Metastable crystal modification and method for its production (I)

Description

[0001] The present invention relates to a novel crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid and a process for preparing this crystal modification.

[0002] N-(Aminoiminomethyl)-2-aminoethanoic acid (CAS No. 352-97-6, molecular formula C 3 H 7 N 3 O 2 ), also known as guanidinoacetic acid, guanidinoacetate, glycocyamine, N-amidinoglycine or N-(aminoiminomethyl)glycine, is a guanidinocarboxylic acid with diverse applications, including in the synthesis of chemical products, in particular pharmaceuticals (cf. WO 2000 / 059528), for direct application as a pharmaceutical active ingredient in kidney diseases (cf. JP 60054320) or neurodegenerative diseases (cf. CN 106361736), in the production of polymers (cf. Du, Shuo et. al., Journal of Materials Science (2018), 53(1), 215-229), as a complexing agent for metals (cf. Lopes de Miranda et al., Polyhedron (2003), 22(2), 225-233 and Singh, Padmakshi et al., Oriental Journal of Chemistry (2008), 24(1), 283-286) and as an additive for the nutrition of animals, in particular mammals, fish, birds (cf. WO 2005 / 120246) and humans (cf. WO 2008 / 092591, DE 102007053369).

[0003] N-(Aminoiminomethyl)-2-aminoethanoic acid can be prepared, for example, according to Strecker, M. (Jahresber. Fortschr. Chem. Verw. (1861), 530) from glycine by reaction with cyanamide. Alternatively, N-(Aminoiminomethyl)-2-aminoethanoic acid can be prepared, for example, by reacting glycine with S-methylisothiourea iodide using potassium hydroxide as the base (cf. US 2,654,779). The reaction of chloroacetic acid with ammonia to form glycine hydrochloride and its further reaction with cyanamide has also been described (cf. US 2,620,354). The reaction of cyanamide with glycine to form glycocyamine at a pH of 9 to 10 was described in DE 964 590.

[0004] GP Jones and PJ Pauling, Journal of Crystal and Molecular Structure, Vol. 9, No. 5, 1979, 273-279, describe a crystal and molecular structure of guanidinoacetic acid. S. Guha, Acta Cryst. (1973), B29, 2163-2166, describes a crystal and molecular structure of glycocyamine.

[0005] In the known processes, N-(aminoiminomethyl)-2-aminoethanoic acid is obtained as a fine crystalline powder which has a considerable proportion of dust, i.e. a considerable proportion of particles with a grain size of less than 63 µm.

[0006] When handling 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. A poorly flowing, dusty powder is completely unsuitable, especially for use as a feed additive.

[0007] To address this issue, it has been proposed, for example, to convert N-(aminoiminomethyl)-2-aminoethanoic acid into moldings, granules, or extrudates by adding polymeric binders (e.g., methylcellulose) in amounts of 0.05 to 15 wt.% and water (cf. WO 2009 / 012960). The disadvantage of this process is that the addition of an impurity, namely a binder, is mandatory, and that the granules or moldings must be produced in an additional process step using special, technically complex, and expensive equipment, such as an extruder, granulator, intensive mixer, or ploughshare mixer, followed by drying.

[0008] Another disadvantage of the process according to the above prior art is that moldings or granules either have a high binder content and thus a low dissolution rate, or with a low binder content they dissolve relatively quickly but at the same time have low strength and high abrasion values, so that freedom from dust can no longer be guaranteed.

[0009] The invention therefore aims to provide N-(aminoiminomethyl)-2-aminoethanoic acid in the form of free-flowing, non-dusting crystal aggregates that do not have the disadvantages of the prior art, but can be produced easily using standard equipment commonly used in the chemical industry, and which also exhibit high solubility. Furthermore, a suitable process for producing these crystal aggregates is to be provided.

[0010] These objects are achieved by a thermodynamically metastable crystal modification according to claim 1 and a method for producing the same according to claim 7. Preferred embodiments of the invention are specified in the subclaims, which can optionally be combined with one another.

[0011] The occurrence of chemical substances in various crystal forms or crystal modifications (polymorphism) is of great importance both for the production and application of the substances and for the development of formulations. Thus, the various crystal modifications of a chemical compound differ not only in their appearance (crystal habit) but also in numerous other physical or physicochemical properties. It is currently not possible to predict the occurrence and number of crystal modifications, including their physical or physicochemical properties. In particular, thermodynamic stability and the different behavior after administration to living organisms cannot be determined in advance.

