Preparation of metastable crystalline modifications of N-(aminoiminomethyl)-2-aminoacetic acid (III)

Abstract

The present invention relates to novel crystalline modifications and crystalline mixtures of N(aminoiminomethyl)-2-aminoacetic acid, as well as methods for preparing said crystalline modifications and said crystalline mixtures.

Description

[Technical field]

[0001] The present invention relates to novel crystalline modifications, crystalline mixtures of N-(aminoiminomethyl)-2-aminoacetic acid, as well as processes for preparing said crystalline modifications and said crystalline mixtures. [Background technology]

[0002] N-(aminoiminomethyl)-2-aminoacetic acid (CAS No. 352-97-6, molecular formula C3H7N3O2), also known as N-(aminoiminomethyl)-2-aminoethanoic acid, guanidinoacetic acid, guanidinoaceate, glycocyamine, N-amidinoglycine or N-(aminoiminomethyl)-glycine, is a widely used chemical compound, particularly in the synthesis of pharmaceuticals (see WO2000 / 059528), for direct use as a medicine in renal diseases (see JP60054320) or neurodegenerative diseases (see CN106361736), in the manufacture of polymers (see Du, Shuo et.al., Journal of Materials Science(2018),53(1),215-229), as a complexing agent for metals (Lopes de Miranda al., Polyhedron (2003), 22(2), 225-233 or Singh, Padmakshi et.al, Oriental Journal of Chemistry (2008), 24(1), 283-286) and as an additive for feeding of animals, in particular mammals, fish, birds (see WO 2005 / 120246) and humans (see WO 2008 / 092591, DE 10 2007 053 369).

[0003] N-(aminoiminomethyl)-2-aminoacetic acid can be prepared, for example, from glycine by reaction with cyanamide according to Strecker, M. (Jahresber. Fortschr. Chem. Verw. (1861), 530). Alternatively, N-(aminoiminomethyl)-2-aminoacetic acid can be prepared, for example, by reacting glycine with S-methylisothiourea iodide using potassium hydroxide as base (see US 2,654,779). The reaction of chloroacetic acid with ammonia to give glycine hydrochloride and its further reaction with cyanamide has also been described (see US 2,620,354). Furthermore, the synthesis from chloroacetic acid and guanidine hydrochloride with the addition of sodium hydroxide solution is known (see CN101525305).

[0004] In the known processes, N-(aminoiminomethyl)-2-aminoacetic acid is obtained as a fine crystalline powder having a significant dust content, ie a significant proportion of particles having a particle size of less than 63 μm.

[0005] When dealing with chemical products in solid form, it is often desirable for them to be in a crystalline, granular, free-flowing, dust-free form with little or no fines. In particular, poorly flowing, dusty powders are completely unsuitable for use as feed additives.

[0006] To address this problem, it has been proposed to convert N-(aminoiminomethyl)-2-aminoacetic acid into moldings, granules or extrudates, for example by adding a polymeric binder (e.g. methylcellulose) in an amount of 0.05 to 15% by weight and by adding water (see WO 2009 / 012960). The disadvantage of this method is that the addition of a foreign material, i.e. a binder, is absolutely necessary and the granules or moldings have to be produced in an additional process step using special, technically complex and expensive equipment such as extruders, granulators, intensive mixers or ploughshare mixers, and subsequent drying.

[0007] A further disadvantage of the above-mentioned state-of-the-art methods is that the moldings or granules have a high binder content and thus a low dissolution rate, or dissolve relatively quickly at low binder contents, but at the same time have low strength and high abrasion values, so that the absence of dust can no longer be guaranteed. Summary of the Invention

[0008] It was therefore an object of the present invention to provide a process for the preparation of N-(aminoiminomethyl)-2-aminoacetic acid in the form of free-flowing, non-dusty crystalline aggregates which does not have the disadvantages of the prior art, but which can be produced simply and in standard equipment widely used in the chemical industry, and which also has high solubility.

[0009] These objects are achieved by a process for the preparation of N-(aminoiminomethyl)-2-aminoacetic acid, which contains N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystalline modification according to claim 1 and by a crystalline mixture containing N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystalline modification according to claim 9. Preferred embodiments of the invention are given in the dependent claims, which may be combined with one another in any way.

[0010] The occurrence of chemical substances in different crystalline forms or crystal modifications (polymorphism) is of great importance both for the production and application of substances and for the development of formulations. That is, the various crystal modifications of a chemical compound differ not only in appearance (crystal habit) but also in many other physical or physicochemical properties. It is not yet possible to predict the occurrence and number of crystal modifications, including their physical or physicochemical properties. In particular, the thermodynamic stability and also the different behavior after administration in the living body cannot be determined in advance.

[0011] Under given pressure and temperature conditions, different polymorphic crystal modifications usually have different lattice energies or standard heats of formation. The crystal form with the lowest energy is called the stable form. Forms with higher energy levels are called metastable (under given pressure and temperature conditions) if they can be separated. Metastable polymorphs have a tendency to transform into stable polymorphs. For metastability, this requires the expenditure of activation energy, for example by the influence of heat, mechanical energy or the influence of a solvent.

[0012] Furthermore, it is generally known that different modifications of a substance can be monotropic or enantiotropic. In the case of monotropic polymorphism, the crystalline form or modification can represent a thermodynamically stable phase over the entire temperature range up to the melting point, whereas in enantiotropic systems there is a transition point where the stability behavior is reversed.

[0013] In the context of the present invention, it has been found that N-(aminoiminomethyl)-2-aminoacetic acid occurs in a thermodynamically metastable crystalline modification in addition to the already known thermodynamically stable crystalline modification, hereinafter also referred to as Form A or crystalline form A. This thermodynamically metastable crystalline form according to the invention is hereinafter also referred to as Form B or crystalline form B.

[0014] This thermodynamically metastable crystalline modification (form B) can be prepared by simple recrystallization of N-(aminoiminomethyl)-2-aminoacetic acid from aqueous solutions containing guanidine compounds. Surprisingly, in fundamental studies it was shown that this previously unknown thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid can also be prepared by direct synthesis of N-(aminoiminomethyl)-2-aminoacetic acid in solutions containing guanidine compounds.

[0015] Moreover, it is surprising that this new metastable crystalline modification, Form B, is stable up to its melting point. No solid-state transformation of Form B to Form A or reversible Form A / Form B solid-state transformation can be observed. That is, Form B is an example of a monotropic polymorphism. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Thus, according to a first embodiment of the invention, the subject of the present invention is a process for the preparation of N-(aminoiminomethyl)-2-aminoacetic acid, which contains the thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid, in which the N-(aminoiminomethyl)-2-aminoacetic acid is crystallized from an aqueous solution in the presence of at least one guanidine compound according to formula (I), where formula (I) is:

[0017] [ka]

[0018] (wherein the group R in formula (I) 1 , R 2 , R 3 , R 4 and X, Y and the index k are, independently of each other: R 1 ,R 2 = independently of each other hydrogen, C1 to C4 alkyl or together forming a ring, a group of formula (II), where formula (II) is

[0019] [ka]

[0020] (wherein Y=CH2, O, NH, NCH3 or a bond), R 3 ,R 4 = independently hydrogen or C1 to C4 alkyl, X = CH3COO, Cl, Br, NO3, SO3(NH2) or 1 / 2SO4, k=0 or 1).

[0021] The N-(aminoiminomethyl)-2-aminoacetic acid produced by this method can be present as a crystalline mixture, i.e. a crystalline mixture of Form A and Form B, or in pure form, i.e. 100% Form B. Thus, according to a further embodiment of the present invention, it is also an object of the present invention to provide a method for preparing a thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid, in which N-(aminoiminomethyl)-2-aminoacetic acid is crystallized from an aqueous solution in the presence of at least one guanidine compound of formula (I). This method can provide N-(aminoiminomethyl)-2-aminoacetic acid in pure form, i.e. 100% Form B.

