A method for reducing the content of trace and trace impurities in creatine monohydrate

Abstract

The application provides a method for reducing the content of trace and trace impurities in creatine monohydrate, and relates to the technical field of chemical production.The method provided by the application reduces the content of trace and trace impurities in creatine monohydrate by inhibiting side reactions through a catalyst and reducing the content of trace and trace impurities in creatine monohydrate through recrystallization technology.The catalyst can not only catalyze the formation of non-radical to inhibit the generation of dicyandiamide from cyanamide radical, but also catalyze the oxidation of trace formaldehyde in sodium creatine to inhibit the generation of dihydrotriazine, and finally high-purity creatine monohydrate product can be produced through recrystallization.The content of dicyandiamide and creatinine in creatine monohydrate produced by the prior art is 300-400 mg·kg ‑1 , the content of dihydrotriazine is 20-30 mg·kg ‑1 , and these impurities are harmful to human body, so it is difficult to further reduce them by the prior art.The method provided by the application can reduce the content of dicyandiamide and creatinine in creatine to less than 50 mg·kg ‑1 , and the content of dihydrotriazine is reduced to less than 5 mg·kg ‑1 .

Description

Technical Field

[0001] This application relates to the field of chemical production technology, and more specifically, to a method for reducing the content of trace and ultra-trace impurities in creatine monohydrate. Background Technology

[0002] Creatine monohydrate is an important pharmaceutical raw material and health supplement additive. It can inhibit the production of muscle fatigue factors, reduce fatigue and tension, restore physical strength, accelerate the synthesis of human protein, make muscles stronger, enhance muscle elasticity, and lower cholesterol, blood lipids, and blood sugar levels. It can also improve muscular atrophy in middle-aged and elderly people and delay aging. In recent years, creatine monohydrate has become an important health supplement additive and has been favored by bodybuilders and athletes, with a very promising future.

[0003] The production method for creatine, both domestically and internationally, is generally the sodium aminocyanide sarcosinate process. However, because the raw material aminocyanide is highly toxic, the production process is very dangerous, and the yield of sodium sarcosinate is also low.

[0004] Research on the synthesis of creatine monohydrate has made some progress. Patent CN116041226A discloses a method for the continuous synthesis of creatine monohydrate, which utilizes a microchannel reactor for continuous creatine production. Replacing the aqueous solution of monomethylamine with monomethylamine gas improves mass transfer efficiency, reduces the amount of monomethylamine used, and increases the yield of creatine. Urea and dimethyl sulfate react to obtain o-methylisourea sulfate, which can then react with sodium sarcosinate to obtain creatine without further purification. Compared with the process using aminocyanide as a raw material, this process requires inexpensive and abundant raw materials, has mild reaction conditions, is safe to operate, and reduces environmental harm.

[0005] Currently produced creatine monohydrate contains 300–400 mg / kg of dicyandiamide and creatinine. -1 The content of dihydrotriazine is 20-30 mg / kg. -1 Existing technologies make it difficult to further reduce the levels of impurities. Dicyandiamide is produced by the polymerization of monocyanamide and is harmful to the human body; dihydrotriazine is a carcinogen, mainly derived from the reaction of dicyandiamide and formaldehyde; creatinine is formed by the cyclization reaction of creatine under alkaline conditions. Although the human body contains creatinine, high levels can lead to an increased metabolic burden on the kidneys. Therefore, producing high-purity creatine monohydrate is of great significance for improving product competitiveness. Patent CN115626882A discloses a purification method for creatine monohydrate by dissolving it in an acidic solution and then decolorizing and removing impurities with activated carbon. However, this method can only process crude creatine and has no significant effect on treating trace amounts of dicyandiamide, creatinine, and dihydrotriazine in creatine monohydrate. Currently, no technology has been reported to reduce the content of trace and ultra-trace impurities in creatine monohydrate.