[0012] Under given pressure and temperature conditions, the various polymorphic crystal modifications typically 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, if they can be isolated, are called metastable (under the given pressure and temperature conditions). Metastable polymorphs tend to transform into the stable polymorph. Due to their metastability, this requires the expenditure of activation energy, e.g., through the action of heat, mechanical energy, or the influence of a solvent.

[0013] Furthermore, it is well known that the various modifications of a substance can exist monotropic or enantiotropic. In the case of monotropic polymorphism, a crystal form or crystal modification can represent the thermodynamically stable phase over the entire temperature range up to the melting point, whereas in enantiotropic systems, a transition point exists at which the stability ratio is reversed.

[0014] Surprisingly, a previously unknown, thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid was discovered. Thus, according to a first embodiment of the present invention, a thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid is the subject of the present invention. The X-ray powder diffractogram of the crystal modification using Cu-Kα 1 radiation shows the strongest reflection bands at 2Θ (2 theta) = 20.2° and 23.3° and 23.8° and 25.3° with a measurement accuracy of + / - 0.2°.

[0015] Here and in the following, Cu-Kα 1 radiation means copper-K-alpha-1 radiation of wavelength 1.5406 Å, as commonly used in crystallographic investigations.

[0016] Preferably, the thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid according to the invention has an X-ray powder diffractogram when using Cu-Kα 1 radiation as in Figure 2 shown on.

[0017] Preferred is a thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid, which has the orthorhombic space group P2 1 2 1 2 1 with Z = 8 and lattice constants a = 7.7685 Å, b = 7.7683 Å, and c = 17.4261 Å, with a measurement accuracy of + / - 0.001 Å. The single-crystal measurement was performed using Mo-Kα radiation with a wavelength of 0.71073 Å at 105 K (Kelvin). The unit cell volume is 1052 Å 3 and the calculated X-ray crystal density is 1.479 g / cm 3 at 105 Kelvin.

[0018] Further preferred is a thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid which crystallizes in the orthorhombic, polar space group P2 1 2 1 2 1 with Z = 8, i.e. with two crystallographically independent molecules, and which exhibits pseudo-tetragonal packing. The unit cell has the lattice constants a = 7.7685 Å, b = 7.7683 Å, c = 17.4261 Å at 105 Kelvin, with a measurement accuracy of + / - 0.001 Å. The single-crystal measurement was carried out 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 3 at 105 Kelvin.

[0019] According to the present invention, an orthorhombic space group means a space group whose unit cell has three right angles (right angle = 90 °) and whose three crystal axes a, b and c have different lengths.

[0020] According to a preferred embodiment, the present invention also relates to a thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid, which in the X-ray powder diffractogram of the crystal modification using Cu-Kα 1 radiation shows the strongest reflection bands at 2Θ = 20.2 ° and 23.3 ° and 23.8 ° and 25.3 ° with a measurement accuracy of + / - 0.2 °, which crystallizes in the orthorhombic, polar space group P2 1 2 1 2 1 with two crystallographically independent molecules, ie Z = 8, and which has a pseudo-tetragonal packing. At 105 Kelvin, the unit cell has the lattice constants a = 7.7685 Å, b = 7.7683 Å, c = 17.4261 Å with a measurement accuracy of + / - 0.001 Å.

[0021] More preferably, the crystal modification has a cell volume of 1052 Å 3< and an X-ray crystal density of 1.479 g / cm 3< at 105 Kelvin.

[0022] Within the scope of the present invention, it was discovered that N-(aminoiminomethyl)-2-aminoethanoic acid, in addition to a previously known, thermodynamically stable crystal modification (hereinafter also referred to as Form A or Crystal Form A), also occurs in a thermodynamically metastable crystal modification. This thermodynamically metastable crystal form according to the invention is also referred to as Form B or Crystal Form B below.

