode chamber-anode membrane-[acid chamber-anion exchange membrane-alkali chamber-bipolar membrane] ₁₀₀ -acid chamber-cathode membrane-cathode chamber-cathode electrode, 100 is the number of repeating units. The anode and cathode electrodes are made of corrosion-resistant Ti, Pt and Ir alloy materials. The compartment between the membrane and the membrane is lined with grids and gaskets corresponding to the flow channel, and all the alkali chambers or acid chambers are connected in series through the same flow channel. Install the membrane stack to the electrodialysis equipment, connect the anode plate to the positive power supply, the cathode plate to the negative power supply, connect each compartment to the corresponding storage barrel and circulation pump, and fill the storage barrel with a certain amount of reverse osmosis water. Start the circulating pump to make the reverse osmosis water flow between the storage barrels and the corresponding compartments. After circulating for 10 minutes to eliminate bubbles, set the flow rate to 2000L/h. After checking that the membrane stack has no leakage, the installation of the membrane stack is completed;

(2) Dissolve 288kg of L-ornithine acetate in 1000L water to prepare a solution with a concentration of 1.5mol/L of L-ornithine acetate, and add the L-ornithine acetate solution to the alkali chamber for storage Bucket, add 200L of reverse osmosis water to the acid chamber storage tank, add 1000L of 2% sodium hydroxide solution and 1% nitric acid solution to the anode and cathode chamber storage barrels, and start the corresponding cycle of each compartment The pump makes each material and liquid circulate between the storage barrel and the corresponding compartment. After circulating for 10 minutes to remove the bubbles, set the flow rate to 2000L/h, and adjust the flow rate of each compartment in a small range to make the pressure of each compartment equal;

(3) After the compartment liquid circulates in the electrodialysis membrane stack for 10 minutes, start the membrane stack power supply, set the membrane stack voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the liquid level of the alkali chamber and the conductivity. If the pH value of the acid chamber no longer drops, add 100L of reverse osmosis water to the acid chamber to reduce the acid concentration of the acid chamber; if the liquid level of the alkali chamber drops, replenish 100L reverse osmosis water makes the liquid level equal to the beginning of the experiment. The experiment runs until the conductivity of the alkali chamber drops below 3.0ms/cm and stops. At this time, the CH ₃ COO ^- in the caustic chamber drops below 10 ppm, the acetic acid concentration in the acid chamber reaches 1.57 mol/L, and the free L-ornithine solution concentration in the caustic chamber is 1.50 mol/L;

(4) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 180-200kg L-aspartic acid to adjust the pH value to 6.0-7.0, add 2.0kg activated carbon to decolorize for 30 minutes, and filter the plate and frame until the filtrate is clear. The filtrate was concentrated under reduced pressure to 600L, the concentration was 2.5mol/L, and the temperature was maintained at 50℃; 1800kg of ethanol (4.5:1) was added to the crystallization tank, the temperature was raised to 50℃, and L-ornithine was added with 4% ethanol by mass. 72kg of L-aspartic acid seed crystals, stirring for more than 30 minutes, add L-ornithine-L-aspartate salt concentrate into the crystallization tank at a flow rate of 50L/min, after the addition is completed, keep warm and stir quickly After 30 minutes, the ice salt water was cooled to room temperature, centrifuged and dried to obtain 448.75 kg of L-ornithine-L-aspartate (including 72 kg of seed crystals), with a yield of 94.78%.

_{Effect data: CH 3} COO ^- in the free L-ornithine solution in the alkali chamber is reduced to below 10 ppm; the yield of L-ornithine-L-aspartate is 94.78%.

Example 5

(1) Use the bipolar membrane electrodialysis device with two compartments as shown in Figure 3, the arrangement of the membrane stack is anode electrode-anode chamber-anode membrane-[alkali chamber-bipolar membrane-acid chamber-cation exchange membrane] ₁₀₀ -alkali chamber-cathode membrane-cathode chamber-cathode electrode, 100 is the number of repeating units. The anode and cathode electrodes are made of corrosion-resistant Ti, Pt and Ir materials. The compartment between the membrane and the membrane is lined with grids and gaskets corresponding to the flow channel, and all the alkali chambers or acid chambers are connected in series through the same flow channel. Install the membrane stack to the electrodialysis equipment, connect the anode plate to the positive power supply, the cathode plate to the negative power supply, connect each compartment to the corresponding storage barrel and circulation pump, and fill the storage barrel with a certain amount of reverse osmosis water. Start the circulating pump to make the reverse osmosis water flow between the storage barrels and the corresponding compartments. After circulating for 10 minutes to eliminate bubbles, set the flow rate to 2000L/h. After checking that the membrane stack has no leakage, the installation of the membrane stack is completed;

(2) Dissolve 504kg of L-ornithine hydrochloride in 1000L of water to prepare a solution with a concentration of 3mol/L of L-ornithine hydrochloride, and add the L-ornithine hydrochloride solution to the acid chamber storage tank , Add 200L of reverse osmosis water to the alkali chamber storage tank, add 1000L of 3% hydrochloric acid solution to the anode chamber storage tank, add 3% sodium hydroxide solution to the cathode chamber storage tank, start each compartment corresponding Circulating pump to make each material and liquid circulate between the storage barrel and the corresponding compartment. After circulating for 10 minutes to remove the bubbles, set the flow rate to 2000L/h, and adjust the flow rate of each compartment in a small range to make the pressure of each compartment equal;

(3) After the compartment liquid circulates in the electrodialysis membrane stack for 10 minutes, start the membrane stack power supply, set the membrane stack voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the liquid level of the acid chamber, the pH value and conductivity of the alkali chamber. If the pH value of the alkali chamber no longer rises, add 100L of reverse osmosis water to the alkali chamber to reduce the L-ornithine concentration in the alkali chamber; When the liquid level drops, 100L of reverse osmosis water is added to make the liquid level level with the beginning of the experiment. The experiment will stop when the pH value of the acid chamber no longer decreases, the conductivity no longer changes, and the current drops below 5A. At this time, the concentration of hydrochloric acid in the acid chamber reaches 2.3 mol/L, the concentration of the free L-ornithine solution in the alkali chamber reaches 3.01 mol/L, and the Cl ^- drops below 10 ppm.