[0022] Furthermore, the present invention relates to a process for the preparation of a crystalline mixture containing N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystalline modification, in particular containing N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystalline modification and N-(aminoiminomethyl)-2-aminoacetic acid in a stable crystalline modification, wherein N-(aminoiminomethyl)-2-aminoacetic acid is crystallized from an aqueous solution in the presence of at least one guanidine compound represented by formula (I).

[0023] According to the present invention, a crystalline mixture is to be understood as a mixture comprising crystalline forms of N-(aminoiminomethyl)-2-aminoacetic acid, where N-(aminoiminomethyl)-2-aminoacetic acid a) consists of crystals of form A and crystals of form B, or b) consists of crystals having at least a first partial region of form A and at least one second partial region of form B, or c) consists of crystals of form A and crystals of form B and at least one first partial region of form A and at least one second partial region of form B.

[0024] According to the invention, the crystalline mixture preferably has at least 10% by weight, more preferably at least 20% by weight, even more preferably at least 30% by weight of N-(aminoiminomethyl)-2-aminoacetic acid of form B. Preferred are crystalline mixtures in which at least 50% by weight, more preferably at least 75% by weight, even more preferably at least 90% by weight of N-(aminoiminomethyl)-2-aminoacetic acid is present in form B. Form B is characterized by a crystalline modification having the most intense reflection bands at 2Θ (2 theta) = 20.2° and 23.3° and 23.8° and 25.3° with a measurement accuracy of + / - 0.2° in the X-ray powder diffractogram, in particular using Cu-Kα radiation.

[0025] The remaining part of the N-(aminoiminomethyl)-2-aminoacetic acid is present in the crystal mixture according to the invention in another crystalline form, preferably in form A. Thus, the crystal mixture preferably comprises at least 10% by weight, preferably at least 20% by weight, more preferably at least 30% by weight of N-(aminoiminomethyl)-2-aminoacetic acid in form A.

[0026] The aqueous solutions used in these processes preferably contain at least 40% by weight, preferably at least 45% by weight, particularly preferably at least 50% by weight of water (based on the total weight of the solution). Very preferably, water may be used as the solvent in the process.

[0027] More preferably, N-(aminoiminomethyl)-2-aminoacetic acid can be dissolved in water or an aqueous solution in a first process step and N-(aminoiminomethyl)-2-aminoacetic acid containing the thermodynamically metastable crystalline modification can be crystallized in a second process step from the solution prepared in the first process step in the presence of the guanidine compound of formula (I).

[0028] It is also possible to use water or an aqueous solution which contains the guanidine compound of formula (I) already in the first method step.

[0029] Alternatively, however, the process can also be performed in such a way that N-(aminoiminomethyl)-2-aminoacetic acid is prepared in a first process step from cyanamide and glycine in water or in an aqueous solution, and N-(aminoiminomethyl)-2-aminoacetic acid containing the thermodynamically metastable crystalline modification is crystallized in a second reaction step from the reaction mixture prepared in the first process step in the presence of the guanidine compound of formula (I).

[0030] Thus, a process can be provided in which the desired product can be obtained directly without subsequent recrystallization.

[0031] It is also possible to use water or an aqueous solution which contains the guanidine compound of formula (I) already in the first process step, ie the reaction of cyanamide and glycine.

[0032] The product of crystallization in the presence of guanidine compounds is a thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid which in pure form shows the most intense reflection bands at 2Θ (2 theta) = 20.2° and 23.3° and 23.8° and 25.3° with a measurement accuracy of + / - 0.2° in the X-ray powder diffraction diagram of the crystalline modification when using Cu-Kα radiation.

[0033] As used herein and hereinafter, Cu-Kα radiation means copper K-alpha radiation of wavelength 1.5406 Å, commonly used in crystallographic studies.

[0034] The product of crystallization in the presence of guanidine compounds is a thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid, which crystallizes in pure form with Z=8, i.e. in the orthorhombic space group P212121 with two crystallographically independent molecules, and in particular exhibits pseudo-tetragonal packing. The unit cell has lattice parameters a=7.7685 Å, b=7.7683 Å, c=17.4261 Å with a measurement accuracy of + / - 0.001 Å at 105 Kelvin. Single crystal measurements were performed with Mo-Kα radiation of wavelength 0.71073 Å at 105 K (Kelvin).

[0035] According to the present invention, an orthorhombic space group means a space group in which the unit cell has three right angles (right angles=90°) and the three crystal axes a, b and c have different lengths.

[0036] According to a preferred embodiment, the present invention thus also relates to a method for the preparation of a thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid, which in its pure form preferably exhibits the most intense reflection bands at 2Θ=20.2° and 23.3° and 23.8° and 25.3° with a measurement accuracy of + / -0.2° in the X-ray powder diffraction diagram of said crystalline modification using Cu-Kα radiation, more preferably exists in the orthorhombic space group P212121, in particular in the orthorhombic polar space group P212121 with Z=8, more preferably has a pseudo-tetragonal packing. The unit cell has lattice parameters a=7.7685 Å, b=7.7683 Å, c=17.4261 Å with a measurement accuracy of + / -0.001 Å at 105 Kelvin. Single crystal measurements were carried out using Mo-Kα radiation with a wavelength of 0.71073 Å at 105 K (Kelvin).

[0037] Under suitable crystallization conditions, this new crystalline form B forms polygonal or spherical, radially radiating, acicular subcrystallite aggregates with a rounded habit and an almost uniform aggregate size. That is, they ensure optimal handling as a solid by providing a dust-free, flowable product with no tendency to caking. The crystalline modification B can be classified as low-dusty since the proportion of crystals with a particle size (mesh size) of less than 63 μm is less than 10%, preferably less than 5% (see examples). Due to the structure of the fine acicular subcrystallites, this habit of the new crystalline form B of N-(aminoiminomethyl)-2-aminoacetic acid also ensures a higher dissolution rate. Furthermore and quite unexpectedly, the crystalline form B of N-(aminoiminomethyl)-2-aminoacetic acid also provides a higher absolute solubility in aqueous media.

[0038] When N-(aminoiminomethyl)-2-aminoacetic acid is prepared by one of the known methods, especially from a reaction mixture containing water, the compound is obtained in the well-known crystalline form A. One and the same crystal structure has been described by three groups of authors: Sankarananda Guha, Acta Cryst. B29 (1973), 2163 and Par J. Berthou et. al. Acta Cryst B32 (1976), 1529 and Wei Wang et. al, Tetrahedron Letters 56 (2015), 2684, respectively. In all three papers, N-(aminoiminomethyl)-2-aminoacetic acid (herein referred to as form A) is described as having a crystal structure of about 510 Å with Z=4 and approximate lattice parameters a=4.95 Å, b=6.00 Å, c=17.2 Å, β=94.5°. 3 It has been described as a monoclinic structure in space group P21 / n with a lattice volume of 1.0 g / cm, whereby in Berthou et al. the published space group P21 / c was converted to space group P21 / n via coordinate transformation. The experimental crystal density of form A of N-(aminoiminomethyl)-2-aminoacetic acid is approximately 1.50 g / cm. 3A characteristic powder diffractogram of N-(aminoiminomethyl)-2-aminoacetic acid form A is shown in FIG. 1. In particular, the band positions 2Θ (2 theta)=20.7° and 26.0° are characteristic of form A when Cu-Kα radiation (copper K-alpha radiation) is used. The powder diffractogram is consistent with the diffraction pattern calculated from the published single crystal structure data.