[0006] In summary, existing methods for preparing creatine monohydrate suffer from the problem of difficulty in reducing the content of harmful byproducts such as dicyandiamide, creatinine, and dihydrotriazine. Summary of the Invention

[0007] To address the problem of difficulty in reducing the content of harmful byproducts such as dicyandiamide, creatinine, and dihydrotriazine in existing methods for preparing creatine monohydrate, this application adopts the following technical solution: a method for reducing the content of trace and ultra-trace impurities in creatine monohydrate, comprising the following steps:

[0008] (1) Add porous alumina-supported ferric chloride catalyst to a mixed solution of sodium sarcosinate and cyanamide, and then heat and stir, separate and dry to obtain creatine monohydrate;

[0009] (2) Add the creatine monohydrate obtained in step (1) to solvent A, heat it to dissolve it completely, stir, and adjust the pH to neutral with acid solution;

[0010] (3) Slowly add the solution obtained in step (2) to solvent B and crystallize at a constant temperature;

[0011] (4) Separate and dry the product obtained in step (3) to obtain high-purity creatine monohydrate.

[0012] Preferably, the mixed solution of sodium sarcosinate and cyanamide consists of sodium sarcosinate, cyanuric acid and hydrochloric acid in a weight ratio of 2:1:1; the mass ratio of the porous alumina-supported ferric chloride catalyst to the mixed solution of sodium sarcosinate and cyanamide in step (1) is any one of 1:20, 1:40, 1:60 and 1:80.

[0013] Preferably, the preparation of the porous alumina-supported ferric chloride catalyst includes the following steps:

[0014] Solution A is prepared by mixing and stirring ferric chloride, aluminum oxide and alcohol solution; solution B is prepared by mixing and stirring citric acid and water; solution B is added dropwise to solution A, stirred and aged, and dried to obtain the catalyst.

[0015] Preferably, in the preparation of the catalyst, ferric chloride, alumina and alcohol are mixed in a molar ratio of n(Fe+Al):n(alcohol) = 1:10-80; the alumina and ferric chloride in solution A are prepared in a molar ratio of n(Fe):n(Al) = 1:1-8; the alcohol solution is selected from methanol or ethanol.

[0016] Preferably, citric acid and water are mixed in a molar ratio of citric acid:water = 1:5 to 15.

[0017] Preferably, the aging time is 6-12 hours, the stirring temperature is 40-80℃, the drying temperature is 80-120℃, and the total ratio of solution A to solution B is 1:1.

[0018] Preferably, in step (1), the heating temperature is 60-120°C, the stirring time is 1-10h, the separation is centrifugal separation or filtration separation, the drying temperature is 40-80°C, and the drying time is 5-48h.

[0019] Preferably, in step (2), solvent A is any one of methanol, ethanol, water, and acetone; the heating temperature is 30-80℃, and the stirring time is 2-6h; the acid solution is any one of acetic acid, hydrochloric acid, nitric acid, and sulfuric acid.

[0020] Preferably, the slow dripping acceleration rate in step (3) is 0.1–1.0 mL·min. -1 Solvent B is any one of methanol, ethanol, diethyl ether, acetone, and N,N-dimethylformamide; the constant temperature is 0–20℃.

[0021] Preferably, the separation in step (4) is by filtration or centrifugation; the drying temperature is 40-60℃ and the drying time is 6-24h.

[0022] The beneficial effects of this invention are:

[0023] 1. By using a catalyst to suppress side reactions and recrystallization technology, the content of trace and measurable impurities in creatine monohydrate can be reduced. The catalyst not only catalyzes the formation of non-radicals from monocyanamide free radicals, inhibiting the formation of dicyandiamide, but also catalyzes the oxidation of trace formaldehyde in sodium sarcosinate, inhibiting the formation of dihydrotriazine. Finally, recrystallization produces a high-purity creatine monohydrate product. In this invention, by using a catalyst to suppress side reactions and recrystallizing the product, the content of dicyandiamide and creatinine in creatine can be reduced to 50 mg / kg. -1 Within this range, dihydrotriazine decreased to 5 mg / kg. -1 within;

[0024] 2. The catalyst is an inorganic catalyst, which does not contain heavy metals or toxic and harmful substances. It is easy to remove from the reactants and can be reused, making it economical. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of this application, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0026] Figure 1 This is the high-performance liquid chromatogram of creatine monohydrate in Example 1. Detailed Implementation

[0027] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the following detailed description is provided in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and are not intended to limit the scope of this application.