(4) Discharge the free L-ornithine solution in the storage tank of the alkali chamber, add about 380～400kg L-aspartic acid to adjust the pH value to 6.0～7.0, add 4.0kg activated carbon to decolorize for 30min, and filter the plate and frame until the filtrate is clear , The filtrate was concentrated under reduced pressure to 880L, the concentration was 3.4mol/L, and the temperature was maintained at 60℃; 2400kg of ethanol (3:1) was added to the crystallization tank, the stirring was started, the temperature was raised to 60℃ to keep warm, and the ethanol content was 1.5% L -36kg of ornithine L-aspartic acid seed crystals, stirring for more than 30 minutes, add the L-ornithine L-aspartic acid concentrate into the crystallization tank at a flow rate of 50L/min in reverse flow, after the addition is complete , Heat preservation and rapid stirring for 30 minutes, cooling the ice brine to room temperature, centrifuging the material, and drying to obtain 781.30 kg of L-ornithine-L-aspartate finished product (including 36 kg of seed crystals), with a yield of 94%.

^{Effect data: Cl-in the} free L-ornithine solution in the alkali compartment drops below 10 ppm; the yield of L-ornithine-L-aspartate is 94%.

Example 6

(1) Use a three-compartment bipolar membrane electrodialysis device as shown in Figure 4, the arrangement of the membrane stack: anode electrode-anode chamber-[bipolar membrane-acid chamber-anion exchange membrane-salt chamber-cation exchange membrane -Alkali chamber] ₁₀₀ -Bipolar membrane-cathode chamber-cathode electrode; 100 is the number of repeating units. The anode and cathode electrodes are made of corrosion-resistant Ti, Pt and Ir alloy materials. The compartment between the membrane and the membrane is lined with grids and gaskets corresponding to the flow channel. All salt chambers, alkali chambers or acid chambers are connected in series through the same flow channel. Install the membrane stack to the electrodialysis equipment, connect the anode plate to the positive power supply, the cathode plate to the negative power supply, connect each compartment to the corresponding storage barrel and circulation pump, and fill the storage barrel with a certain amount of reverse osmosis water. Start the circulating pump to make the reverse osmosis water flow between the storage barrels and the corresponding compartments. After circulating for 10 minutes to eliminate bubbles, set the flow rate to 2000L/h. After checking that the membrane stack has no leakage, the installation of the membrane stack is completed;

(2) Dissolve 504kg of L-ornithine hydrochloride in 1000L of water to prepare a solution with a concentration of 3mol/L of L-ornithine hydrochloride, and add the L-ornithine hydrochloride solution to the salt chamber storage tank , Add 200L of reverse osmosis water into the storage tanks of acid and alkali compartments, and add 1000L of 2% sodium chloride solution to the storage tanks of the anode and cathode compartments respectively, and start each corresponding circulating pump to make each material liquid in the corresponding Circulate between the compartments and the storage barrel. After circulating for 10 minutes to remove the bubbles, set the flow rate to 2000L/h, and adjust the flow rate of each compartment in a small amount to make the pressure of each compartment equal;

(3) After the compartment liquid circulates in the electrodialysis membrane stack for 10 minutes, start the membrane stack power supply, set the membrane stack voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the pH value of the alkali chamber, the liquid level and the conductivity of the salt chamber. If the pH value of the acid chamber no longer drops and the pH value of the alkali chamber no longer rises, 100L of reverse osmosis water is added to the acid chamber or The alkali chamber is used to reduce the concentration of the acid chamber or the alkali chamber; if the liquid level in the salt chamber drops, 100L of reverse osmosis water is added to make the liquid level equal to the beginning of the experiment. The experiment runs until the conductivity of the salt chamber drops below 0.1ms/cm and stops. At this time, the L-ornithine hydrochloric acid content in the salt chamber is less than 0.1%, the hydrochloric acid concentration in the acid chamber reaches 2.51 mol/L, the concentration of the free L-ornithine solution in the alkali chamber reaches 2.88 mol/L, and Cl ^- drops to 10 ppm the following.

(4) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 380-400kg L-aspartic acid to adjust the pH value to 6.0-7.0, add 4.0kg activated carbon for decolorization for 30 minutes, and filter the plate and frame until the filtrate is clear. The filtrate was concentrated under reduced pressure to 880L, the concentration was 3.4mol/L, and the temperature was maintained at 60°C; 2400kg of ethanol (3:1) was added to the crystallization tank, the stirring was started, the temperature was raised to 60°C to keep warm, and the ethanol content was 2% L- 48 kg of ornithine-L-aspartate seed crystals, stirred for more than 30 minutes, the L-ornithine-L-aspartate salt concentrate was poured into the crystallization tank at a flow rate of 50L/min in reverse flow, After the addition is completed, heat preservation and rapid stirring for 30 minutes, the ice salt water is cooled to normal temperature, centrifuged and dried to obtain 789.3 kg of L-ornithine-L-aspartate finished product with a yield of 93.5%.

