Method for preparing free-flowing particles comprising or consisting of N-guanidino amino acids

Abstract

The present invention relates to a process for preparing free-flowing particles comprising or consisting of N-guanidino amino acids wherein the process comprises the following steps: a) providing a solution or suspension comprising an N-guanidino amino acid, b) converting the pH of the solution or suspension provided in step a) to a pH below the pKa value of the N-guanidino amino acid, and c) converting the pH of the solution or suspension obtained in step b) to a pH greater than the pKa value of the N-guanidino amino acid and less than the pKb value of the N-guanidino amino acid, where step c) further comprises precipitating or crystallizing particles comprising or consisting of N-guanidino amino acids, where the pH of each of steps b) and c) is measured by a pH electrode.

Description

[0001] The present invention relates to a method for preparing free-flowing granules comprising or consisting of N-guanylamino acid.

[0002] N-guanidino amino acids are derivatives of amino acids with a guanidine group, which can be obtained by adding cyanamide to the amino acid in question. The most important N-guanidino amino acid is guanidinoacetic acid, also known as N-guanidinoglycine. It is an endogenous substance in animals and humans and plays a central role in the biosynthesis of creatine. Creatine can be ingested through the diet and can also be formed endogenously. Its biosynthesis occurs from glycine and L-arginine. In mammals, guanidinoacetic acid is formed primarily in the kidneys by transferring the guanidino group of L-arginine to the amino acid glycine via the enzyme L-Arg:Gly-guanyltransferase (AGAT). Thus, L-ornithine is produced from L-arginine, which is metabolized in the urea cycle via carbamylation to L-citrulline. In a further step, guanidinoacetic acid is methylated with S-adenosylmethionine to creatine by the enzyme guanidinoacetate N-methyltransferase (GAMT). The creatine thus obtained is released into the mammalian bloodstream and transported across the cell membrane into the cells of target organs via specific creatine transporters.

[0003] Guanidinoacetic acid was first prepared in 1861 by Adolph Strecker by adding cyanamide to glycine in aqueous solution, particularly in a weak ammonia solution (M. Strecker, compt. Rend. 1861, 52, 1212; cited in Ber. Chem. Ges. (now Eur. J. Inorg. Chem.) 1904, 41, 4385). In later publications, guanidinoacetic acid was prepared from cyanamide and glycine in isopropanol as a solvent in the presence of sodium hydroxide or sodium carbonate as a base (CN 102329250 A or CN 101462983 A). Since isopropanol readily forms flammable mixtures of vapor and air, it is not a good and desirable solvent for industrial processes. However, the synthesis of guanidinoacetic acid from cyanamide and glycine in alkaline aqueous solution under the reaction conditions disclosed in the prior art is not without its problems. In particular, the particles obtained from such syntheses have significant limitations on their commercial use. For example, a large number of these particles are too fine or not abrasion-resistant. Both of these aspects also cause dust problems during particle handling. In addition, these particles also have unsatisfactory flow properties.

[0004] The physical properties of the granules thus obtained can be improved by granulation (see WO 2009 / 012960 A) or coating (see CN 110663821 A). However, the granules thus obtained containing N-guanidino amino acids always contain auxiliary substances, which reduce the purity and quality of the product. Even more additional processing makes the product more expensive.

[0005] The fermentative production of N-guanidino amino acids faces similar problems. The product obtained from the fermentation process may contain biomass and other impurities. However, this compromises product purity and quality.

[0006] Therefore, there remains a need to improve the physical properties of particles comprising or consisting of N-guanidino amino acids, such as guanidinoacetic acid (GAA). It has been found that this problem is solved in that a solution or suspension comprising an N-guanidino amino acid (e.g., guanidinoacetic acid) first undergoes a pH transition to a pH below the pKa value of the N-guanidino amino acid and then undergoes a pH transition back to a pH greater than the pKa value of the N-guanidino amino acid and below the pKb value of the N-guanidino amino acid.