[0028] Example 1

[0029] (1) Catalyst preparation:

[0030] Solution A is formed by mixing and stirring ferric chloride, aluminum oxide and ethanol solutions in a molar ratio of n(Fe+Al):n(ethanol) = 1:20, where n(Fe):n(Al) = 1:5.

[0031] Then mix them in a ratio of n(citric acid):n(water) = 1:10 to form solution B;

[0032] Solution B was added dropwise to solution A, with a mass ratio of 1:1 between solution B and solution A. The mixture was stirred and aged at 65°C for 10 hours and then dried at 100°C to obtain the catalyst sample.

[0033] (2) Creatine monohydrate for impurity removal:

[0034] The mixed solution of sodium sarcosinate and monocyanate consisted of sodium sarcosinate, monocyanate, and hydrochloric acid in a weight ratio of sodium sarcosinate:monocyanate:hydrochloric acid = 2:1:1. A catalyst was added to the mixed solution at a mass ratio of catalyst to solution of 1:60. The mixture was heated and stirred at 60°C for 4 hours, filtered, and dried at 80°C for 12 hours to obtain creatine monohydrate.

[0035] Creatine monohydrate was added to deionized water and heated to 60°C until completely dissolved. The solution was stirred for 4 hours, and the pH was adjusted to neutral with acetic acid. The solution was then pumped at 0.5 mL / min. -1 The solution was slowly added dropwise to ethanol and crystallized at a constant temperature of 10°C. The product obtained from the constant temperature crystallization was filtered and separated, and dried at 50°C for 12 hours to obtain high-purity creatine monohydrate.

[0036] The contents of dicyandiamide, dihydrotriazine, and creatinine in high-purity creatine monohydrate were analyzed by high-performance liquid chromatography. The contents of dicyandiamide were 43.2 mg / kg, dihydrotriazine were 39.6 mg / kg, and creatinine were 3.4 mg / kg.

[0037] Example 2

[0038] (1) Catalyst preparation:

[0039] Solution A is formed by mixing and stirring ferric chloride, aluminum oxide and methanol solutions in a molar ratio of n(Fe+Al):n(methanol) = 1:10, where n(Fe):n(Al) = 1:6.

[0040] Then mix them in a ratio of n(citric acid):n(water) = 1:5 to form solution B;

[0041] Solution B was added dropwise to solution A at a mass ratio of 1:1. The mixture was stirred and aged at 40°C for 6 hours and then dried at 120°C to obtain the catalyst sample.

[0042] (2) Creatine monohydrate for impurity removal:

[0043] The mixed solution of sodium sarcosinate and monocyanate consisted of sodium sarcosinate, monocyanate, and hydrochloric acid in a weight ratio of sodium sarcosinate:monocyanate:hydrochloric acid = 2:1:1. A catalyst was added to the mixed solution at a mass ratio of catalyst to solution of 1:80. The mixture was heated and stirred at 80°C for 5 hours, centrifuged, and dried at 60°C for 24 hours to obtain creatine monohydrate.

[0044] Creatine monohydrate was added to methanol and heated to 30°C until completely dissolved. The solution was stirred for 3 hours, and the pH was adjusted to neutral with hydrochloric acid. The solution was then pumped at 0.2 mL / min. -1 The solution was slowly added dropwise to methanol and crystallized at a constant temperature of 0°C. The product obtained from the constant temperature crystallization was filtered and separated, and dried at 60°C for 24 hours to obtain high-purity creatine monohydrate.

[0045] The contents of dicyandiamide, dihydrotriazine, and creatinine in high-purity creatine monohydrate were analyzed by high-performance liquid chromatography. The contents of dicyandiamide were 47.1 mg / kg, dihydrotriazine were 40.7 mg / kg, and creatinine were 4.8 mg / kg.