^{Effect data: Cl-in the} free L-ornithine solution in the alkali compartment drops below 10 ppm; the yield of L-ornithine-L-aspartate is 93.5%.

Example 7

A three-compartment bipolar membrane electrodialysis device consistent with Example 6 was used.

(1) Dissolve 168kg of L-ornithine hydrochloride in 2000L water to prepare a solution with a concentration of 0.5mol/L of L-ornithine hydrochloride, and add the L-ornithine hydrochloride solution to the salt chamber for storage Barrel, add 200L of reverse osmosis water to acid and alkali chamber storage barrels, add 1000L of 2% sodium chloride solution to the anode and cathode chamber storage barrels, start each corresponding circulating pump, make each material liquid in Circulate between the corresponding compartments and storage barrels. After circulating for 10 minutes to eliminate bubbles, set a flow rate of 2000L/h, and adjust the flow rate of each compartment in small steps to make the pressure of each compartment equal;

(2) After the compartment liquid circulates in the electrodialysis membrane stack for 10 minutes, start the membrane stack power supply, set the membrane stack voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the pH value of the alkali chamber, the liquid level and the conductivity of the salt chamber. If the pH value of the acid chamber no longer drops and the pH value of the alkali chamber no longer rises, 100L of reverse osmosis water is added to the acid chamber or The alkali chamber is used to reduce the concentration of the acid chamber or the alkali chamber; if the liquid level in the salt chamber drops, 100L of reverse osmosis water is added to make the liquid level equal to the beginning of the experiment. The experiment runs until the conductivity of the salt chamber drops below 0.1ms/cm and stops. At this time, the L-ornithine hydrochloric acid content in the salt chamber is less than 0.1%, the hydrochloric acid concentration in the acid chamber reaches 1.82 mol/L, and the free L-ornithine solution concentration in the alkali chamber reaches 1.03 mol/L.

(3) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 110～120kg α-ketoglutarate to adjust the pH value to 3.0～4.0, add 1.3kg activated carbon to decolorize for 30min, filter the plate and frame until clear, and the filtrate Concentrate under reduced pressure to 500L, with a concentration of 2mol/L, and maintain the temperature at 40℃; add 840kg methanol (3:1) into the crystallization tank, start stirring, heat up to 40℃ and keep warm, add L-ornithine with 2% methanol content Acid-α-ketoglutarate (1:1) seed crystal 10kg, add L-ornithine-α-ketoglutarate (1:1) concentrate into the crystallization tank at a flow rate of 50L/min After the addition is completed, heat preservation and rapid stirring for 30 minutes, the ice salt water is cooled to normal temperature, centrifuged, and dried to obtain 263.2 kg of L-ornithine-α-ketoglutarate (1:1) with a yield of 91%.

Effect data: The content of L-ornithine hydrochloride in the salt chamber is less than 0.1%; the yield of L-ornithine-α-ketoglutarate (1:1) is 91%.

Example 8

A three-compartment bipolar membrane electrodialysis device consistent with Example 6 was used.

(1) Dissolve 168kg of L-ornithine hydrochloride in 2000L water to prepare a solution with a concentration of 0.5mol/L of L-ornithine hydrochloride, and add the L-ornithine hydrochloride solution to the salt chamber for storage Barrel, add 200L of reverse osmosis water to acid and alkali chamber storage barrels, add 1000L of 2% sodium chloride solution to the anode and cathode chamber storage barrels, start each corresponding circulating pump, make each material liquid in Circulate between the corresponding compartments and storage barrels. After circulating for 10 minutes to eliminate bubbles, set a flow rate of 2000L/h, and adjust the flow rate of each compartment in small steps to make the pressure of each compartment equal;

(2) After the compartment liquid circulates in the electrodialysis membrane stack for 10 minutes, start the membrane stack power supply, set the membrane stack voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the pH value of the alkali chamber, the liquid level and the conductivity of the salt chamber. If the pH value of the acid chamber no longer drops and the pH value of the alkali chamber no longer rises, 100L of reverse osmosis water is added to the acid chamber or The alkali chamber is used to reduce the concentration of the acid chamber or the alkali chamber; if the liquid level in the salt chamber drops, 100L of reverse osmosis water is added to make the liquid level equal to the beginning of the experiment. The experiment runs until the conductivity of the salt chamber drops below 0.1ms/cm and stops. At this time, the content of L-ornithine hydrochloride in the salt chamber is less than 0.1%, the concentration of hydrochloric acid in the acid chamber reaches 1.36 mol/L, and the concentration of the free L-ornithine solution in the alkali chamber reaches 1.20 mol/L.

(3) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 210kg of R-(+)-lipoic acid, add 1.7kg of activated carbon to decolorize for 30 minutes, filter the plate and frame until the filtrate is clear, and concentrate the filtrate under reduced pressure to 800L , The concentration is 1.25mol/L, maintain the temperature at 55℃; add 1100kg methanol (3.3:1) into the crystallization tank, start stirring, heat up to 55℃ and keep warm, add 2% methanol content of L-ornithine-α- 16kg of ketoglutarate seed crystals, add the concentrated solution to the crystallization tank at a flow rate of 50L/min in reverse flow, after the addition is completed, keep warm and stir quickly for 30min, cool the ice brine to room temperature, centrifuge the material, and dry to obtain L -Ornithine-R-(+)-lipoic acid salt 319.57kg, the yield is 90%.