[0007] Therefore, an object of the present invention is a method for preparing free-flowing particles comprising or consisting of an N-guanidinoamino acid such as guanidinoacetic acid, wherein the method comprises the following steps:

[0008] a) providing a solution or suspension comprising an N-guanidino amino acid such as GAA,

[0009] b) shifting the pH of the solution or suspension provided in step a) to a pH below the pKa value of the N-guanidino amino acid (e.g. GAA), and

[0010] c ) shifting the pH of the solution or suspension obtained in step b) to a pH greater than the pKa value of the N-guanidino amino acid and lower than the pKb value of the N-guanidino amino acid (e.g. GAA), wherein step c) further comprises precipitating or crystallizing particles comprising or consisting of the N-guanidino amino acid (e.g. guanidinoacetic acid),

[0011] The pH in any of steps b) and c) is measured by a pH electrode.

[0012] Based on the example of guanidinoacetic acid as an N-guanidino amino acid, the experimental data show that the process according to the invention consistently produces granules with improved pourability and, therefore, improved flow properties: the guanidinoacetic acid granules obtained by the process according to the invention consistently have improved flow properties, in particular better pourability than commercially available guanidinoacetic acid and granulated guanidinoacetic acid. These results are independent of the previous preparation of the guanidinoacetic acid, i.e., whether it was prepared chemically or fermentatively.

[0013] It is believed that the pH shift performed in step b) of the method according to the present invention results in the protonation of the nitrogen atom of the guanidino group of an N-guanidino amino acid, such as guanidinoacetic acid. This facilitates the solvation or dissolution of the N-guanidino amino acid. Thus, compared to prior art methods, renewed precipitation or crystallization is avoided, and the dissolved N-guanidino amino acid is removed from the precipitation / dissolution equilibrium.

[0014] It is believed that the pH shift in step c) causes the N-guanidino amino acid (e.g., guanidinoacetic acid) to precipitate or crystallize from the solution or suspension. The N-guanidino amino acid, e.g., guanidinoacetic acid, thus precipitated or crystallized can then be used for any further processing or use. For this purpose, the precipitated or crystallized N-guanidino amino acid, e.g., guanidinoacetic acid, is separated from the solution or suspension and dried. However, the precipitated or crystallized N-guanidino amino acid, e.g., guanidinoacetic acid, can also be further processed directly in a liquid medium, for example to prepare a dispersion comprising the N-guanidino amino acid.

[0015] According to the present invention, step c) further comprises precipitating or crystallizing particles comprising or consisting of an N-guanidinoamino acid, such as guanidinoacetic acid.

[0016] In one embodiment, the method according to the present invention further comprises the following steps:

[0017] d) separating the precipitated or crystallized particles comprising or consisting of an N-guanidinoamino acid, such as guanidinoacetic acid, from the solution or suspension obtained in step c), and

[0018] e) The particles separated in step d) are dried.

[0019] In step e), the particles are dried to dryness.The temperature and time used in step e) depend on the solvent of the solution or suspension provided in step a) of the process according to the invention.

[0020] First, the solvent of the solution or suspension provided in step a) is given by a previous method that results in the formation of N-guanidino amino acids such as guanidinoacetic acid. When forming N-guanidino amino acids in a chemical reaction, the solvent is preferably water, an organic solvent (such as isopropanol) or a mixture of water and an organic solvent. In the context of the present invention, suitable organic solvents are water-miscible organic solvents, particularly polar and / or protic organic solvents. When forming N-guanidino amino acids during fermentation, the solvent is typically water. In any case, it is preferred that the medium of the solution or suspension comprises a protic solvent such as alcohol or water or is composed of a protic solvent such as alcohol or water, which promotes the protonation of the guanidine group of the N-guanidino amino acids. In addition to the above-mentioned solvents, the solution of the suspension can also include another solubilizing agent.

[0021] In one embodiment of the process according to the invention, the solvent of the solution or suspension provided in step a) comprises or consists of water, an organic solvent or a mixture thereof.