[0046] Example 3

[0047] (1) Catalyst preparation:

[0048] Solution A is formed by mixing and stirring ferric chloride, aluminum oxide and methanol solutions in a molar ratio of n(Fe+Al):n(methanol) = 1:25, where n(Fe):n(Al) = 1:4.

[0049] Then mix them in a ratio of n(citric acid):n(water) = 1:8 to form solution B;

[0050] Solution B was added dropwise to solution A, with a mass ratio of 1:1 between solution B and solution A. The mixture was stirred and aged at 80°C for 12 hours and then dried at 100°C to obtain the catalyst sample.

[0051] (2) Creatine monohydrate for impurity removal:

[0052] The mixed solution of sodium sarcosinate and monocyanate consisted of sodium sarcosinate, monocyanate, and hydrochloric acid in a weight ratio of sodium sarcosinate:monocyanate:hydrochloric acid = 2:1:1. A catalyst was added to the mixed solution at a mass ratio of catalyst to solution of 1:60. The mixture was heated and stirred at 100°C for 6 hours, filtered, and dried at 80°C for 12 hours to obtain creatine monohydrate.

[0053] Add creatine monohydrate to deionized water, heat to 70°C until completely dissolved, stir for 2 hours, and adjust the pH of the solution to neutral with nitric acid; then dilute the solution at 1 mL / min. -1 The solution was slowly added dropwise to the ether and crystallized at a constant temperature of 10°C. The product obtained from the constant temperature crystallization was filtered and separated, and dried at 40°C for 12 hours to obtain high-purity creatine monohydrate.

[0054] The contents of dicyandiamide, dihydrotriazine, and creatinine in high-purity creatine monohydrate were analyzed by high-performance liquid chromatography. The contents of dicyandiamide were 48.6 mg / kg, dihydrotriazine were 35.2 mg / kg, and creatinine were 4.3 mg / kg.

[0055] Example 4

[0056] (1) Catalyst preparation:

[0057] Solution A is formed by mixing and stirring ferric chloride, aluminum oxide and ethanol solutions in a molar ratio of n(Fe+Al):n(ethanol) = 1:30, where n(Fe):n(Al) = 1:5.

[0058] Then mix them in a ratio of n(citric acid):n(water) = 1:10 to form solution B;

[0059] Solution B was added dropwise to solution A, with a mass ratio of 1:1 between solution B and solution A. The mixture was stirred and aged at 60°C for 12 hours and then dried at 80°C to obtain the catalyst sample.

[0060] (2) Creatine monohydrate for impurity removal:

[0061] The mixed solution of sodium sarcosinate and monocyanate consisted of sodium sarcosinate, monocyanate, and hydrochloric acid in a weight ratio of sodium sarcosinate:monocyanate:hydrochloric acid = 2:1:1. A catalyst was added to the mixed solution at a mass ratio of catalyst to solution of 1:20. The mixture was heated and stirred at 80°C for 1 hour, filtered, and dried at 70°C for 12 hours to obtain creatine monohydrate.

[0062] Creatine monohydrate was added to acetone and heated to 80°C until completely dissolved. The mixture was stirred for 2 hours, and the pH was adjusted to neutral with sulfuric acid. The solution was then pumped at 0.1 mL / min. -1 The solution was slowly added dropwise to acetone and crystallized at a constant temperature of 5°C. The product obtained from the constant temperature crystallization was filtered and separated, and dried at 40°C for 6 hours to obtain high-purity creatine monohydrate.

[0063] The contents of dicyandiamide, dihydrotriazine, and creatinine in high-purity creatine monohydrate were analyzed by high-performance liquid chromatography. The contents of dicyandiamide were 43.7 mg / kg, dihydrotriazine were 45.2 mg / kg, and creatinine were 4.5 mg / kg.