Effect data: The content of L-ornithine hydrochloride in the salt chamber is less than 0.1%; the yield of L-ornithine-R-(+)-lipoic acid salt is 91%.

Example 9

A two-compartment bipolar membrane electrodialysis device consistent with Example 1 was used.

(1) Dissolve 100±1kg of L-ornithine hydrochloride in 2000L water to prepare a solution with a concentration of 0.3mol/L, add the L-ornithine hydrochloride solution to the caustic compartment storage tank, and add 200L reaction The permeate water is added to the acid chamber storage barrel, 200L of sulfuric acid solution with a concentration of 1% is added to the anode and anode chamber storage barrels respectively, and the circulation pump corresponding to each compartment is started, so that each material liquid is between the storage barrel and the corresponding compartment Circulate the flow, after circulating for 10 minutes to eliminate the bubbles, set the flow rate to 6000L/h, and adjust the flow rate of each compartment in a small range to make the pressure of each compartment equal;

(2) After the compartment liquid circulates in the bipolar membrane electrodialysis device for 10 minutes, start the power supply of the bipolar membrane electrodialysis device, set the voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the liquid level of the alkali chamber and the conductivity. If the pH value of the acid chamber no longer drops, add 100L of reverse osmosis water to the acid chamber to reduce the acid concentration of the acid chamber; if the liquid level of the alkali chamber drops, replenish 100L of reverse osmosis water makes the liquid level approximately equal to the beginning of the experiment. The experiment runs until the conductivity of the alkali chamber drops below 3.0ms/cm and stops. At this time, the Cl ^- in the alkali compartment drops below 10 ppm, the concentration of hydrochloric acid in the acid compartment reaches 1.1 mol/L, and the concentration of the free L-ornithine (orn) solution in the alkali compartment is about 0.3 mol/L.

(3) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 80kg L-aspartic acid to adjust the pH to 6.0-7.0, add 1.6kg activated carbon to decolorize for 30 minutes, filter the plate and frame until the filtrate is clear, and the filtrate Concentrate under reduced pressure to 600L, with a concentration of 1.00mol/L; add about 950kg ethanol (6:1) into the concentrated solution at a rate of 50L/min. With the addition of ethanol, an oil phase is generated in the solution, and the oil phase is in one stage. After time, it turns into a solid phase on the wall of the container, causing agglomeration. Collect the agglomerated solids, centrifuge the material, and dry to obtain 138 kg of L-ornithine-L-aspartate, with a yield of 87.0% .

^{Effect data: Cl-in the} free L-ornithine solution in the alkali compartment drops below 10 ppm; the yield of L-ornithine-L-aspartate is 87%.

Example 10

A two-compartment bipolar membrane electrodialysis device consistent with Example 2 was used.

(1) Dissolve 100±1kg of L-ornithine hydrochloride in 2000L water to prepare a solution with a concentration of 0.3mol/L, add the L-ornithine hydrochloride solution to the caustic compartment storage tank, and add 200L reaction Add permeate water to the acid chamber storage tank, add 200L of 1% sulfuric acid solution to the anode chamber storage tank, add 200L of 2% sodium hydroxide solution to the cathode chamber storage tank, and start the circulation pump corresponding to each compartment , Make each material and liquid circulate between the storage barrel and the corresponding compartment. After circulating for 10 minutes to eliminate the bubbles, set the flow rate to 6000L/h, and adjust the flow rate of each compartment in a small range to make the pressure of each compartment equal;

(2) After the compartment liquid circulates in the bipolar membrane electrodialysis device for 10 minutes, start the power supply of the bipolar membrane electrodialysis device, set the voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the liquid level of the alkali chamber and the conductivity. If the pH value of the acid chamber no longer drops, add 100L of reverse osmosis water to the acid chamber to reduce the acid concentration of the acid chamber; if the liquid level of the alkali chamber drops, replenish 100L of reverse osmosis water makes the liquid level approximately equal to the beginning of the experiment. The experiment runs until the conductivity of the alkali chamber drops below 3.0ms/cm and stops. At this time, the Cl ^- in the alkali compartment drops below 10 ppm, the concentration of hydrochloric acid in the acid compartment reaches 1.05 mol/L, and the concentration of the free L-ornithine (orn) solution in the alkali compartment is about 0.3 mol/L.

(3) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 80kg L-aspartic acid to adjust the pH to 6.0-7.0, add 1.6kg activated carbon to decolorize for 30 minutes, filter the plate and frame until the filtrate is clear, and the filtrate Concentrate under reduced pressure to 600L, with a concentration of 1.00mol/L; add about 950kg ethanol (6:1) into the crystallization tank, start stirring, and add the concentrated solution of L-ornithine-L-aspartate to 50L/L The flow rate of min is added to the crystallization tank. The moment the concentrated solution is mixed with the ethanol solution, crystallization occurs and agglomerates to produce agglomerated solids. After the flow is completed, the agglomerated solids are collected, centrifuged, and dried to obtain L-ornithine- The L-aspartate salt was 139.9 kg, and the yield was 88%.

^{Effect data: Cl-in the} free L-ornithine solution in the alkali chamber drops below 10 ppm; the yield of L-ornithine-L-aspartate is 88%.

Example 11

A two-compartment bipolar membrane electrodialysis device consistent with Example 1 was used.