[0023] Under suitable crystallization conditions, this new crystal form B forms polygonal or spherical, radially radiating aggregates of needle-like partial crystallites with a rounded habit and a largely uniform aggregate size. This ensures optimal handling as a solid, producing a dust-free, free-flowing product with no tendency to caking. Crystal modification B can be classified as low-dust, as the proportion of crystals with a grain size of < 63 µm (mesh size) is below 10%, preferably below 5%. Due to its structure of fine, needle-like partial crystallites, this habit of the new crystal form B of N-(aminoiminomethyl)-2-aminoethanoic acid also ensures a higher dissolution rate. In addition, and quite unexpectedly, N-(aminoiminomethyl)-2-aminoethanoic acid of crystal form B also offers higher absolute solubility in water-containing media.

[0024] The metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid according to the invention is preferably present in pure form. Preferably, at least 50 wt.%, more preferably at least 75 wt.%, even more preferably at least 90 wt.%, in particular at least 95 wt.%, and most preferably at least 99 wt.% of the N-(aminoiminomethyl)-2-aminoethanoic acid in a composition exhibits a crystal modification in the X-ray powder diffractogram using Cu-Kα 1 radiation with strongest reflection bands at 2Θ = 20.2° and 23.3° and 23.8° and 25.3° with a measurement accuracy of + / - 0.2°.

[0025] If N-(aminoiminomethyl)-2-aminoethanoic acid is prepared by one of the known processes, particularly from aqueous reaction mixtures, the compound is obtained in the well-known crystal form A. One and the same crystal structure was described by three groups of authors: by Sankarananda Guha, Acta Cryst. B29 (1973), 2163, by Par J. Berthou et al., Acta Cryst B32 (1976), 1529, and by Wei Wang et al. al., Tetrahedron Letters 56 (2015), 2684. In all three studies, N-(aminoiminomethyl)-2-aminoethanoic acid (here called form A) is described as a monoclinic structure of the space group P2 1 / n with Z = 4 and the approximate lattice constants a = 4.95 Å, b = 6.00 Å, c = 17.2 Å, β = 94.5 °, with a cell volume of approximately 510 Å 3< . In Berthou et al., the published space group P2 1 / n was converted to the space group P2 1 / n via a coordinate transformation. The experimental crystal density of N-(aminoiminomethyl)-2-aminoethanoic acid of form A is approximately 1.50 g / cm 3< .The characteristic powder diffractogram of N-(aminoiminomethyl)-2-aminoethanoic acid in form A is shown in . Figure 1 shown. Using Cu-Kα 1 radiation (copper K-alpha 1 radiation), the band positions 2Θ (2Theta) = 20.6 ° and 26.0 ° are particularly characteristic of form A. The powder diffractogram agrees with the diffraction pattern calculated from the published single-crystal structures.

[0026] If N-(aminoiminomethyl)-2-aminoethanoic acid is recrystallized from or prepared in conventional solvents, such as water, methanol, ethanol, isopropanol or mixtures of methanol, ethanol, ethanediol, or acetonitrile with water, N-(aminoiminomethyl)-2-aminoethanoic acid is obtained exclusively in crystal form A, as has been shown by experiments.

[0027] Completely surprisingly, it was found that N-(aminoiminomethyl)-2-aminoethanoic acid crystallizes from a calcium chloride-containing solution, in particular an aqueous calcium chloride solution with a calcium chloride content of 5 to 50 wt.%, especially with a calcium chloride content of 10 to 40 wt.%, in a new, previously unknown crystal form.

[0028] N-(Aminoiminomethyl)-2-aminoethanoic acid of form B is characterized by its powder diffractogram with Cu-Kα 1 radiation (see Figure 2), with the bands at 2Θ (2 theta) = 20.2 ° and 25.3 ° as well as a weaker double reflection at 2Θ (2 theta) = 23.3 ° / 23.8 ° being characteristic. A single crystal X-ray structure analysis showed that N-(aminoiminomethyl)-2-aminoethanoic acid of form B has the orthorhombic, polar space group P2 1 2 1 2 1 with two crystallographically independent molecules, i.e. Z = 8. The packing of the molecules exhibits pseudo-tetragonal symmetry. The unit cell has the lattice constants a = 7.7685 Å, b = 7.7683 Å, c = 17.4261 Å at 105 Kelvin with a measurement accuracy of + / - 0.001 Å. The single-crystal measurement was 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 3 at 105 Kelvin.

[0029] According to a further embodiment, the present invention also relates to a thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid, which crystallizes in an orthorhombic space group P2 1 2 1 2 1 , in particular an orthorhombic, polar space group P2 1 2 1 2 1 , with Z = 8 and which, in particular, has a pseudo-tetragonal packing. At 105 Kelvin, the unit cell has the lattice constants a = 7.7685 Å, b = 7.7683 Å, c = 17.4261 Å with a measurement accuracy of + / - 0.001 Å.