[0064] Example 5

[0065] (1) Catalyst preparation:

[0066] Solution A is formed by mixing and stirring ferric chloride, aluminum oxide and ethanol solutions in a molar ratio of n(Fe+Al):n(ethanol) = 1:80, where n(Fe):n(Al) = 1:8.

[0067] Then mix them in a ratio of n(citric acid):n(water) = 1:15 to form solution B;

[0068] Solution B was added dropwise to solution A, with a mass ratio of 1:1 between solution B and solution A. The mixture was stirred and aged at 70°C for 10 hours and then dried at 90°C to obtain the catalyst sample.

[0069] (2) Creatine monohydrate for impurity removal:

[0070] The mixed solution of sodium sarcosinate and monocyanate consisted of sodium sarcosinate, monocyanate, and hydrochloric acid in a weight ratio of sodium sarcosinate:monocyanate:hydrochloric acid = 2:1:1. A catalyst was added to the mixed solution at a mass ratio of catalyst to solution of 1:60. The mixture was heated and stirred at 100°C for 7 hours, filtered, and dried at 40°C for 5 hours to obtain creatine monohydrate.

[0071] Creatine monohydrate was added to deionized water and heated to 60°C until completely dissolved. The solution was stirred for 6 hours, and the pH was adjusted to neutral with acetic acid. The solution was then pumped at 0.5 mL / min. -1 The solution was slowly added dropwise to N,N-dimethylformamide and crystallized at a constant temperature of 20°C. The product obtained from the constant temperature crystallization was centrifuged and dried at 40°C for 24 hours to obtain high-purity creatine monohydrate.

[0072] The contents of dicyandiamide, dihydrotriazine, and creatinine in high-purity creatine monohydrate were analyzed by high-performance liquid chromatography. The contents of dicyandiamide were 42.4 mg / kg, dihydrotriazine were 48.37 mg / kg, and creatinine were 3.9 mg / kg.

[0073] Example 6

[0074] (1) Catalyst preparation:

[0075] Solution A is formed by mixing and stirring ferric chloride, aluminum oxide and ethanol solutions in a molar ratio of n(Fe+Al):n(ethanol) = 1:50, where n(Fe):n(Al) = 1:2.

[0076] Then mix them in a ratio of n(citric acid):n(water) = 1:10 to form solution B;

[0077] Solution B was added dropwise to solution A, with a mass ratio of 1:1 between solution B and solution A. The mixture was stirred and aged at 60°C for 10 hours and then dried at 80°C to obtain the catalyst sample.

[0078] (2) Creatine monohydrate for impurity removal:

[0079] The mixed solution of sodium sarcosinate and monocyanate consisted of sodium sarcosinate, monocyanate, and hydrochloric acid in a weight ratio of sodium sarcosinate:monocyanate:hydrochloric acid = 2:1:1. A catalyst was added to the mixed solution at a mass ratio of catalyst to solution of 1:40. The mixture was heated and stirred at 120°C for 8 hours, filtered, and dried at 60°C for 48 hours to obtain creatine monohydrate.

[0080] Creatine monohydrate was added to ethanol and heated to 50°C until completely dissolved. The mixture was stirred for 3 hours, and the pH was adjusted to neutral with acetic acid. The solution was then pumped at 0.5 mL / min. -1 The solution was slowly added dropwise to ethanol and crystallized at a constant temperature of 20°C. The product obtained from the constant temperature crystallization was centrifuged and dried at 40°C for 24 hours to obtain high-purity creatine monohydrate.

[0081] The contents of dicyandiamide, dihydrotriazine, and creatinine in high-purity creatine monohydrate were analyzed by high-performance liquid chromatography. The contents of dicyandiamide were 44.5 mg / kg, dihydrotriazine were 36.8 mg / kg, and creatinine were 4.3 mg / kg.

[0082] Example 7

[0083] (1) Catalyst preparation:

[0084] Solution A is formed by mixing and stirring ferric chloride, aluminum oxide and ethanol solutions in a molar ratio of n(Fe+Al):n(ethanol) = 1:50, where n(Fe):n(Al) = 1:1.