(1) Dissolve 100±1kg of L-ornithine hydrochloride in 2000L water to prepare a solution with a concentration of 0.3mol/L, add the L-ornithine hydrochloride solution to the caustic compartment storage tank, and add 200L reaction The permeate water is added to the acid chamber storage barrel, 200L of sulfuric acid solution with a concentration of 1% is added to the anode and anode chamber storage barrels respectively, and the circulation pump corresponding to each compartment is started, so that each material liquid is between the storage barrel and the corresponding compartment Circulate the flow, after circulating for 10 minutes to eliminate the bubbles, set the flow rate to 6000L/h, and adjust the flow rate of each compartment in a small range to make the pressure of each compartment equal;

(2) After the compartment liquid circulates in the bipolar membrane electrodialysis device for 10 minutes, start the power supply of the bipolar membrane electrodialysis device, set the voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the liquid level of the alkali chamber and the conductivity. If the pH value of the acid chamber no longer drops, add 100L of reverse osmosis water to the acid chamber to reduce the acid concentration of the acid chamber; if the liquid level of the alkali chamber drops, replenish 100L of reverse osmosis water makes the liquid level approximately equal to the beginning of the experiment. The experiment runs until the conductivity of the alkali chamber drops below 3.0ms/cm and stops. At this time, the Cl ^- in the alkali compartment drops below 10 ppm, the concentration of hydrochloric acid in the acid compartment reaches 1.05 mol/L, and the concentration of the free L-ornithine (orn) solution in the alkali compartment is about 0.3 mol/L.

(3) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 80kg L-aspartic acid to adjust the pH to 6.0-7.0, add 1.6kg activated carbon to decolorize for 30 minutes, filter the plate and frame until the filtrate is clear, and the filtrate Concentrate under reduced pressure to 600L, the concentration is 1.00mol/L, maintain the temperature at 40℃; add about 950kg ethanol (6:1) into the crystallization tank, start stirring, heat up to 40℃ and keep warm, add 1% ethanol L- 9.5 kg of ornithine-L-aspartate seed crystals, stir for more than 30 minutes, add the concentrated solution of L-ornithine-L-aspartate salt into the crystallization tank at a flow rate of 50L/min, flow After the addition is completed, keep warm and stir quickly for 30 minutes, cool the ice salt water to room temperature, centrifuge the material, and dry to obtain 162.5 kg of L-ornithine-L-aspartate (containing 9.5 kg of seed crystals), with a yield of 96.2% .

^{Effect data: Cl-in the} free L-ornithine solution in the alkali compartment drops below 10 ppm; the yield of L-ornithine-L-aspartate is 96.2%.

Example 12

A two-compartment bipolar membrane electrodialysis device consistent with Example 1 was used.

(1) Dissolve 100±1kg of L-ornithine hydrochloride in 2000L water to prepare a solution with a concentration of 0.3mol/L, add the L-ornithine hydrochloride solution to the caustic compartment storage tank, and add 200L reaction The permeate water is added to the acid chamber storage barrel, and 200L of sulfuric acid solution with a concentration of 2% is added to the anode and cathode chamber storage barrels respectively, and the circulation pump corresponding to each compartment is started, so that each material liquid is between the storage barrel and the corresponding compartment Circulate the flow, after circulating for 10 minutes to eliminate the bubbles, set the flow rate to 6000L/h, and adjust the flow rate of each compartment in a small range to make the pressure of each compartment equal;

(2) After the compartment liquid circulates in the bipolar membrane electrodialysis device for 10 minutes, start the power supply of the bipolar membrane electrodialysis device, set the voltage to 220V, and set the upper current limit to 200A. During the experiment, monitor the pH value of the acid chamber, the liquid level of the alkali chamber and the conductivity. If the pH value of the acid chamber no longer drops, add 100L of reverse osmosis water to the acid chamber to reduce the acid concentration of the acid chamber; if the liquid level of the alkali chamber drops, replenish 100L of reverse osmosis water makes the liquid level approximately equal to the beginning of the experiment. The experiment runs until the conductivity of the alkali chamber drops below 3.0ms/cm and stops. At this time, the Cl ^- in the alkali compartment drops below 10 ppm, the concentration of hydrochloric acid in the acid compartment reaches 1.2 mol/L, and the concentration of the free L-ornithine (orn) solution in the alkali compartment is about 0.3 mol/L.

(3) Discharge the free L-ornithine solution in the caustic chamber storage tank, add about 88kg α-ketoglutarate to adjust the pH to 6.0-7.0, add 3.2kg activated carbon to decolorize for 30 minutes, and filter the plate and frame until the filtrate is clear and the filtrate Concentrate under reduced pressure to 600L, the concentration is 1.00mol/L, maintain the temperature at 40℃; add about 1000kg ethanol (6:1) into the crystallization tank, start stirring, heat up to 40℃ and keep warm, add 1% ethanol L- 10kg seed crystals of ornithine-α-ketoglutarate, stir for more than 30 minutes, add the concentrated liquid of L-ornithine-α-ketoglutarate into the crystallization tank at a flow rate of 50L/min, and add After completion, heat preservation and rapid stirring for 30 minutes, cool the ice salt water to room temperature, centrifuge the material, and dry to obtain 168.8 kg of L-ornithine-α-ketoglutarate (1:1) (including 10 kg of seed crystals). The rate is 95.1%.

^{Effect data: Cl-in the} free L-ornithine solution in the alkali compartment drops below 10 ppm; the yield of L-ornithine-α-ketoglutarate is 95.1%.