[0039] When N-(aminoiminomethyl)-2-aminoacetic acid is crystallized, recrystallized or prepared from conventional solvents such as water, methanol, ethanol, isopropanol or mixtures of methanol, ethanol, ethanediol or acetonitrile with water in the absence of the guanidine compound according to formula (I), N-(aminoiminomethyl)-2-aminoacetic acid is obtained exclusively in crystalline form A, as has been shown by experiments.

[0040] Surprisingly, it has been found that N-(aminoiminomethyl)-2-aminoacetic acid is preferentially formed in crystalline form B during crystallization from water or an aqueous solution containing a guanidine compound. This is all the more surprising since in the known synthesis of N-(aminoiminomethyl)-2-aminoacetic acid from chloroacetic acid and guanidine hydrochloride no further crystalline forms are formed in addition to the known crystalline form A (see examples).

[0041] N-(aminoiminomethyl)-2-aminoacetic acid in form B (pure form) is characterized by its powder diffractogram with Cu-Kα radiation (see Figure 2), in which bands at 2Θ (2theta) = 20.2° and 25.3° and a weaker double reflection at 2Θ (2theta) = 23.3° / 23.8° are characteristic. Single crystal X-ray structure analysis revealed for N-(aminoiminomethyl)-2-aminoacetic acid in form B an orthorhombic polar space group P212121 with Z = 8, i.e., with two crystallographically independent molecules. The molecular packing shows pseudotetragonal symmetry. The unit cell has lattice constants a = 7.7685 Å, b = 7.7683 Å, c = 17.4261 Å with a measurement accuracy of + / - 0.001 Å at 105 Kelvin. The single crystal measurements here were performed using Mo-Kα radiation with a wavelength of 0.71073 Å. The unit cell volume is 1052 Å. 3 and the calculated X-ray crystal density is 1.479 g / cm at 105 Kelvin. 3 It is.

[0042] The experimental crystal density of form B of N-(aminoiminomethyl)-2-aminoacetic acid is 1.41 g / cm at 20 °C. 3 + / -0.03g / cm 3 That is, the experimental crystal density of Form B is 1.50 g / cm at 20° C. 3 + / -0.03g / cm 3 This difference in crystal density indicates the thermodynamic instability of form B compared to form A.

[0043] Crystalline form B of N-(aminoiminomethyl)-2-aminoacetic acid exists in the form of spherical or polygonal radially radiating aggregates with an outer rounded habit. Single crystals represent the finest needles from which the spherical aggregates are formed. This has the surprising advantage that form B can be used to provide a physical form of N-(aminoiminomethyl)-2-aminoacetic acid, including spherical or polygonal granular wear-resistant aggregates, with nearly uniform aggregate size, excellent pourability and almost no dust. A typical crystalline aggregate of N-(aminoiminomethyl)-2-aminoacetic acid in form B is shown in FIG. 4. For comparison, prior art N-(aminoiminomethyl)-2-aminoacetic acid in form A, with a matted fine crystalline needle habit, is shown in FIG. 3.

[0044] Forms A and B of N-(aminoiminomethyl)-2-aminoacetic acid also differ in their infrared spectra. Form A is characterized by peaks at 1005.9, 940.3 and 816.8 cm. -1 Form B is characterized by stronger bands at 1148.0, 997.7 and 815 cm -1 It is the only weak band in the.

[0045] Furthermore, the two crystalline forms exhibit different melting and decomposition points in their pure forms. - N-(aminoiminomethyl)-2-aminoacetic acid form A: DSC onset 280.5°C, peak 286.3°C, heat of fusion 887+ / -1J / g - N-(aminoiminomethyl)-2-aminoacetic acid form B: DSC onset 272.5°C, peak 280.4°C, heat of fusion 860+ / -1J / g

[0046] These data impressively show that N-(aminoiminomethyl)-2-aminoacetic acid form B is a thermodynamically metastable crystalline modification that is the thermodynamically more unstable form compared to form A, with an energy difference of about 27 J / g between the two forms and an 8 K difference in the onset of the melting region.

[0047] Further investigations showed that N-(aminoiminomethyl)-2-aminoacetic acid form B has approximately 20% higher water solubility than that of N-(aminoiminomethyl)-2-aminoacetic acid form A, and that this fact holds true in the temperature range between 5 and 95° C. (see FIG. 5). This effect is completely unpredictable.

[0048] In summary, it should be emphasized here that N-(aminoiminomethyl)-2-aminoacetic acid in the crystalline modification B, produced in particular by crystallization of N-(aminoiminomethyl)-2-aminoacetic acid from aqueous solutions containing guanidine compounds, surprisingly combines advantageous and usually opposite properties, such as, for example, coarse, free-flowing particles and at the same time a high dissolution rate, the formation of crystalline aggregates without the addition of binders, and provides increased absolute solubility at a given temperature, despite an identical chemical composition.

[0049] Due to its excellent properties, this new crystalline modification is suitable for use as a feed additive for animals. That is, a feed additive comprising the thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid described herein is also an object of the present invention. The feed additive is particularly suitable for poultry.

[0050] Such a feed additive may be formulated as a premix, i.e., furthermore, the use of the thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid described herein or a crystalline mixture containing said crystalline modification for the preparation of a feed additive is also an object of the present invention.

[0051] Surprisingly, fundamental investigations have shown that this previously unknown thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid as well as N-(aminoiminomethyl)-2-aminoacetic acid containing this thermodynamically metastable crystalline modification and crystalline mixtures containing this thermodynamically metastable crystalline modification can be prepared by direct synthesis of N-(aminoiminomethyl)-2-aminoacetic acid in an aqueous solution containing a guanidine compound.

[0052] The present invention thus also relates to a1) a method for producing a thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid, a2) a method for producing N-(aminoiminomethyl)-2-aminoacetic acid containing a thermodynamically metastable crystalline modification, and a3) a method for producing a crystalline mixture containing N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystalline modification, in particular a crystalline mixture containing N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystalline modification and N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically stable crystalline modification. The method comprises the steps of: preparing N-(aminoiminomethyl)-2-aminoacetic acid from cyanamide and glycine in water or in an aqueous solution in a first method step; and a1) obtaining said thermodynamically metastable crystalline modification; or a2) obtaining N-(aminoiminomethyl)-2-aminoacetic acid containing said thermodynamically metastable crystalline modification; or a3) obtaining said crystalline mixture in a second method step from the reaction mixture prepared in the first method step in the presence of a guanidine compound of formula (I).

[0053] The guanidine compounds suitable for the method according to the invention are those of formula (I)

[0054] [ka]

[0055] (wherein the group R in formula (I) 1 , R 2 , R 3 , R 4 and X, Y and the index k are, independently of each other: R 1 ,R 2 = independently of each other hydrogen, C1 to C4 alkyl or, taken together to form a ring, a group of formula (II), where formula (II) is:

[0056] [ka]

[0057] (wherein Y=CH2, O, NH, NCH3 or a bond), R 3 ,R 4 = independently hydrogen or C1 to C4 alkyl, X = CH3COO, Cl, Br, NO3, SO3(NH2) or 1 / 2SO4, (meaning k=0 or 1).

[0058] In this specification, C1 to C4 alkyl means in particular methyl, ethyl, n-propyl, 2-methyl-ethyl, n-butyl, 2-methyl-propyl or 1-methyl-propyl. Particularly preferably, C1 to C4 alkyl means methyl or ethyl.

[0059] At least one group R 1 , R 2 , R 3 , R 4 Further preferred are guanidine compounds of formula (I) wherein is not hydrogen.