[0022] Preferably, the solvent of the solution or suspension provided in step a) is water.

[0023] To dissolve the N-guanidino amino acid completely and quickly, it is beneficial to protonate the guanidino group of the N-guanidino amino acid as completely as possible. This is achieved when the pH of the solution or suspension is shifted in step b) to a pH below the pKa value of the N-guanidino amino acid. Maintaining this pH for a certain period of time is beneficial, as it also helps to protonate the guanidino group of the N-guanidino amino acid as completely as possible.

[0024] In order to achieve the subsequent pH shift in step c) as completely and rapidly as possible, it is advantageous to deprotonate the guanidine group of the N-guanidine amino acid as completely as possible. This is achieved in step c) when the pH of the solution or suspension obtained in step b) is shifted to a pH greater than the pKa value of the N-guanidine amino acid and less than the pKb value of the N-guanidine amino acid. Maintaining this pH for a certain period of time is advantageous, as it also contributes to the most complete deprotonation of the guanidine group of the N-guanidine amino acid.

[0025] The method according to the present invention is not subject to any restrictions regarding the time for which the respective pH value set in step b) and / or step c) is maintained, provided that the time is sufficient to achieve the effect of the step in question. For example, the time for which the pH value is maintained in any step b) and / or c) may be up to 30 minutes, 5 to 25 minutes, or 10 to 20 minutes.

[0026] In a further embodiment of the process according to the invention, the pH value set in step b) and / or c) is maintained for a period of at most 30 minutes.

[0027] In principle, the method according to the invention is not subject to any restrictions with regard to a specific N-guanidino amino acid. However, since guanidinoacetic acid is the most commercially relevant N-guanidino amino acid, it is preferred that the N-guanidino amino acid is guanidinoacetic acid.

[0028] In one embodiment of the method according to the invention the N-guanidinoamino acid is guanidinoacetic acid.

[0029] The pH of the solution or suspension provided in step a) depends on the individual N-guanidino amino acids, such as guanidinoacetic acid, contained in the solution or suspension, and on the prior synthesis used to prepare the N-guanidino amino acid, such as guanidinoacetic acid, in question. For example, when preparing an N-guanidino amino acid (e.g., guanidinoacetic acid) in a chemical synthesis, the pH of the solution or suspension provided in step a) is preferably in the neutral or alkaline range, i.e., the pH is greater than the pKa of the N-guanidino amino acid (e.g., guanidinoacetic acid) and lower than the pKb. In this case, the pH is preferably in the range of about 7 to a value lower than the pKb of the N-guanidino amino acid, for example, in the range of from about 7 to a value lower than about 11. When preparing an N-guanidino amino acid (e.g., guanidinoacetic acid) in a biochemical synthesis (i.e., in a fermentation), the pH of the solution or suspension provided in step a) is preferably in the neutral range, i.e., the pH is greater than the pKa of the N-guanidino amino acid (e.g., guanidinoacetic acid) and lower than the pKb. In this case, the pH is preferably in the range of from about 5 to about 9, or from about 6 to about 8. Therefore, in any case, the pH of the solution or suspension provided in step a) is always greater than the pKa of the N-guanidinoamino acid (e.g., guanidinoacetic acid) and lower than the pKb. In addition, the solvent or solvent mixture of the solution or suspension provided in step a) may also have an influence on the pH.

[0030] In the context of the present invention, any specific value mentioned for pH always refers to the corresponding value measured in an aqueous solution or suspension using a pH electrode. However, the specific value of the pH in any of steps a) to c) may be influenced by the solvent or solvent mixture of the solution or suspension provided in step a), the individual N-guanidinoamino acids (e.g. guanidinoacetic acid) contained in the solution or suspension and / or the previous synthesis used to prepare the N-guanidinoamino acid (e.g. guanidinoacetic acid) in question. Therefore, the method according to the present invention is not subject to any restrictions regarding any specific pH value in any of steps a), b) and / or c), provided that they achieve the beneficial effects of the present invention. On the contrary, any deviations from the values ​​explicitly mentioned above and below are still included within the scope of the present invention, as long as they allow the benefits of the present invention to be achieved.