Example of effects

(1) Nuclear magnetic determination: (BRUKER-AVANCEIII-400) was used to compare the L-ornithine-L-aspartate salt of Example 3 and the L-ornithine-α-ketoglutarate of Example 7 respectively. Acid salt (1:1) and the L-ornithine-R-(+)-lipoic acid salt of Example 8 were measured, and the L-ornithine-L-aspartate salt of Example 3 The NMR data are as follows:

¹ HNMR (400MHz, D ₂ O) 4.66 (1H, m), 3.56 (1H, t), 3.39 (1H, m), 3.31 (1H, t), 2.63 (2H, m), 1.82 (2H, m) , 1.53 (2H, m).

¹³ C NMR (100 MHz, d ₆ -DMSO) δ=177.2, 60.1, 55.2, 42.3, 39.4, 31.1, 28.7 ppm.

As shown in the above nuclear magnetic data, L-ornithine-L-aspartate can be prepared by the preparation method of the present invention. The NMR data of Examples 1 to 2, and Examples 4 to 6, and 9 to 11 are the same as those of Example 3 above.

The NMR data of L-ornithine-α-ketoglutarate (1:1) of Example 7 are as follows:

¹ HNMR (D ₂ O) 3.79 (2H, t), 3.4 (1H, m), 2.63-2.65 (4H, m), 1.76 (2H, m), 1.50-1.53 (2H, m).

¹³ C NMR (100 MHz, d ₆ -DMSO) δ=192.6, 177.3, 60.1, 42.3, 31.2, 29.5, 28.7, 25.6 ppm.

As shown in the above nuclear magnetic data, L-ornithine-α-ketoglutarate (1:1) can be prepared by the preparation method of the present invention. The nuclear magnetic data of Example 12 is the same as that of Example 7 above.

The NMR data of L-ornithine-R-(+)-lipoic acid salt of Example 8 are as follows:

¹³ C NMR (100 MHz, d ₆ -DMSO) δ=177.2, 60.1, 52.0, 43.4, 42.1, 35.8, 35.0, 31.1, 28.7, 25.7, 24.7 ppm.

The structural formula of L-ornithine-R-(+)-lipoic acid salt is as follows:

(2) High performance liquid chromatography determination: The L-ornithine-L-aspartate salt of Example 3 was measured by high performance liquid chromatography using a high performance liquid chromatograph (model: Thermo3000), and the high performance liquid chromatogram was shown As shown in Figure 6, the data analysis is shown in Table 1 and Table 2:

Table 1

Table 2

The L-ornithine-L-aspartate prepared by the method of the present invention has high purity, and the total impurities are only 0.097%. The impurities measured in the liquid chromatography of Examples 4-6 are equivalent to those of Example 3 above.

(3) Crystal shape SEM measurement: SEM measurement was performed on the product crystals of Examples 1 to 6 using a scanning electron microscope (model: QUANTA), as shown in Figure 5, using the traditional forward flow and reverse flow methods to crystallize. The product is a lamellar crystal, with uneven and irregular crystal (Examples 1 and 2). The product obtained by the crystallization method of the present invention (Examples 3-6) is a needle columnar crystal with uniform and regular crystal .

(4) XRD measurement of crystal form: The L-ornithine-L-aspartate salt of Example 3 was subjected to XRD crystal form determination. The spectrum is shown in Figure 7. The characteristic diffraction angle (2θ), crystal plane spacing (d value) The data analysis of) and intensity (%) is shown in Table 3 below:

table 3

2θ angle measured value	d measured value	strength(%)
7.263	12.1614	13.5
8.24	10.7207	33.1
19.321	4.5902	17.7
19.844	4.4705	23.7
21.764	4.0802	70.6
22.474	3.9529	100
24.075	3.6935	60.2
24.573	3.6197	13.4
27.148	3.282	19.1
27.565	2.2332	15.5
28.877	3.0893	12.4
31.349	2.8511	40.3
36.18	2.4807	20.8
37.809	2.3775	15.2
38.122	2.3586	12.3
39.23	2.2946	23.5
41.091	2.1949	10.4

It can be seen from the graph of FIG. 7 and Table 3 that the product prepared by the preferred crystallization method of the present invention has high crystallinity and uniform crystal form.

(5) Moisture determination: Refer to the 0831 weight loss measurement method in the fourth appendix of the Chinese Pharmacopoeia 2015 edition, take 1g of this product and dry it to constant weight at a constant temperature of 120°C. The weight loss does not exceed 3.0% as anhydrous.

The moisture content of the products of Examples 1 to 6 and 9 to 11 was determined, and the results are as follows:

Table 4

Numbering	Moisture%
Example 1	7.86
Example 2	6.09
Example 3	1.36
Example 4	1.05

Example 5	1.41
Example 6	1.25
Example 9	7.07
Example 10	5.76
Example 11	1.01

It can be seen from the above data that the moisture content of the product obtained by the traditional forward flow addition and the reverse flow addition method is 7.86% and 6.09%, respectively; the moisture content of the products of Examples 3 to 6 and Example 11 obtained by the crystallization method of the present invention Low, and both are less than 2%, which is good for preservation.

(6) Accelerated stability test: Take the samples according to the simulated commercial packaging, divide them into 4 separate packages, and place them in the stability test box (the comprehensive drug stability test box purchased from Chongqing Chuangce Technology Co., Ltd., In the model CSH-SGD), set the temperature of the test chamber to 40℃±2℃ and relative humidity 75%±5%. Detect the properties, specific rotation, light transmittance, related substances, loss on drying and content of the samples at the first 1, 2, 3, and 6 months respectively. The detection method refers to the detection of ornithine aspartate in the 2015 edition of the Chinese Pharmacopoeia Standard, the test result is compared with 0 month.