[0060] More preferably, R 1 ,R 2 = independently of each other hydrogen, methyl or ethyl or, taken together to form a ring, a radical of formula (II), where formula (II) is:

[0061] [ka]

[0062] (wherein Y=O, NH or NCH3), R 3 ,R 4 = hydrogen, X = CH3COO, Cl, Br, NO3, SO3(NH2) or 1 / 2SO4, Guanidine compounds of formula (I) where k=0 or 1 can be used.

[0063] The preferred compound is (HX) k is not a hydrochloride or hydrobromide. More preferably, the group X is: X = CH3COO, NO3, SO3(NH2) or 1 / 2SO4 is a guanidine compound of formula (I) which means:

[0064] More preferably, R 1 ,R 2 = independently hydrogen, methyl or ethyl, R 3 ,R 4 = hydrogen, X = CH3COO, Cl, Br, NO3, SO3(NH2) or 1 / 2SO4, Guanidine compounds of formula (I) where k=0 or 1 can be used.

[0065] More preferably, salts can be used as the guanidine compounds, i.e., the guanidine compounds of formula (I) in which the following applies: k=1 can be preferably used.

[0066] Alternatively, and preferably, charge-neutral compounds may be used as guanidine compounds, i.e., preferably, guanidine compounds of formula (I) with k = 0 may be used. These compounds may be generated in situ by the addition of a base.

[0067] That is, alternatively and preferably:

[0068] [ka]

[0069] (wherein the group R in formula (I) 1 , R 2 , R 3 , R 4 and X, Y and the index k are, independently of each other: R 1 ,R 2= independently of each other hydrogen, C1 to C4 alkyl or, taken together to form a ring, a group of formula (II), where formula (II) is:

[0070] [ka]

[0071] (wherein Y=CH2, O, NH, NCH3 or a bond), R 3 ,R 4 = independently hydrogen or C1 to C4 alkyl, Guanidine compounds according to formula (I) for which k=0) may also be used.

[0072] The guanidine compounds required for the process of the present invention can be prepared in part by known routes. 1 =R 2 =R 3 =R 4 =H) can be prepared by reacting ammonium salts with cyanamide or dicyandiamide. N-substituted or N,N'-disubstituted guanidines can be prepared, for example, by reacting amines or amino acids with cyanamide or O-alkylisoureas, respectively. Higher substituted guanidine compounds are accessible by reacting chloro or bromo cyanogen with amines or amino acids. Alternatively, these compounds can be prepared by reacting thiourea derivatives with amines or amino acids.

[0073] Said guanidine compounds of formula (I) can be used as individual substances or in combination, in particular in combinations of two or more different guanidine compounds of formula (I), to induce the formation of the thermodynamically metastable form B during the crystallization of N-(aminoiminomethyl)-2-aminoacetic acid. The amounts of the mentioned guanidine compounds added can vary within wide limits.

[0074] Preferably, the guanidine compound of formula (I) can be used in an amount corresponding to 80% of the maximum amount that can be dissolved in water at normal pressure and 25°C. In this way, it can be ensured that the guanidine compound necessary for the crystallization of form B is not included in the crystal structure during crystallization. More preferably, the guanidine compound of formula (I) can be used in an amount of at least 0.1% by weight and at most 60% by weight (based on the total weight of the solution). Preferably, the guanidine compound of formula (I) can be used in an amount of at least 0.5% by weight, more preferably at least 1% by weight, more preferably at least 2% by weight, more preferably at least 5% by weight, more preferably at least 8% by weight, more preferably at least 10% by weight, more preferably at least 15% by weight, even more preferably at least 20% by weight, particularly preferably at least 25% by weight and very particularly preferably at least 30% by weight, even more preferably at most 60% by weight (based on the total weight of the solution in each case). At the same time, the guanidine compounds of formula (I) can be used in an amount of preferably up to 50% by weight, more preferably up to 40% by weight, preferably up to 30% by weight, particularly preferably up to 25% by weight and very particularly preferably up to 20% by weight (in each case based on the total weight of the solution).

[0075] Preferred is a process for the preparation of N-(aminoiminomethyl)-2-aminoacetic acid containing the thermodynamically metastable crystalline modification, in which N-(aminoiminomethyl)-2-aminoacetic acid is crystallized from an aqueous solution in the presence of at least one guanidine compound of formula (I), the guanidine compound being used in an amount of at least 8% by weight and at most 60% by weight, more preferably at least 10% by weight and at most 60% by weight, and very particularly preferably at least 15% by weight and at most 60% by weight.

[0076] According to the invention, if it is desired to obtain N-(aminoiminomethyl)-2-aminoacetic acid in pure form B or with the highest possible content of form B, the guanidine compound of formula (I) is preferably used in an amount of at least 30% by weight, more preferably at least 40% by weight and even more preferably at least 50% by weight, in each case based on the total weight of the solution.

[0077] The higher the concentration of the defined guanidine compound according to the invention, the higher the content of Form B in the crystallized product.

[0078] The present invention thus also relates to a1) a process for the preparation of a thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid, a2) a process for the preparation of N-(aminoiminomethyl)-2-aminoacetic acid containing a thermodynamically metastable crystalline modification, and a3) a process for the preparation of a crystalline mixture containing N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystalline modification, in particular a crystalline mixture containing N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystalline modification and N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically stable crystalline modification, in which an aqueous solution is used, the amount of water being at least 40% by weight, preferably at least 45% by weight, more preferably at least 50% by weight and particularly preferably at most 95% by weight (based on the total weight of the solution) and the amount of guanidine compounds according to formula (I) being at least 0.5% by weight and at most 60% by weight (based on the total weight of the solution).

[0079] Further preferred is a method in which glycine is provided in water or an aqueous solution containing at least one dissolved guanidine compound of formula (I) in a concentration of at least 5% by weight and at most 60% by weight, and cyanamide is added, which can thereby further preferably be in the form of a solid or in the form of a solution, in particular an aqueous cyanamide solution.

[0080] The aqueous solution may be a solution capable of dissolving glycine and cyanamide.

[0081] The aqueous solution provided for dissolving glycine can preferably contain at least 40% by weight of water and one or more, in particular up to 20, different guanidine compounds according to formula (I), each individually in a concentration of 0.1 to 60% by weight, so that the sum of all guanidine compounds constitutes a proportion of 0.5 to 60% by weight. Glycine dissolved therein in a concentration of 3 to 30% by weight, as well as other substances or mixtures that may contain water (for example sodium hydroxide solution), are added. The mixture before administration of cyanamide preferably has a water content of 35 to 90% by weight. Cyanamide is preferably administered as an aqueous solution, in particular in a concentration of 5 to 60% by weight, preferably 28 to 52% by weight (based on aqueous cyanamide solution).

[0082] It is also recommended that the reactants of the reaction, i.e. cyanamide and glycine, are reacted, i.e. converted, at a reaction temperature in the range of 20 to 100° C., preferably in the range of 60 to 100° C. This can occur at normal pressure, under vacuum or even under pressure. Preferably, the reaction can occur at normal pressure in the temperature range of 20 to 100° C.

[0083] However, it is also recommended to carry out the reaction at a pH ranging from 7.0 to 10.0, preferably from 8.0 to 10.0. The pH is adjusted with a suitable base, which can be both organic and inorganic bases. Preferably, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia or aqueous solutions thereof can be used. Particular preference can be given to sodium hydroxide, calcium hydroxide and aqueous solutions thereof.