[0031] For example, when the N-guanidino amino acid contained in the solution or suspension provided in step a) is guanidinoacetic acid, the pH of the solution or suspension is shifted to a value below the pKa of guanidinoacetic acid, i.e., below about 2.9 (measured by a pH electrode) in step b), and then the pH is shifted to a value greater than the pKa of guanidinoacetic acid, i.e., greater than about 2.9 (measured by a pH electrode) and below the pKb of guanidinoacetic acid, i.e., below about 10.91, in step c). With regard to step c), it is further preferred that the pH be set to a value at which crystallization of the N-guanidino amino acid (e.g., guanidinoacetic acid) begins, for example, to a value in the range of about 5 to below the pKb of guanidinoacetic acid, i.e., below about 10.91.

[0032] In a preferred embodiment of the process according to the invention, when the N-guanidinoamino acid contained in the solution or suspension provided in step a) is guanidinoacetic acid, the pH of the solution or suspension obtained in step b) is below the pKa of guanidinoacetic acid. Preferably, in this case, the pH is below about 2.9.

[0033] In another preferred embodiment of the method according to the present invention, when the N-guanidinoamino acid contained in the solution or suspension provided in step a) is guanidinoacetic acid, the pH of the solution or suspension obtained in step c) is greater than the pKa of guanidinoacetic acid and less than the pKb of guanidinoacetic acid. Preferably, in this case, the pH is greater than about 2.9 and less than the pKb of guanidinoacetic acid, in particular, the pH is greater than 4 and less than about 10.91 or between 5 and less than about 10.91. In particular, crystallization of guanidinoacetic acid begins at a pH of 5 or higher.

[0034] The method according to the present invention is also not limited to any particular temperature in any of steps a), b), and / or c), provided that the selected temperature does not negatively impact the outcome of any of these steps. In principle, the temperature in any of steps a) to c) of the method according to the present invention is determined by the solvent or solvent mixture of the solution or suspension and the solubility of the N-guanidino amino acid (e.g., guanidinoacetic acid) in the solvent or solvent mixture. The temperature should be selected to achieve the best possible solubility of the N-guanidino amino acid (e.g., guanidinoacetic acid) without negative side effects. For example, when ammonia or ammonium hydroxide is used as the base in step b), ammonia is not released and foaming does not occur from the solution or suspension. In general, it is preferred that the temperature in any of steps a) to c), particularly in steps b) and / or c), be less than 100°C, preferably at most 95°C or 90°C, and in particular at most 80°C or 85°C, for example, in the range of 20°C to 95°C, 20°C to 90°C, 20°C to 85°C, or 20°C to 80°C.

[0035] In principle, the method according to the present invention is not subject to any restrictions regarding the use of a specific acid in step b) and / or a specific base in step c), provided that the concentration of the acid and / or base is suitable for shifting the pH of the solution or suspension to the desired pH range. Therefore, in step b) and / or step c), any inorganic or organic acid or mixture thereof, and any inorganic or organic base or mixture thereof, that meets this condition can be used. For example, sulfuric acid can be used in step b), and / or caustic soda (NaOH) can be used in step c).

[0036] In principle, the method according to the present invention is also not subject to any restrictions regarding the source of the N-guanidino amino acid (e.g. guanidinoacetic acid) or the source of the solution or suspension comprising the N-guanidino amino acid (e.g. guanidinoacetic acid). Thus, the N-guanidino amino acid (e.g. guanidinoacetic acid) used in step a) or the solution or suspension comprising the N-guanidino amino acid (e.g. guanidinoacetic acid) provided in step a) can be produced by a chemical or fermentation process.