The accelerated stability test was performed on Examples 1 to 6 and Example 11 respectively, and the results are shown in Table 5 below:

table 5

From the above data, it can be seen that the products obtained by the traditional forward flow and reverse flow methods have different stability in high temperature and high humidity environments: especially the properties will change after about 2 months, and the light transmittance will become worse. There is a tendency of higher content of related impurities and higher weight loss on drying; while the products of Examples 3 to 6 and 11 obtained by using the crystallization method of the present invention have better overall stability. Among them, the effects of Example 4 and Example 11 in terms of weight loss on drying are particularly significant.

(7) Long-term stability test: Take the samples according to the simulated commercial packaging, divide them into 4 separate packages, place them in a simulated small barrel, and place them in a stability test box (purchased from Chongqing Chuangce Technology Co., Ltd. Set the test temperature of 25℃±2℃ and relative humidity of 60%±5% in the comprehensive drug stability test box, model CSH-SGD), respectively in the first 1, 2, 3, 6, 9, 12, and 18 At the end of the month, each batch will take out 1 bag to test the properties, specific rotation, light transmittance, related substances, loss on drying and content of the sample. The test method refers to the Chinese Pharmacopoeia 2015 edition of ornithine aspartate, and the test results Compare with 0 month.

The accelerated stability test was performed on Examples 1 to 6 and Example 11 respectively, and the results are shown in Table 6 below:

Table 6

From the above data, it can be seen that the products obtained by the traditional forward flow and reverse flow methods are different in the long-term stability test: at the 6th month and the 9th month, there are changes in properties. The specific rotation decreases, the light transmittance becomes worse, the content of related impurities increases, and the loss on drying is significantly higher; the product obtained by the crystallization method of the present invention has high stability and a long shelf life of up to 18 months. Among them, the effects of Example 4 and Example 11 in terms of weight loss on drying are particularly significant.

Claims (10)

1. A preparation method of L-ornithine composite salt, characterized in that it comprises the following steps:

   (1) Using L-ornithine salt solution as raw material, prepare free L-ornithine solution through a bipolar membrane electrodialysis device;

   (2) The free L-ornithine solution is mixed and reacted with substance A to obtain L-ornithine complex salt solution; the substance A is L-aspartic acid, α-ketoglutarate or R- (+)-Lipoic acid;

   (3) The L-ornithine composite salt solution can be crystallized to obtain the L-ornithine composite salt.
2. The preparation method according to claim 1, wherein in step (1), the anode compartment and/or the cathode compartment of the bipolar membrane electrodialysis device contain an electrolyte solution, preferably a strong electrolyte solution;

   And/or, in step (1), the bipolar membrane electrodialysis device adopts two compartments or three compartments.
3. 3. The preparation method of claim 2, wherein the volume concentration of the strong electrolyte solution is 1 to 3%, such as 2%;

   And/or, the type of the strong electrolyte is sulfuric acid, hydrochloric acid, nitric acid, sodium hydroxide, sodium chloride, sodium sulfate, sodium nitrate, potassium sulfate, potassium nitrate, potassium sulfide or ammonium sulfate, preferably sulfuric acid, hydrochloric acid , Nitric acid or sodium chloride;

   And/or, the two compartments are separated by a bipolar membrane and an "anion exchange membrane or cation exchange membrane";

   Alternatively, the three-compartment compartment is separated by a bipolar membrane, an anion exchange membrane and a cation exchange membrane.
4. The preparation method of claim 2, wherein when the bipolar membrane electrodialysis device adopts the two compartments, the arrangement of the membrane stacks in the bipolar membrane electrodialysis device is: anode electrode- Anode chamber-anode membrane-[acid chamber-anion exchange membrane-alkaline chamber-bipolar membrane] _n -acid chamber-cathode membrane-cathode chamber-cathode electrode, where n is the number of repeating units and the value range is 1-100 Integer between

   When the bipolar membrane electrodialysis device uses the two compartments, the arrangement of the membrane stacks in the bipolar membrane electrodialysis device is: anode electrode-anode chamber-anode membrane-[alkaline chamber-bipolar membrane- Acid Chamber-Cation Exchange Membrane] _n -Alkaline Chamber-Cathode Membrane-Cathode Chamber-Cathode, where n is the number of repeating units and the value range is an integer between 1 and 100;

   When the bipolar membrane electrodialysis device adopts the three compartments, the arrangement of the membrane stacks in the bipolar membrane electrodialysis device is: anode electrode-anode chamber-[bipolar membrane-acid chamber-anion exchange membrane -Salt chamber-Cation exchange membrane-Alkaline chamber] _n -Bipolar membrane-Cathode chamber-Cathode; where n is the number of repeating units and the value range is an integer between 1-100.
5. The preparation method according to claims 1 to 4, wherein in step (1), the bipolar membrane electrodialysis device has a constant voltage direct current at both ends, and the parameter of the constant voltage direct current is: the voltage is 220V, The current density is 10 to 700 A/m ² ; the current density is preferably 100 to 200 A/m ² ;

   And/or, in step (1), the type of L-ornithine salt in the L-ornithine salt solution is L-ornithine hydrochloride, L-ornithine sulfate, L-ornithine Acid acetate, L-ornithine nitrate, L-ornithine citrate or L-ornithine malate, for example the L-ornithine sulfate, L-ornithine hydrochloride Salt or the L-ornithine acetate, more preferably L-ornithine hydrochloride or L-ornithine acetate;