[0084] The reaction proceeds without complications under these conditions, whereby the product formed is gradually formed in the reaction mixture and can already crystallize during the reaction. After the addition of cyanamide is complete, the reaction mixture can continue to react for some time. As soon as the saturation point, i.e. the maximum concentration at the reaction temperature, is reached, crystallization begins. According to the method of the present invention, crystal nucleation and crystallization preferably occur in the state of form B, and the presence of at least one of the mentioned guanidine compounds is considered essential to the present invention. Crystallization of the desired product can occur at temperatures ranging from -40 to 100 ° C.

[0085] Surprisingly, it has also been found that the presence of the guanidine compound of formula (I) in the reaction mixture increases the solubility of N-(aminoiminomethyl)-2-aminoacetic acid, in some cases significantly, such that most of the N-(aminoiminomethyl)-2-aminoacetic acid is obtained from the aqueous solution, even in crystalline form B. Preferably, the process is carried out by crystallizing N-(aminoiminomethyl)-2-aminoacetic acid, i.e. in a temperature range of from -40 to 100°C, in particular in a temperature range of from -40 to 70°C, more preferably in a temperature range of from -40 to 50°C, more preferably in a temperature range of from -40 to 40°C.

[0086] However, particularly preferred are methods in which the crystallization occurs in a controlled manner, where the reaction mixture is exposed to a defined temperature difference for a certain time interval, in this way a particularly uniform crystallization can be achieved.

[0087] Thus, a particularly preferred method is one in which N-(aminoiminomethyl)-2-aminoacetic acid is crystallized in the temperature range of -40 to 100°C with a cooling rate in the range of 0.01 to 5 K / min, more preferably in the range of 0.1 to 5 K / min, more preferably in the range of 0.5 to 5 K / min.

[0088] In both cases, conventional stirred reactors are preferably used. The use of complex technical equipment is not necessary.

[0089] After complete crystallization of the desired N-(aminoiminomethyl)-2-aminoacetic acid form B, the crystallized product is preferably collected by filtration, for example by centrifugation, pressure suction filter, belt filter or filter press. To remove excess reactants and guanidine compounds, the product is preferably washed with a solvent or solvent mixture as described above. Preferably, washing is carried out with water, whereby the temperature of the washing water is preferably between 0 and 50° C.

[0090] Of course, in order to improve the economics of the process, it is possible to recycle the mother liquor obtained from the separation of N-(aminoiminomethyl)-2-aminoacetic acid in crystalline form B to the process, optionally by adding further guanine compound and / or increasing its concentration, for example by evaporation.

[0091] After drying, preferably in the temperature range of 40 to 100° C., the process according to the invention results in a dry, free-flowing, granular product consisting of radially radiating polygonal or rounded agglomerates. The crystalline agglomerates have an external dimension, in particular a mesh size, of 150 to 3,000 μm, preferably 300 to 1,500 μm and a dust content of less than 5% by weight (i.e. a particle content of less than 63 μm).

[0092] The N-(aminoiminomethyl)-2-aminoacetic acid form B thus produced has a high purity, typically >99.0%, is easy to handle and hardly exhibits any mechanical wear. These properties make the crystalline form B of N-(aminoiminomethyl)-2-aminoacetic acid according to the invention particularly suitable for the above mentioned applications, in particular as a food additive or as a medicinal drug.

[0093] That is, according to a further aspect, the present invention also relates to the use of a1) the thermodynamically metastable crystalline modification of N-(aminoiminomethyl)-2-aminoacetic acid and a2) N-(aminoiminomethyl)-2-aminoacetic acid containing the thermodynamically metastable crystalline modification and a3) a crystalline mixture containing N-(aminoiminomethyl)-2-aminoacetic acid in the thermodynamically metastable crystalline modification, in particular a crystalline mixture containing N-(aminoiminomethyl)-2-aminoacetic acid in the thermodynamically metastable crystalline modification and N-(aminoiminomethyl)-2-aminoacetic acid in the thermodynamically stable crystalline modification, in each case for the preparation of a food supplement or for the preparation of a feed additive.

[0094] According to the present invention, N-(aminoiminomethyl)-2-aminoacetic acid can be provided in a thermodynamically metastable crystalline modification, wherein the N-(aminoiminomethyl)-2-aminoacetic acid is completely, i.e. 100%, in form B.

[0095] Namely, a method for preparing the thermodynamically metastable crystalline modification of N-(aminoiminoethyl)-2-aminoacetic acid is also an object of the present invention, whereby the thermodynamically metastable crystalline modification has the orthorhombic space group P212121 with Z=8 and lattice parameters a=7.7685 Å, b=7.7683 Å and c=17.4261 Å at 105 Kelvin and a measurement accuracy of + / - 0.001 Å.

[0096] Alternatively, N-(aminoiminomethyl)-2-aminoacetic acid according to the present invention may exist as a crystalline mixture, where form B and form A of N-(aminoiminomethyl)-2-aminoacetic acid crystallize side-by-side in different crystals or side-by-side within a crystal.

[0097] That is, it is also an object of the present invention to provide a crystal mixture containing N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystal modification. Preferably, the crystal mixture contains N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystal modification and N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically stable crystal modification.

[0098] Further preferably, the crystalline mixture contains N-(aminoiminomethyl)-2-aminoacetic acid in the thermodynamically metastable crystalline modification and N-(aminoiminomethyl)-2-aminoacetic acid in the thermodynamically stable crystalline modification in a weight ratio in the range of 0.1:9.9 to 9.9:0.1, more preferably in the range of 1:9 to 9:1, more preferably in the range of 1:1 to 9:1, more preferably in the range of 2:1 to 9:1 and particularly preferably in the range of 4:1 to 9:1.

[0099] Due to their crystalline properties, these crystal mixtures are excellently suitable as feed additives for breeding and fattening animals. Namely, a feed additive for breeding and fattening animals comprising a crystal mixture containing N-(aminoiminomethyl)-2-aminoacetic acid in the thermodynamically metastable crystalline modification and N-(aminoiminomethyl)-2-aminoacetic acid in the thermodynamically stable crystalline modification is also an object of the present invention.

[0100] Particularly preferred is a feed additive, wherein the crystalline mixture contains N-(aminoiminomethyl)-2-aminoacetic acid in the thermodynamically metastable crystalline modification and N-(aminoiminomethyl)-2-aminoacetic acid in the thermodynamically stable crystalline modification in a weight ratio in the range of 0.1:9.9 to 9.9:0.1, more preferably in the range of 1:9 to 9:1, more preferably in the range of 1:1 to 9:1, more preferably in the range of 2:1 to 9:1 and especially preferred in the range of 4:1 to 9:1.

[0101] The following examples further illustrate the principles of the present invention. [Brief description of the drawings]

[0102] Description of the drawings The drawings show: [Figure 1] FIG. 2 is an X-ray powder diffraction diagram of N-(aminoiminomethyl)-2-aminoacetic acid Form A of Example 1. [Diagram 2] X-ray powder diffraction pattern of N-(aminoiminomethyl)-2-aminoacetic acid Form B of Example 2.1. [Diagram 3]FIG. 2 is a photomicrograph (image width 8 mm) of N-(aminoiminomethyl)-2-aminoacetic acid Form A prepared according to Example 1. [Figure 4] Micrograph (image width 8 mm) of polygonal aggregates of N-(aminoiminomethyl)-2-aminoacetic acid, form B, prepared by recrystallization from 50% aqueous guanidine hydrochloride solution according to Example 2.1. [Diagram 5] Solubility curves of N-(aminoiminomethyl)-2-aminoacetic acid in water for Form A and Form B, respectively. [Figure 6] Diagram of two crystallographically independent molecules of N(aminoiminomethyl)-2-aminoacetic acid from single crystal X-ray structure analysis. [Figure 7] Diagram of molecular packing of N-(aminoiminomethyl)-2-aminoacetic acid in the crystal structure. The direction of view is along the a-axis. Separate molecular chains arranged perpendicular to each other and connected by H-bridges can be clearly seen parallel to the a- and b-axes. These chains are stacked along the c-axis. [Figure 8] Concentration-dependent bulk density of Form B. [Figure 9] Calibration curve for the ratio of crystalline form B to crystalline form A. [Figure 10] DSC N-(aminoiminomethyl)-2-aminoacetic acid form A. [Figure 11] DSC N-(aminoiminomethyl)-2-aminoacetic acid form B. EXAMPLES