[0037] In one embodiment of the method according to the invention, the solution or suspension comprising an N-guanidinoamino acid (e.g. guanidinoacetic acid) provided in step a) or the N-guanidinoamino acid (e.g. guanidinoacetic acid) contained in said solution or suspension is produced by a chemical reaction of an amino acid with cyanamide.

[0038] In another embodiment of the method according to the present invention, the solution or suspension comprising an N-guanidino amino acid (e.g. guanidinoacetic acid) provided in step a) or the N-guanidino amino acid (e.g. guanidinoacetic acid) contained in the solution or suspension is produced by fermentation of an N-guanidino amino acid (e.g. guanidinoacetic acid).

[0039] The method according to the invention allows the provision of granules comprising or consisting of N-guanidinoamino acids (e.g. guanidinoacetic acid) which have improved, superior handling properties compared to prior art granules comprising N-guanidinoamino acids (e.g. guanidinoacetic acid). Thus, in contrast to prior art methods, the method according to the invention does not require any granulation step.

[0040] It was found that the particles comprising or consisting of N-guanidinoamino acids, such as guanidinoacetic acid, obtained by the process according to the invention are large uniform particles. Figure 1 and 2 This is illustrated by the example of guanidine acetic acid. Figure 1 Shown is a comparison of the summed distribution of the particle sizes of granulated guanidinoacetic acid (GAA) particles not according to the invention (black, solid line) with non-granulated GAA particles precipitated according to the invention with NaOH (black dot-dashed line) and GAA particles precipitated according to the invention with NH4OH (black, broken line). Figure 2A comparison of the particle size density distribution of granulated GAA particles not according to the invention (black, solid line) is shown, along with ungranulated GAA particles precipitated with NaOH according to the invention (black dot-dashed line) and GAA particles precipitated with NH4OH according to the invention (black, broken line). These figures show that the particles obtained by the method according to the invention have a larger particle size than the granulated GAA particles and / or the GAA subjected to step a) of the method according to the invention. It is believed that the larger particle size of the particles obtained by the method according to the invention results in their improved flow properties, such as improved pourability. Description of the drawings:

[0041] Figure 1 : Comparison of the total particle size distribution of granulated GAA particles not according to the invention (black, solid line) with ungranulated GAA particles precipitated by NaOH according to the invention (black dot-dashed line) and GAA particles precipitated by NH4OH according to the invention (black, broken line)

[0042] Figure 2 : Comparison of the density distribution of the particle size of granulated GAA particles not according to the invention (black, solid line) with ungranulated GAA particles precipitated by NaOH according to the invention (black dot-dashed line) and GAA particles precipitated by NH4OH according to the invention (black, broken line)

[0043] Figure 3 : The measurement results of the angle of repose of the test product.

[0044] Figure 4 : Schematic diagram of the pourability test.

[0045] Figure 5 : Determination result of pourability of the tested product. Example:

[0046] 1. According to an embodiment of the present invention

[0047] 1.1 Ungranulated GAA, NaOH precipitated

[0048] A glass beaker was filled with 100.3 g of guanidinoacetic acid (GAA) and water was added to a total weight of 1002.5 g. The suspension thus obtained was stirred from the top at 150 revolutions per minute with a stirrer (Minister 20 digital). The temperature of the suspension was 20.9 ° C and the pH of the suspension was 9.38. Sulfuric acid (80% w / w) was added to the suspension over 17 minutes. After adding 73.3 g of sulphuric acid, the pH of the suspension was 1.02 and clarified. Next, a total of 266.2 g of caustic soda (20% w / w) was added over 17 minutes to reach a pH of 8.3, which resulted in a temperature increase of 37.8 ° C. A precipitate was formed, which was separated from the solution via a suction filter and dried overnight at 60 ° C.