   And/or, in step (1), the concentration of the L-ornithine salt in the L-ornithine salt solution is 0.3-3 mol/L, for example, 0.3 mol/L, 0.5 mol/L, 1.5 mol/L Or 3mol/L;

   And/or, in step (1), when the free L-ornithine solution is prepared, the corresponding acid is also generated. Preferably, the amount of the corresponding acid is the same as that of the L-ornithine. The amount of the corresponding anion in the acid salt solution is equivalent; preferably, the concentration of the corresponding acid is 0-3.0 mol/L, for example 1.05 mol/L, 1.2 mol/L, 1.3 mol/L, 1.36mol/L, 1.1mol/L, 1.57mol/L, 2.3mol/L, 2.51mol/L or 1.82mol/L;

   And/or, in step (1), the amount of L-ornithine in the free L-ornithine solution is compared with the amount of the L-ornithine cation in the L-ornithine salt solution The amount is equivalent, or the concentration of L-ornithine in the free L-ornithine solution is 0.3-3.0 mol/L, for example, 0.3 mol/L, 0.61 mol/L, 0.96 mol/L, 1.0 mol/L , 1.03mol/L, 1.2mol/L, 1.5mol/L, 2.88mol/L or 3.01mol/L.

   And/or, in step (1), when the bipolar membrane electrodialysis device adopts two compartments, and the two compartments are separated by a bipolar membrane and an anion exchange membrane, by detecting the conductivity and The current controls the progress of the reaction; preferably, the reaction in step (1) is stopped when the conductivity of the alkali chamber drops to 0.1-3.0 ms/cm; preferably, the step (1) is stopped when the conductivity drops below 3.0 ms/cm ( 1) The reaction in;

   In step (1), when the bipolar membrane electrodialysis device adopts two compartments, and the two compartments are separated by a bipolar membrane and a cation exchange membrane, the pH value, current and conductivity of the acid chamber are detected Control the reaction process; preferably, the reaction in step (1) is stopped when the pH value of the acid chamber no longer decreases and the conductivity no longer changes;

   In step (1), when the bipolar membrane electrodialysis device adopts three compartments, and the three compartments are separated by a bipolar membrane, a cation exchange membrane and an anion exchange membrane, the conductivity of the salt chamber is detected by And current control the reaction process; preferably, the reaction in step (1) is stopped when the conductivity of the salt chamber drops to 0.1-3.0 ms/cm, and preferably, the reaction in step (1) is stopped when the conductivity drops below 0.1 ms/cm The reaction in step (1).
6. The preparation method according to claims 1 to 5, wherein in step (2), the molar ratio of the substance A to the L-ornithine in the free L-ornithine solution is 1:1 ~ 1:1.3;

   And/or, in step (2), when the substance A is L-aspartic acid, the L-aspartic acid is also used to adjust the pH value of the L-ornithine complex salt solution, The pH value is preferably 6-7;

   And/or, in step (3), before the crystallization operation step, the L-ornithine composite salt solution is sequentially decolorized, filtered and concentrated;

   And/or, in step (3), the crystallization method is carried out as follows: the L-ornithine composite salt solution, the eluent and the seed crystals of the L-ornithine composite salt are mixed;

   Preferably, the crystallization method is carried out as follows: adding the L-ornithine composite salt solution to the mixing of "the seed crystals of the L-ornithine composite salt and the eluent" Just in solution.
7. 7. The preparation method of claim 6, wherein the decolorization operation is completed by adding activated carbon; the amount of the activated carbon preferably accounts for 0.1-10% by weight of the L-ornithine composite salt, For example, 1 wt%; the decolorization time is preferably 0 to 2 hours, such as 30 minutes;

   And/or, the concentration of the L-ornithine complex salt in the concentrated solution after concentration is 1.00-3.4 mol/L, for example, 1.251.0 mol/L, 2 mol/L, 2.5 mol/L or 3.4 mol/L .
8. The preparation method according to claim 6, characterized in that, before the seed crystals of the L-ornithine composite salt are mixed with the eluent, the eluent is preheated to 40-60°C. , Such as 55°C;

   And/or, the type of the eluent is any one of methanol, ethanol, acetone and their aqueous solutions, such as methanol or ethanol;

   And/or, the mass ratio of the eluent to the L-ornithine complex salt is 3-6:1, for example, 6:1, 4.5:1, 3.3:1 or 3:1;

   And/or, the amount of the seed crystals of the L-ornithine composite salt accounts for 1 to 4 wt% of the eluent, for example, 1 wt%, 1.5 wt%, 2 wt% or 4 wt%.
9. A L-ornithine compound salt, characterized in that the L-ornithine compound salt is L-ornithine-L-aspartate, L-ornithine-α-ketoglutarate Any one of salt (1:1) and L-ornithine-R-(+)-lipoic acid salt;

   In the powder X-ray diffraction spectrum of the L-ornithine-L-aspartate salt using Cu-Kα as the radiation source, the diffraction angle 2θ=7.263, 8.24, 19.321, 19.844, 21.764, 22.474, 24.075, There are main peaks at 24.573, 27.148, 27.565, 28.877, 31.349, 36.18, 37.809, 38.122, 39.23 and 41.091 degrees. Preferably, the water content of the L-ornithine-L-aspartate salt is less than 2% .
10. An application of a bipolar membrane electrodialysis device in the preparation of L-ornithine composite salt, characterized in that, during the application process, the raw materials are L-ornithine salt and substance A, and the substance A is L -Aspartic acid, α-ketoglutarate or R-(+)-lipoic acid, preferably, the L-ornithine salt is as described in claim 5.

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