[0030] The experimental crystal density of N-(aminoiminomethyl)-2-aminoethanoic acid of Form B is 1.41 g / cm 3 < + / - 0.03 g / cm 3 < at 20 °C. Thus, the experimental crystal density of Form B is significantly lower than that of crystal Form A, which is 1.50 g / cm 3 < + / - 0.03 g / cm 3 < at 20 °C. This difference in crystal density indicates a thermodynamic instability of Form B compared to Form A.

[0031] Thus, the invention preferably also relates to a thermodynamically metastable crystal modification which has an experimental crystal density of 1.41 g / cm 3< + / - 0.03 g / cm 3< at 20 °C.

[0032] Crystal form B of N-(aminoiminomethyl)-2-aminoethanoic acid is preferably present in the form of spherical or polygonal, radially radiating aggregates with a rounded outer habit. The individual crystals represent extremely fine needles from which the spherical aggregates are constructed. This has the surprising advantage that form B can be used to provide a physical form of N-(aminoiminomethyl)-2-aminoethanoic acid that comprises spherical or polygonal, granular, abrasion-resistant aggregates with a largely uniform aggregate size, excellent flowability, and a largely dust-free appearance. Typical crystal aggregates of N-(aminoiminomethyl)-2-aminoethanoic acid of form B are in Figure 4 and Figure 5For comparison, conventional, state-of-the-art N-(aminoiminomethyl)-2-aminoethanoic acid of form A, which has the habit of matted, fine crystal needles, is Figure 3 shown.

[0033] N-(Aminoiminomethyl)-2-aminoethanoic acid Form A and Form B also differ in the infrared spectrum. Form A is characterized by stronger bands at 1005.9, 940.3, and 816.8 cm -1 , while Form B is characterized by stronger bands at 1148.0, 997.7, and a weak band at 815 cm -1 .

[0034] The two crystal forms show different melting and decomposition points: N-(Aminoiminomethyl)-2-aminoethanoic acid Form A: DSC onset 280.5 °C, peak 286.3 °C, heat of fusion 887 + / - 1 J / g. N-(Aminoiminomethyl)-2-aminoethanoic acid Form B: DSC onset 272.5 °C, peak 280.4 °C, heat of fusion 860 + / - 1 J / g.

[0035] Thus, the invention preferably also relates to a thermodynamically metastable crystal modification which has an endothermic heat of fusion in the range of 850 to 870 J / g.

[0036] Furthermore, a thermodynamically metastable crystal modification which has a decomposition point in the range of 270 to 275 °C is also preferably the subject of the invention.

[0037] These data clearly demonstrate that N-(aminoiminomethyl)-2-aminoethanoic acid form B is a thermodynamically metastable crystal modification, which is the thermodynamically more unstable form compared to form A, with the energy difference between the two forms being approximately 27 J / g and the onset point of the melting ranges having a difference of 8 K.

[0038] Further investigations have shown that N-(aminoiminomethyl)-2-aminoethanoic acid form B has a water solubility that is approximately 20% higher than N-(aminoiminomethyl)-2-aminoethanoic acid form A, and that this applies in the temperature range between 5 and 95 °C (cf. Figure 6 ). This effect is completely unpredictable.

[0039] It has been found that the metastable crystal modification Form B according to the invention is stable as a solid up to its melting point. A solid transformation from Form B to Form A or a reversible solid transformation Form A / Form B cannot be observed. Thus, Form B is an example of a monotropic polymorphism.

[0040] In summary, it should be emphasized here that N-(aminoiminomethyl)-2-aminoethanoic acid in the crystal modification B, in particular prepared by crystallization of N-(aminoiminomethyl)-2-aminoethanoic acid from a calcium chloride-containing, preferably aqueous or water-containing solution, surprisingly advantageous and usually opposite properties, such as a coarse, free-flowing grain and at the same time a high dissolution rate, the formation of crystal aggregates without the addition of a binder, combined, and an increased absolute solubility at a given temperature, despite identical chemical composition.

[0041] Due to its outstanding properties, this novel crystal modification is suitable for use as a feed additive for animals. Thus, the present invention also relates to a feed additive comprising the thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid described herein.