[0103] Guanidine compounds used Technically available guanidine compounds were purchased commercially. Guanidine hydrochloride: Sigma-Aldrich order number G4505 Guanidine sulfamate: TCI Chemicals order number G0022 Guanidine nitrate: Sigma-Aldrich order number 234249 Guanidine acetate: Sigma-Aldrich order number 50920 N,N'-Dimethylguanidine hydrochloride: AlzChem AG N,N'-Dimethylguanidine sulfate: Sigma-Aldrich order number 276669 N,N'-Diethylguanidine sulfate: TCI Chemicals order number D2035, 1-(Aminoiminomethyl)-4-methyl-piperazine sulfate: ABCR GmbH, order number AB288540 4-(Aminoiminomethyl)-morpholine acetate: ABCR GmbH, order number AB301888 N-Methylguanidine sulfate: TCI Chemicals, order number M1691 N-Ethylguanidine sulfate: Sigma-Aldrich, order number 275557

[0104] X-ray powder diffraction measurements In the scope of this example, X-ray powder diffraction measurements were carried out using a Bruker D2 Phaser powder diffractometer with theta / 2theta geometry, a LYNXEYE detector, Cu-Kα radiation of wavelength 1.5406 Å with an accelerating voltage of 30 kV and an anode current of 10 mA, a nickel filter and an increment of 0.02°. Samples for examination were ground in an agate mortar and pressed onto a sample plate according to the manufacturer's instructions to smooth the surface.

[0105] Calibration curve for radiographic determination of form A / B ratio XRD data was obtained using mechanical mixtures of pure GAA form A and form B samples. For quantitative evaluation via peak height, the peak heights at 20.7° and 20.2° were used. A calibration curve (calibration line) determined from this with very good correlation coefficients was used for unknown samples to determine the ratio of form A / B (see Table 1 and Figure 9).

[0106] [Table 1]

[0107] For quantitative determination of the ratio of N-(aminoiminomethyl)-2-amino-ethanoic acid crystalline form B to crystalline form A, mechanical mixtures of powder samples of each pure crystalline form were prepared and measured on an X-ray powder diffractometer. The mixture ratios were 100:0, 95:5, 90:10, 80:20, 67:33, 50:50, 33:67, 20:80, 10:90, 5:95 and 0:100. The signal height (count rate) at 2-theta 20.2° (form B) was related to the sum of the signal heights at 2-theta 20.7° (form A) and 2-theta 20.2° (form B) and a calibration curve was determined from this. The correlation coefficient R 2 = 0.998, the following linear relationship was found:

[0108]

number

[0109] This formula was used in the following examples to determine the respective proportions of Form A and Form B.

[0110] Single crystal X-ray structure analysis Suitable crystals were prepared by evaporation of an aqueous solution of N-(aminoiminomethyl)-2-aminoacetic acid in the presence of N,N'-guanidinodiacetic acid. Single crystal measurements were performed at 105 Kelvin on a crystal of dimensions 0.02*0.02*0.09 mm using a dual cycle Bruker D8 Venture TXS diffractometer, using monochromatic Mo-Kα (molybdenum K-alpha) radiation of wavelength 0.71073 Å. Refinement of the X-ray crystal data using 2072 independent reflections gave an R value (F obs ) was performed by the least squares error method. The positions of the NH and OH hydrogen atoms were refined and the position of the CH hydrogen atom was fixed to the calculated position. The results of the X-ray single crystal structure analysis are illustrated in Figures 6 and 7. The back-calculated powder diffractogram from the single crystal structure analysis matched exactly with the measured powder diffractogram shown in Figure 2.

[0111] Example 1(Comparison) - Recrystallization of N-(aminoiminomethyl)-2-aminoacetic acid from water 400 g of water was provided at 80° C., into which a total of 11.66 g of N-(aminoiminomethyl)-2-aminoacetic acid present in crystalline form A with a content of 99.0% was dissolved spoon by spoon, exceeding the solubility limit with the last portion. It was then filtered at 80° C., and the filtrate was mixed with another 100 g of water and heated to 80° C. A nearly saturated clear solution was formed. By slowly cooling to 20° C. within 4 hours, N-(aminoiminomethyl)-2-aminoacetic acid crystallized. The precipitated crystals were filtered and dried in vacuum at 60° C., yielding 6.51 g of N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.1%.

[0112] The product obtained is in the form of fine crystalline needles, which were examined under a microscope (see FIG. 3). X-ray powder diffraction measurements produced the powder diffractogram shown in FIG. 1, which shows the well-known crystalline form A.

[0113] Example 2 Crystallization of N-(aminoiminomethyl)-2-aminoacetic acid from 2-guanidine hydrochloride solutions. A 50% solution was prepared from 250 g of guanidine hydrochloride and 250 g of water. To 400 g of this solution, N-(aminoiminomethyl)-2-aminoacetic acid of the same composition as in Example 1 was added spoon by spoon at 80° C. The solubility limit was exceeded with only an addition of 26.37 g. Small solids were filtered off at 80° C., and the filtrate was added to the remaining 100 g of the 50% solution of guanidine hydrochloride and stirred at 80° C. for 1 hour. A clear, colorless solution was obtained. Upon slow cooling to 20° C. within 4 hours, N-(aminoiminomethyl)-2-aminoacetic acid crystallized. The precipitated crystalline aggregates were filtered off, washed three times with water at 20° C. and dried at 60° C. 15.56 g of N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.2% was obtained. That is, the amount obtained was 2.4 times higher than that in Example 1, which is due to the significantly increased solubility of N-(aminoiminomethyl)-2-aminoacetic acid caused by the guanidine hydrochloride solution.

[0114] The powder diffractogram recorded likewise (see FIG. 2) showed the previously unknown crystalline form B. The polygonal rounded crystalline aggregates were examined microscopically (see FIG. 4).

[0115] The experiment was repeated in a similar manner with different concentrations of guanidine hydrochloride in water. It was found that form A of N-(aminoiminomethyl)-2-aminoacetic acid was increasingly formed with decreasing concentration (see Table 2). Thus, the concentration of the guanidine compound used in the solvent used for recrystallization of N-(aminoiminomethyl)-2-aminoacetic acid is of critical importance.

[0116] [Table 2]

[0117] Example 3 -Recrystallization of N-(aminoiminomethyl)-2-aminoacetic acid from aqueous solutions of other guanidine compounds Analogously to Example 2, aqueous solutions of various guanidine compounds were prepared at the respective concentrations (C) indicated. In 400 g of each solution, the respective indicated amount (M) of N-(aminoiminomethyl)-2-aminoacetic acid was dissolved at 80° C. After filtration at 80° C., another 100 g of the respective indicated aqueous solution of the guanidine compound was added, and the clear solution was stirred at 80° C. for 1 hour. By slow cooling to 20° C. within 4 hours, N-(aminoiminomethyl)-2-aminoacetic acid crystallized. The precipitated crystalline aggregates were filtered off, washed three times with water at 20° C. and dried at 60° C. In each case, the indicated amount (A) of N-(aminoiminomethyl)-2-aminoacetic acid with content (G) was obtained (see Table 3a / b).