[0085] Then mix them in a ratio of n(citric acid):n(water) = 1:15 to form solution B;

[0086] Solution B was added dropwise to solution A, with a mass ratio of 1:1 between solution B and solution A. The mixture was stirred and aged at 70°C for 8 hours, and then dried at 100°C to obtain the catalyst sample.

[0087] (2) Creatine monohydrate for impurity removal:

[0088] The mixed solution of sodium sarcosinate and monocyanate consisted of sodium sarcosinate, monocyanate, and hydrochloric acid in a weight ratio of sodium sarcosinate:monocyanate:hydrochloric acid = 2:1:1. A catalyst was added to the mixed solution at a mass ratio of catalyst to solution of 1:60. The mixture was heated and stirred at 80°C for 10 hours, filtered, and dried at 70°C for 24 hours to obtain creatine monohydrate.

[0089] Creatine monohydrate was added to acetone and heated to 50°C until completely dissolved. The mixture was stirred for 3 hours, and the pH was adjusted to neutral with hydrochloric acid. The solution was then pumped at 0.5 mL / min. -1 The solution was slowly added dropwise to acetone and crystallized at a constant temperature of 20°C. The product obtained from the constant temperature crystallization was filtered and separated, and dried at 40°C for 12 hours to obtain high-purity creatine monohydrate.

[0090] The contents of dicyandiamide, dihydrotriazine, and creatinine in high-purity creatine monohydrate were analyzed by high-performance liquid chromatography. The contents of dicyandiamide were 41.7 mg / kg, dihydrotriazine were 38.9 mg / kg, and creatinine were 4.5 mg / kg.

[0091] Comparative Example 1

[0092] The difference between this comparative example and Example 1 is that no catalyst was used; only recrystallization was performed, while all other experimental parameters remained the same.

[0093] The mixed solution of sodium sarcosinate and monocyanate consisted of sodium sarcosinate, monocyanate, and hydrochloric acid in a weight ratio of sodium sarcosinate:monocyanate:hydrochloric acid = 2:1:1. The mixed solution of sodium sarcosinate and monocyanate was heated and stirred at 60°C for 4 hours, filtered, and dried at 80°C for 12 hours to obtain creatine monohydrate.

[0094] Creatine monohydrate was added to deionized water and heated to 60°C until completely dissolved. The solution was stirred for 4 hours, and the pH was adjusted to neutral with acetic acid. The solution was then pumped at 0.5 mL / min. -1 The solution was slowly added dropwise to ethanol and crystallized at a constant temperature of 10°C. The product obtained from the constant temperature crystallization was filtered and separated, and dried at 50°C for 12 hours to obtain creatine monohydrate.

[0095] The contents of dicyandiamide, dihydrotriazine, and creatinine in high-purity creatine monohydrate were analyzed by high-performance liquid chromatography. The contents of dicyandiamide were 223.6 mg / kg, dihydrotriazine were 45.2 mg / kg, and creatinine were 37.2 mg / kg.

[0096] As can be seen from Example 1 and Comparative Example 1, the recrystallization process reduced the content of the impurity creatinine.

[0097] Comparative Example 2

[0098] The difference between this comparative example and Example 1 is that only a catalyst was used and recrystallization was not performed, while all other experimental parameters remained the same.

[0099] (1) Catalyst preparation:

[0100] Solution A is formed by mixing and stirring ferric chloride, aluminum oxide and ethanol solutions in a molar ratio of n(Fe+Al):n(ethanol) = 1:20, where n(Fe):n(Al) = 1:5.

[0101] Then mix them in a ratio of n(citric acid):n(water) = 1:10 to form solution B;

[0102] Solution B was added dropwise to solution A, with a mass ratio of 1:1 between solution B and solution A. The mixture was stirred and aged at 65°C for 10 hours and then dried at 100°C to obtain the catalyst sample.