[0042] In particular, the present invention also relates to a feed additive comprising a thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid, the X-ray powder diffractogram of which, when using Cu-Kα 1 radiation, shows the strongest reflection bands at 2Θ = 20.2 ° and 23.3 ° and 23.8 ° and 25.3 ° with a measurement accuracy of + / -0.2 °.

[0043] Very particularly preferred is a feed additive comprising a thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid, which does not comprise any binders or which is free from binders that are usually used for granulation.

[0044] Such feed additives can be formulated as premixes. Thus, the invention also relates to the use of the thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid described herein for the production of a feed additive.

[0045] Surprisingly, it was discovered that N-(aminoiminomethyl)-2-aminoethanoic acid can exist in various crystal modifications. The thermodynamically metastable crystal form B of N-(aminoiminomethyl)-2-aminoethanoic acid according to the invention can be prepared by crystallizing N-(aminoiminomethyl)-2-aminoethanoic acid in the presence of calcium chloride.

[0046] The proportion of calcium chloride (based on the anhydrous salt) is preferably at least 5 to a maximum of 50 wt%, particularly preferably 10 to 40 wt%. The proportion of calcium chloride refers to the total weight of the solution used to crystallize the N-(aminoiminomethyl)-2-aminoethanoic acid.

[0047] Furthermore, the calcium chloride (based on the anhydrous salt) can preferably be used in an amount of at least 5 wt.% and at most 50 wt.% (based on the total weight of the solution). Preferably, the calcium chloride can be used in an amount of at least 7 wt.%, more preferably at least 10 wt.%, particularly preferably at least 15 wt.%, and most preferably at least 20 wt.%, with further preferably at most 50 wt.% (in each case based on the total weight of the solution). At the same time, the calcium chloride can be used in an amount of at most 50 wt.%, more preferably at most 45 wt.%, and most preferably at most 40 wt.% (in each case based on the total weight of the solution).

[0048] Thus, a process for producing this thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid, wherein the crystal modification in the X-ray powder diffractogram of the crystal modification when using Cu-Kα 1 radiation shows the strongest reflection bands at 2Θ = 20.2 ° and 23.3 ° and 23.8 ° and 25.3 ° with a measurement accuracy of + / - 0.2 °, is also the subject of the present invention, by crystallizing N-(aminoiminomethyl)-2-aminoethanoic acid from a solution containing 5 to 50 wt.% calcium chloride, preferably 5 to 40 wt.% calcium chloride, preferably 10 to 40 wt.% calcium chloride.

[0049] The procedure can be performed: a) by recrystallization of N-(aminoiminomethyl)-2-aminoethanoic acid of any crystal structure from a solvent containing calcium chloride, or b) by synthesis of N-(aminoiminomethyl)-2-aminoethanoic acid, preferably by reaction of glycine with cyanamide in a solvent containing calcium chloride.

[0050] Preferably, the process can be carried out by crystallizing the N-(aminoiminomethyl)-2-aminoethanoic acid in a temperature range of -40 to 100 °C.

[0051] Particularly preferred is a process in which N-(aminoiminomethyl)-2-aminoethanoic acid is crystallized at a cooling rate in the range of 0.01 to 5 K / min in a temperature range of -40 to 100 °C.

[0052] Solvents that can be used are more preferably water, alcohols, esters, nitriles, ketones, or mixtures of these solvents. Aqueous or water-containing solvent mixtures are preferred, with water being particularly preferred.

[0053] Surprisingly, it was also found that the presence of calcium chloride significantly increases the solubility of N-(aminoiminomethyl)-2-aminoethanoic acid. This can be advantageous, among other things, when more concentrated solutions or liquid formulations of N-(aminoiminomethyl)-2-aminoethanoic acid are desired.

[0054] In the calcium chloride-containing solvent or solvent mixture mentioned, N-(aminoiminomethyl)-2-aminoethanoic acid is dissolved either to saturation according to a) or produced according to b) from glycine and cyanamide by a synthesis reaction, so that the saturation point is reached as the reaction progresses. According to the process of the invention, crystal nucleation and crystallization preferably take place in form B, whereby the presence of calcium chloride is considered essential to the invention.