[0118] Powder diffractograms of each product were obtained and examined for the presence of each crystalline form using the above formula for determining the proportion of Form A and Form B.

[0119] [Table 3]

[0120] [Table 4]

[0121] That is, the guanidine compounds according to formula (I) of the invention preferably induce crystalline form B during crystallization of N-(aminoiminomethyl)-2-aminoacetic acid (see Table 3b), although in some cases a mixture with form A also occurs. Other guanidines not according to the invention are unable to do this (see Table 3a).

[0122] Example 4 (Comparison)-Synthesis of N-(aminoiminomethyl)-2-aminoacetic acid from glycine and cyanamide in aqueous solution. 112.6 g (1.5 mol) of glycine was dissolved in 300 g of water. 21.6 g (0.27 mol) of 50% sodium hydroxide solution was added to the solution, resulting in a pH of 8.4. A solution of 42.04 g (1.0 mol) of cyanamide dissolved in 42 g of water was added over 4 hours at 80° C. The post-reaction was carried out for another hour at 80° C. The resulting suspension was cooled to 20° C., filtered, washed with water and dried at 60° C. 100.6 g of N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.1% was obtained. The yield was 85.9%.

[0123] The powder diffractogram of the resulting fine needle-like crystals showed the sole presence of Form A (100% Form A).

[0124] Example 5 (Comparative)-The synthesis of N-(aminoiminomethyl)-2-aminoacetic acid from chloroacetic acid and guanidine hydrochloride. As described in CN 101525305, 200 g of NaOH (solid, 5.0 mol) were dissolved in 600 g of water. At a maximum of 15° C., 480 g (5.03 mol) of solid guanidine hydrochloride were introduced. An aqueous solution of guanidine base was obtained. 460 g (4.87 mol) of chloroacetic acid were dissolved in 460 g of water. To this, 760 g of 25% sodium hydroxide solution (corresponding to 4.75 mol of NaOH) was added at 20° C. over 1 hour. An aqueous solution of sodium chloroacetate was obtained. The guanidine solution was dosed over 2 hours into the solution of sodium chloroacetate heated to 40° C. The after-reaction was carried out at 40° C. for 24 hours. The resulting white suspension was filtered, washed with water and dried at 60° C. 404 g (71%) of GAA with a content of 98% was obtained. X-ray powder diffraction analysis showed that the obtained GAA was in 100% crystalline form A. Despite the presence of guanidine (base) as a reactant, its concentration is not sufficient to affect the crystalline form of GAA. This is consistent with Example 2, since a measurable effect was only seen with guanidine hydrochloride at a concentration above 30% by weight. Since such a concentration is not achieved in the preparation process according to CN 101525305, only crystalline form A can be assumed for the product prepared by this process.

[0125] Example 6 (According to the invention) -Synthesis of N-(aminoiminomethyl)-2-aminoacetic acid from glycine and cyanamide in a 50% solution of guanidine hydrochloride. A solution was prepared from 150 g of guanidine hydrochloride and 150 g of water. 112.6 g (1.5 mol) of glycine were dissolved therein and a pH of 8.4 was adjusted with 22.4 g (0.28 mol) of 50% sodium hydroxide solution. A solution of 42.04 g (1.0 mol) of cyanamide dissolved in 42 g of water was added over 4 hours at 80° C. The post-reaction was carried out for another hour at 80° C. The resulting suspension was cooled to 20° C., filtered, washed with water and dried at 60° C. 100.8 g of N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.1% was obtained. The yield was 86.0%.

[0126] The powder diffractogram of the resulting radially radiating single crystalline rounded crystalline aggregates showed the sole presence of Form B (100% Form B).

[0127] Example 7 -Physicochemical properties of N-(aminoiminomethyl)-2-aminoacetic acid forms A and B 7.1 Melting or decomposition point A Mettler DSC 3+ instrument with a 40 μl aluminum crucible was used for dynamic differential scanning calorimetry (DSC). The heating rate was 10 Kelvin per minute in the temperature range of 30 to 350° C. Approximately 1.4 mg of each of the products of Examples 1 and 2.1 were weighed into the aluminum crucible and measured at atmospheric pressure (960 mbar at an altitude of 500 m above sea level).

[0128] The sample of Example 1 (=N-(aminoiminomethyl)-2-aminoacetic acid Form A) showed an onset (inflection point of the melting curve projected onto the baseline) of 280.5° C. and a peak temperature of the melting curve of 286.3° C. The total endothermic heat of fusion was 887 J / g (see FIG. 10). The product turned from white to brown during melting.

[0129] A sample of Example 2.1 (=N-(aminoiminomethyl)-2-aminoacetic acid Form B) was similarly measured: it showed an onset of 272.5° C. and a peak at 280.4° C. with a heat of fusion of 860 J / g and the same color change (see FIG. 11).

[0130] That is, Form B melts about 6 to 8 Kelvin lower and has a 27 J / g lower heat of fusion or 27 J / g higher lattice energy than Form A. In other words, to achieve the same energy melting state, Form B requires 27 J / g less energy than Form A. That is, Form B represents a metastable crystalline form or polymorph of N-(aminoiminomethyl)-2-aminoacetic acid that is higher in energy under ambient pressure and temperature conditions.

[0131] This new metastable crystalline modification, Form B, is stable up to the melting point. No solid state transformation of Form B to Form A or reversible Form A / Form B solid state transformation can be observed.

[0132] 7.2 Determination of Water Solubility 100 g of water at 5° C. was provided. The product of Example 1 (=N-(aminoiminomethyl)-2-aminoacetic acid form A) was dissolved therein until saturation was reached and the amount dissolved was determined by back-weighing. The temperature was then increased to 20° C. and as much sample as possible was added until the saturation point was reached again. The same was repeated at further temperatures, up to 95° C. Similar measurements were carried out with the product of Example 2.1 (=N-(aminoiminomethyl)-2-aminoacetic acid form B). The solubility data obtained for both products are graphically summarized in FIG. 5.

[0133] Both crystalline forms of N-(aminoiminomethyl)-2-aminoacetic acid are more soluble in water with increasing temperature. N-(aminoiminomethyl)-2-aminoacetic acid form B of the present invention is about 20% more soluble than the known form A at both temperatures.

[0134] 7.3 Density determination Crystals of N-(aminoiminomethyl)-2-aminoacetic acid Form A from Example 1 were introduced into tetrachloromethane at 20° C., where they floated on the surface. By adding dichloromethane dropwise, the density of the liquid medium was reduced until the crystals just began to float in the liquid without rising and sinking to the bottom. The density of the liquid phase was determined with a pycnometer. 1.50+ / -0.03 g / cm 3 The density of was measured.

[0135] The same procedure was followed using crystals of Form B from Example 2.1. The density at 20°C was 1.41 + / - 0.03 g / cm 3 It was determined that.

[0136] That is, form B has a 6% lower density than form A. This correlates with the lower lattice energy of form B determined above. The measured crystal density also agrees with the X-ray crystal density calculated from the respective lattice constants.

[0137] 7.4 Determination of dust content The product of Example 1 was sieved through a sieve with a mesh size of 63 μm (equivalent to a 230 mesh-mesh size). 46% by weight of fines was obtained. A similar procedure was followed with the sample of Example 2.1, consisting of polygonal rounded crystal agglomerates. Here, a fines content of less than 3% by weight was determined. A low-dust material that can be safely handled should therefore have a dust content of less than 10% (i.e. a particle content of <63 μm). The product of Example 2.1 (N-(aminoiminomethyl)-2-aminoacetic acid in crystalline form B) meets this, whereas Comparative Example 1 (N-(aminoiminomethyl)-2-aminoacetic acid in crystalline form A) does not.