[0049] 1.2 Ungranulated GAA, NH4OH precipitated

[0050] A glass beaker was filled with 100.1 g of guanidinoacetic acid (GAA) and water was added to a total weight of 1002.5 g. The suspension thus obtained was stirred from the top at 150 revolutions per minute with a stirrer (Minister 20digital). The temperature of the suspension was 20.2° C. and the pH of the suspension was 9.44. Sulfuric acid (80% w / w) was added to the suspension over 17 minutes. After addition of 71.5 g of sulphuric acid, the pH of the suspension was 1.02 and clarified. Next, a total of 85.4 g of aqueous ammonia (25.5 w / w) was added over 20 minutes to reach a pH of 8.01, which resulted in a temperature increase of 34.8° C. A precipitate was formed, which was separated from the solution by a suction filter and dried overnight.

[0051] 1.3 Unpelleted GAA from fermentation

[0052] The fermentation broth containing guanidine acetic acid at a pH of 7.0 was titrated to a pH of 1.5 at 50° C. using sulfuric acid (75% w / w) under stirring. After the GAA was dissolved, the biomass was removed by ultrafiltration (UF: ATECH Al2O3 tube model, 20kDa cut of) at 50° C. and concentrated (retentate). The retentate obtained was diafiltered (DF) twice with acidic water (adjusted to pH 1 with sulfuric acid (75% w / w). The (UF / DF) permeate was concentrated twice in a rotary evaporator at (80° C. and 250 mbar). The concentrated permeate thus obtained was mixed with aqueous ammonia (25% w / w) at 50° C. to a final pH of 7.2. The resulting precipitate was separated from the solution and washed with water (2 times the solid volume) using a suction filter and dried overnight at 60° C.

[0053] 2. Embodiments Not According to the Invention

[0054] 2.1

[0055] Commercial guanidine acetic acid Purchased from AlzChem, Germany.

[0056] 2.2 Dry chemically produced GAA

[0057] After separation from the reaction mixture, the chemically produced guanidinoacetic acid was dried. The product thus obtained was used directly without any further treatment in the tests.

[0058] 2.3 Chemically produced GAA by granulation

[0059] The procedure for preparing pelletized chemically produced GAA corresponds to the general procedure for preparing pelletized GAA in paragraphs

[0045] and

[0046] of US2010143703 A1.

[0060] Guanidinoacetic acid is placed in an intensive mixer and homogenized for 1 minute at room temperature. Subsequently, starch and water are added with slow stirring. The mixer contents are then stirred at 1500 to 2000 rpm, with a temperature increase. After a granulation time of 5 to 8 minutes, granules in the desired particle size range (32 to 2750 μm) are obtained. The granules are dried to a product temperature of 80°C.

[0061] 3. Determination of particle size distribution

[0062] Use laser diffraction particle size analyzer (LA-950V2, Horiba) to measure particle size distribution. Add about 300mL isopropyl alcohol, and set the agitator to level 6. Start blank measurement. Add a small amount of dry sample and start measurement. For the second and third measurements, apply ultrasound 60 or 120 seconds under the ultrasound setting of level 7. After each ultrasound treatment, start measurement, which results in three measurements: no ultrasound treatment, ultrasound treatment 60 seconds and ultrasound treatment 120 seconds. The evaluation of measurement is carried out by the "Fraunhofer RT" method provided by the particle analyzer.

[0063] Table 1 summarizes the results of the particle size distribution determination. Figure 1 and 2 The results are described.

[0064] 4. Determination of pourability

[0065] Five different funnels are used to measure pourability, each funnel having different orifice diameters: the first funnel has an orifice diameter of 2.5 mm, which is the minimum orifice diameter. The product through the orifice is classified as a pourability value of 1. Next comes the second to the fifth funnel, which has an orifice diameter of 5 mm, 8 mm, 12 mm, and 15 mm. The product through any of these holes is classified, with a pourability value of 2-5. Any product that does not pass through the orifice of the fifth funnel is classified as a pourability value of 6. A pourability value of 5 or a product corresponding to a larger indication is not suitable for an automated high output feed mill. Figure 4 The general procedure of the assay is shown.