[0103] (2) Creatine monohydrate for impurity removal:

[0104] The mixed solution of sodium sarcosinate and monocyanate consisted of sodium sarcosinate, monocyanate, and hydrochloric acid in a weight ratio of sodium sarcosinate:monocyanate:hydrochloric acid = 2:1:1. A catalyst was added to the mixed solution at a mass ratio of catalyst to solution of 1:60. The mixture was heated and stirred at 60°C for 4 hours, filtered, and dried at 80°C for 12 hours to obtain creatine monohydrate.

[0105] The contents of dicyandiamide, dihydrotriazine, and creatinine in high-purity creatine monohydrate were analyzed by high-performance liquid chromatography. The contents of dicyandiamide were 48.2 mg / kg, dihydrotriazine were 402.3 mg / kg, and creatinine were 4.6 mg / kg.

[0106] As can be seen from Example 1 and Comparative Example 2, the content of dicyandiamide and dihydrotriazine was effectively reduced by adding a catalyst.

[0107] Comparative Example 3

[0108] The difference between this comparative example and Example 1 is that neither a catalyst nor recrystallization was used, while all other experimental parameters remained the same.

[0109] The mixed solution of sodium sarcosinate and monocyanate consisted of sodium sarcosinate, monocyanate, and hydrochloric acid in a weight ratio of sodium sarcosinate:monocyanate:hydrochloric acid = 2:1:1. The mixed solution of sodium sarcosinate and monocyanate was heated and stirred at 60°C for 4 hours, filtered, and dried at 80°C for 12 hours to obtain creatine monohydrate.

[0110] The contents of dicyandiamide, dihydrotriazine, and creatinine in high-purity creatine monohydrate were analyzed by high-performance liquid chromatography. The contents of dicyandiamide were 209.8 mg / kg, dihydrotriazine were 418.6 mg / kg, and creatinine were 36.9 mg / kg.

[0111] As can be seen from Example 1 and Comparative Example 1, the combined use of catalyst addition and recrystallization process effectively reduced the content of creatinine, dicyandiamide and dihydrotriazine.

[0112] Table 1. Summary of experimental data and results for the examples and comparative examples.

[0113]

[0114]

[0115] Table 2. Summary of experimental data and results for the examples and comparative examples (continued from Table 1)

[0116]

[0117] Table 3. Summary of experimental data and results for the examples and comparative examples (continued from Table 2)

[0118]

[0119] This invention provides a method for reducing trace and minor impurities in creatine monohydrate. During the production of creatine monohydrate, a catalyst is added to a mixed solution of sodium sarcosinate and cyanamide, followed by heating and stirring, separation, and drying to obtain creatine monohydrate. The creatine monohydrate is then added to a solvent, heated to completely dissolve, stirred, and the pH is adjusted to neutral with acid. The resulting solution is slowly added dropwise to the solvent, and crystallization is carried out at a constant temperature. The obtained product is then separated and dried to obtain high-purity creatine monohydrate. Experimental results from Examples 1-7 show that the content of dicyandiamide and creatinine in creatine monohydrate prepared by this method is reduced to 50 mg / kg. -1 Within this range, dihydrotriazine decreased to 5 mg / kg. -1 within;

[0120] The creatine monohydrate prepared in Example 1 was detected by high performance liquid chromatography (HPLC). The chromatogram results are as follows: Figure 1 As shown. Calibration curves were constructed for dihydrotriazine, dicyandiamide, and creatinine using the internal standard method, and their contents were calculated. The peak time for dicyandiamide was 1.791 min, and its content was 43.2 mg / kg; the peak time for dihydrotriazine was 1.348 min, and its content was 39.6 mg / kg; the peak time for creatinine was 2.027 min, and its content was 3.4 mg / kg.

[0121] The beneficial effects of this invention are:

[0122] 1. By using a catalyst to suppress side reactions and recrystallization technology, the content of trace and measurable impurities in creatine monohydrate can be reduced. The catalyst not only catalyzes the formation of non-radicals from monocyanamide free radicals, inhibiting the formation of dicyandiamide, but also catalyzes the oxidation of trace formaldehyde in sodium sarcosinate, inhibiting the formation of dihydrotriazine. Finally, recrystallization produces a high-purity creatine monohydrate product. In this invention, by using a catalyst to suppress side reactions and recrystallizing the product, the content of dicyandiamide and creatinine in creatine can be reduced to 50 mg / kg. -1 Within this range, dihydrotriazine decreased to 5 mg / kg. -1 within;

[0123] 2. The catalyst is an inorganic catalyst, which does not contain heavy metals or toxic and harmful substances. It is easy to remove from the reactants and can be reused, making it economical.