[0138] 7.5 Determination of angle of repose The product of Example 1, consisting of tangled needle-like crystals, was poured onto a flat surface through a funnel using an apparatus according to DIN ISO 4324. After removing the funnel, the angle of repose of the resulting cone was determined using an angle measuring device. It was about 45°. N-(aminoiminomethyl)-2-aminoacetic acid form A therefore exhibits poor flow behavior. The granular product of Example 2.1 was measured in the same way. Here, an angle of repose of about 25° was obtained. Thus, N-(aminoiminomethyl)-2-aminoacetic acid form B exhibits excellent flow behavior.

[0139] 7.6 Determination of bulk density A weighed amount of the product of Example 1 was placed in a graduated cylinder and partially compressed by tapping it firmly twice on a laboratory bench. From the fill level of the graduated cylinder, the bulk density was found to be 0.37 g / cm 3 The same procedure was followed using the product of Example 2.1, where it was determined to be 0.62 g / cm 3The bulk density of Form B of N-(aminoiminomethyl)-2-aminoacetic acid was determined to be significantly increased, which is advantageous for packaging, shipping and handling of the product.

[0140] 7.7 Thermal stability of N-(aminoiminomethyl)-2-aminoacetic acid form B a) N-(aminoiminomethyl)-2-aminoacetic acid form B from Example 2.1 was placed in a drying oven at 120° C. for 6 hours. X-ray powder diffraction was then used to determine the crystalline form. This remained pure crystalline form B unchanged. b) N-(aminoiminomethyl)-2-aminoacetic acid form B of Example 2.1 was wetted with 20% water and incubated at 65° C. in a closed container for 6 hours and then dried. The X-ray powder diffraction pattern showed no change and form B remained stable. c) N-(aminoiminomethyl)-2-aminoacetic acid form B of Example 2.1 was prepared as a 10% suspension in water. The suspension was stirred at 80° C. for 2 hours. It was then cooled and the solid was filtered off and dried. X-ray powder diffraction showed that a mixture of crystalline forms A and B was present. d) N-(aminoiminomethyl)-2-aminoacetic acid form B of Example 2.1 was mostly recrystallized by dissolving in water at 80° C., cooling the solution, filtering and drying. X-ray powder diffraction gave pure crystalline form A.

[0141] That is, N-(aminoiminomethyl)-2-aminoacetic acid form B is very stable in solid form, but has a tendency to transform into crystalline form A through aqueous solutions. This behavior also confirms the metastable crystalline structure of form B.

[0142] 7.8 Physical properties of mixtures of Form A and Form B In Example 7.6, the bulk density of GAA form A is 0.37 g / cm 3 and that of GAA form B is 0.62 g / cm 3Starting with pure material samples of GAA form A or form B, mixtures of the two forms were weighed and mixed by shaking (not grinding or mortaring!). The bulk density of the crystalline mixture thus produced was determined.

[0143] [Table 5]

[0144] It is found that the bulk density increases with increasing proportion of GAA form B, so that from 50% form B the bulk density favorably exceeds the arithmetic average of the two end members (see also Figure 8).

Claims

1. 1. A method for producing thermodynamically metastable crystals of N-(aminoiminomethyl)-2-aminoacetic acid, characterized in that N-(aminoiminomethyl)-2-aminoacetic acid is crystallized from an aqueous solution in the presence of at least one guanidine compound of formula (I), wherein said thermodynamically metastable crystals show the most intense reflection bands at 2Θ=20.2°, 23.3°, 23.8° and 25.3° with a measurement accuracy of + / -0.2° in the X-ray powder diffraction pattern of the crystal using Cu-Kα radiation, where formula (I) is: 【Chemistry 1】 (wherein the group R in formula (I) １ , R ２ , R ３ , R ４ and X, Y and the index k are, independently of one another: R １ , R ２ = independently of each other hydrogen, C1 to C4 alkyl or together form a ring to form a group of formula (II), 【Chemistry 2】 (In the formula, Y=CH ２ , O, N.H., N.C.H. ３ or a bond), R ３ , R ４ = independently hydrogen or C1 to C4 alkyl, X=CH ３ COO, Cl, Br, NO ３ , S.O. ３ (NH ２ ) or 1 / 2SO ４ , k=0 or 1; The method wherein the guanidine compound of formula (I) is used in an amount of at least 25 weight percent (based on the total weight of the solution).

2. 2. The method of claim 1, wherein the aqueous solution contains at least 40% by weight water (based on the total weight of the solution).

3. 3. The method according to claim 1 or 2, characterized in that N-(aminoiminomethyl)-2-aminoacetic acid is dissolved in water or an aqueous solution in a first method step, and that thermodynamically metastable crystals of N-(aminoiminomethyl)-2-aminoacetic acid are crystallized in a second method step from the solution prepared in the first method step in the presence of the guanidine compound of formula (I).

4. 3. The method according to claim 1 or 2, characterized in that N-(aminoiminomethyl)-2-aminoacetic acid is prepared in a first method step from cyanamide and glycine in water or in an aqueous solution, and that thermodynamically metastable crystals of N-(aminoiminomethyl)-2-aminoacetic acid are crystallized in a second method step from the reaction mixture prepared in the first method step in the presence of the guanidine compound of formula (I).

5. The thermodynamically metastable crystal is of orthorhombic space group P2 with Z=8 and lattice parameters a=7.7685 Å, b=7.7683 Å, and c=17.4261 Å at 105 Kelvin and with a measurement accuracy of + / - 0.001 Å. １ 2 １ 2 １ The method according to any one of claims 1 to 4, characterized in that it comprises:

6. 6. The process according to claim 1, wherein the guanidine compound of formula (I) is used in an amount corresponding to 80% of the maximum amount that can be dissolved in water at 25° C. under normal pressure.

7. 7. The method according to any one of claims 3 to 6, characterized in that N-(aminoiminomethyl)-2-aminoacetic acid is dissolved or prepared in a first method step in an aqueous solution at normal pressure and at a temperature in the range of from 20 to 100°C.

8. A crystal mixture containing thermodynamically metastable crystals of N-(aminoiminomethyl)-2-aminoacetic acid and thermodynamically stable crystals of N-(aminoiminomethyl)-2-aminoacetic acid, wherein the thermodynamically metastable crystals show strongest reflection bands at 2Θ = 20.2°, 23.3°, 23.8° and 25.3° with a measurement accuracy of + / - 0.2° in an X-ray powder diffraction pattern of the crystals using Cu-Kα radiation.

9. 9. The crystal mixture of claim 8, characterized in that the crystal mixture contains thermodynamically metastable crystals of N-(aminoiminomethyl)-2-aminoacetic acid and thermodynamically stable crystals of N-(aminoiminomethyl)-2-aminoacetic acid in a weight ratio ranging from 0.1:9.9 to 9.9:0.

1.

10. A feed additive for breeding and fattening animals, comprising a crystal mixture containing thermodynamically metastable crystals of N-(aminoiminomethyl)-2-aminoacetic acid and thermodynamically stable crystals of N-(aminoiminomethyl)-2-aminoacetic acid, wherein the thermodynamically metastable crystals show strongest reflection bands at 2Θ=20.2°, 23.3°, 23.8° and 25.3° with a measurement accuracy of + / -0.2° in an X-ray powder diffraction pattern of the crystals using Cu-Kα radiation.

11. The feed additive according to claim 10, characterized in that the crystal mixture contains thermodynamically metastable crystals of N-(aminoiminomethyl)-2-aminoacetic acid and thermodynamically stable crystals of N-(aminoiminomethyl)-2-aminoacetic acid in a weight ratio ranging from 0.1:9.9 to 9.9:0.1.

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