[0066] Table 1 and Figure 5 The results of the pourability determination are summarized.

[0067] The results show that the guanidinoacetic acid particles according to the present invention and the guanidinoacetic acid particles obtained by the method according to the present invention are comparable to commercially available guanidinoacetic acid. Compared to dried and granulated guanidinoacetic acid, improved flow properties, in particular improved pourability, were consistently achieved. These results were independent of the previous production methods used to produce the guanidinoacetic acid used in the method according to the invention. The method according to the invention gave similar or even identical results for granules produced by chemical production of guanidinoacetic acid and for granules produced by fermentative production of guanidinoacetic acid.

[0068]

[0069] Table 1: Summary of results for the products tested

[0070] 5. Determination of the angle of repose

[0071] The flow characteristics of powdered substances are determined by measuring the height of the cone formed. For this test, a sieve with a mesh size that the particles should pass through unimpeded is fixed at a distance of 60 mm above the top of a metal cylinder. The substance to be evaluated is gently rubbed through the sieve until a geometrically constant cone is formed on the top of the metal cylinder. The angle of repose is calculated using the following formula:

[0072]

[0073] in

[0074] H = cone height, in mm

[0075] r = radius of the metal cylinder, in mm

[0076] The results are summarized in Figure 3 middle.

Claims

1. A method for preparing free-flowing particles comprising or consisting of an N-guanidino amino acid, wherein the method comprises the following steps: a) providing a solution or suspension comprising an N-guanidino amino acid, b) shifting the pH of the solution or suspension provided in step a) to a pH below the pKa value of the N-guanidino amino acid, and c ) converting the pH of the solution or suspension obtained in step b) to a pH greater than the pKa value of the N-guanidino amino acid and lower than the pKb value of the N-guanidino amino acid, wherein step c) further comprises precipitating or crystallizing particles comprising or consisting of the N-guanidino amino acid, The pH in each of steps b) and c) is measured by a pH electrode.

2. The method according to claim 1, further comprising the steps of: d) separating the precipitated or crystallized particles comprising or consisting of the N-guanidino amino acid from the solution or suspension obtained in step c), and e) The particles separated in step d) are dried.

3. The method according to any one of claims 1 to 2, wherein the solvent of the solution or suspension provided in step a) comprises or consists of water, an organic solvent or a mixture thereof.

4. The process according to claim 1, wherein the pH value set in steps b) and / or c) is maintained for a period of up to 30 minutes.

5. The method according to any one of claims 1 to 4, wherein the N-guanidinoamino acid is guanidinoacetic acid.

6. The process according to claim 5, wherein the pH of the solution or suspension obtained in step b) is below the pKa of guanidinoacetic acid.

7. The process according to claim 6, wherein the pH of the solution or suspension obtained in step b) is below 2.

9.

8. The process according to any one of claims 5 to 7, wherein the pH of the solution or suspension obtained in step c) is greater than the pKa of guanidinoacetic acid and lower than the pKb of guanidinoacetic acid.

9. The process according to claim 8, wherein the pH of the solution or suspension obtained in step c) is greater than 2.9 and below the pKb of guanidinoacetic acid.

10. The process according to claim 8, wherein the pH of the solution or suspension obtained in step c) is greater than 4 and less than 10.

91.

11. The process according to claim 8, wherein the pH of the solution or suspension obtained in step c) is between 5 and below 10.

91.

12. The process according to any one of claims 1 to 11, wherein crystallization of guanidinoacetic acid begins at a pH of 5 or higher.

13. The method according to any one of claims 1 to 12, wherein the solution or suspension comprising an N-guanidino amino acid provided in step a) or the N-guanidino amino acid contained in the solution or suspension is produced by a chemical reaction of an amino acid with cyanamide.

14. The method according to any one of claims 1 to 12, wherein the solution or suspension comprising an N-guanidino amino acid provided in step a) or the N-guanidino amino acid contained in the solution or suspension is produced by fermentation of an N-guanidino amino acid.

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