[0124] The above-described embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of this application, and should all be included within the protection scope of this application.

Claims

1. A method for reducing the content of trace and ultra-trace impurities in creatine monohydrate, characterized in that, Includes the following steps: (1) Add porous alumina-supported ferric chloride catalyst to a mixed solution of sodium sarcosinate and cyanamide, heat and stir, separate and dry to obtain creatine monohydrate; (2) Add the creatine monohydrate obtained in step (1) to solvent A, heat it to dissolve it completely, stir, and adjust the pH to neutral with acid solution; (3) Slowly add the solution obtained in step (2) to solvent B and crystallize at a constant temperature; (4) Separate and dry the product obtained in step (3) to obtain high-purity creatine monohydrate; Solvent A is any one of methanol, ethanol, water, and acetone; Solvent B is any one of methanol, ethanol, diethyl ether, acetone, and N,N-dimethylformamide; The preparation of the porous alumina-supported ferric chloride catalyst includes the following steps: Ferric chloride, aluminum oxide, and alcohol solution are mixed and stirred to form solution A; citric acid and water are mixed and stirred to form solution B; solution B is added dropwise to solution A, stirred and aged, and dried to obtain the catalyst; In the preparation of the catalyst, ferric chloride, alumina, and alcohol are mixed in a molar ratio of n(Fe+Al):n(alcohol) = 1:10~80; the alumina and ferric chloride in solution A are prepared in a molar ratio of n(Fe):n(Al) = 1:1~8; the alcohol solution is selected from methanol or ethanol. Mix citric acid and water in a molar ratio of citric acid:water = 1:5~15; The mass ratio of solution A to solution B is 1:

1.

2. The method for reducing the content of trace and ultra-trace impurities in creatine monohydrate as described in claim 1, characterized in that: The composition of the sodium sarcosinate and cyanamide mixed solution is sodium sarcosinate, cyanuric acid and hydrochloric acid in a weight ratio of 2:1:1; the mass ratio of the porous alumina-supported ferric chloride catalyst to the sodium sarcosinate and cyanamide mixed solution in step (1) is any one of 1:20, 1:40, 1:60 and 1:

80.

3. The method for reducing the content of trace and ultra-trace impurities in creatine monohydrate as described in claim 1, characterized in that: The catalyst is prepared by aging for 6 to 12 hours, stirring at 40 to 80°C, and drying at 80 to 120°C.

4. The method for reducing the content of trace and ultra-trace impurities in creatine monohydrate as described in claim 1, characterized in that: The heating temperature in step (1) is 60 ~ 120℃, the stirring time is 1 ~ 10 h; the separation is centrifugal separation or filtration separation; the drying temperature is 40 ~ 80℃, and the drying time is 5 ~ 48 h.

5. The method for reducing the content of trace and ultra-trace impurities in creatine monohydrate as described in claim 1, characterized in that: In step (2), the heating temperature is 30 ~ 80℃ and the stirring time is 2 ~ 6 h; the acid solution is any one of acetic acid, hydrochloric acid, nitric acid and sulfuric acid.

6. The method for reducing the content of trace and ultra-trace impurities in creatine monohydrate as described in claim 1, characterized in that: The slow drip acceleration rate described in step (3) is 0.1 ~ 1.0 mL•min. -1 The constant temperature is 0 ~ 20℃.

7. The method for reducing the content of trace and ultra-trace impurities in creatine monohydrate as described in claim 1, characterized in that: The separation described in step (4) is either filtration or centrifugation; the drying temperature is 40-60℃ and the drying time is 6-24 h.

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