[0055] N-(Aminoiminomethyl)-2-aminoethanoic acid of form B can thus be preferably prepared by a1) cooling crystallization of a solution saturated at elevated temperature until supersaturation is reached, or a2) evaporation of a portion of the solvent at substantially constant temperature until supersaturation is reached, or b) reaction to form N-(aminoiminomethyl)-2-aminoethanoic acid, whereby the saturation point of solubility is exceeded, so that N-(aminoiminomethyl)-2-aminoethanoic acid Form B crystallizes.

[0056] In all cases, conventional stirred reactors are preferred. The use of complex process equipment is unnecessary.

[0057] The preferred temperature range for processes according to a1), a2) or b) is -40 to 110 °C, particularly preferably -20 to 100 °C.

[0058] For processes according to a1), the dissolution temperature is preferably 40 to 110 °C, the crystallization temperature is preferably -40 to 40 °C.

[0059] Processes according to a2) are preferably carried out in the temperature range 30 to 100 °C.

[0060] Processes according to b) are preferably carried out in the temperature range between 60 and 100 °C.

[0061] After complete crystallization of the desired N-(aminoiminomethyl)-2-aminoethanoic acid Form B, the crystallized product is preferably filtered off by filtration, e.g., using a centrifuge, pressure filter, belt filter, or filter press. To remove excess calcium chloride, the product is preferably washed with the above-mentioned solvent or solvent mixture. Washing is preferably carried out with water, with the temperature of the wash water preferably being 0 to 50 °C.

[0062] Of course, to improve the economic efficiency of the process, it is possible to recycle the mother liquor obtained from the separation of N-(aminoiminomethyl)-2-aminoethanoic acid of crystal form B into the process, if necessary by adjusting the calcium chloride concentration, e.g., by evaporation. After drying, preferably in the temperature range 40 to 100°C, the process according to the invention yields a dry, free-flowing, granular product consisting of radial, polygonal, or rounded aggregates. The crystal aggregates have an external dimension of 150 to 3000 µm, preferably 300 to 1500 µm, and a dust content (i.e., particle content smaller than 63 µm) of less than 5 wt.%, particle sizes in each case mesh size).

[0063] The N-(aminoiminomethyl)-2-aminoethanoic acid Form B produced in this way has a high purity, typically > 99.0%, is easy to handle, and exhibits hardly any mechanical abrasion. Due to these properties, the inventive crystal form B of N-(aminoiminomethyl)-2-aminoethanoic acid is particularly suitable for the above-mentioned applications, in particular as a nutritional additive or as a pharmaceutical active ingredient.

[0064] A further subject of the present invention is therefore the use of the thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid as described herein for the production of a feed additive, as well as a feed additive comprising a thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoethanoic acid as described herein. The feed additive is particularly suitable for feeding poultry.

[0065] The following examples are intended to explain the nature of the invention in more detail.

[0066] The figures show: Figure 1: X-ray powder diffractogram of N-(aminoiminomethyl)-2-aminoethanoic acid of form A from Example 1 Figure 2: X-ray powder diffractogram of N-(aminoiminomethyl)-2-aminoethanoic acid of form B from Example 2 Figure 3: Micrograph of N-(aminoiminomethyl)-2-aminoethanoic acid of form A, prepared according to Example 1 (image width 8 mm) Figure 4: Micrograph of polygonal aggregates of N-(aminoiminomethyl)-2-aminoethanoic acid of form B, prepared by recrystallization from a 30% aqueous calcium chloride solution according to Example 2 (image width 8 mm) Figure 5: Micrograph of spherical aggregates of N-(aminoiminomethyl)-2-aminoethanoic acid of form B, prepared by recrystallization from a 15% aqueous calcium chloride solution according to Example 3 (image width 8 mm) Figure 6: Solubility curve of N-(aminoiminomethyl)-2-aminoethanoic acid of form A orForm B in water. Figure 7: Illustration of the two crystallographically independent molecules of N-(aminoiminomethyl)-2-aminoethanoic acid from single-crystal X-ray structure analysis. Figure 8: Illustration of the packing of the molecules of N-(aminoiminomethyl)-2-aminoethanoic acid in the crystal structure. The view is along the a-axis. Independent, perpendicular molecular chains, bonded via hydrogen bonds, are clearly visible parallel to the a- and b-axes. These chains are stacked along the c-axis. Examples X-ray powder diffractometric measurement

[0067] For the purposes of the present examples, X-ray powder diffractometric measurements were performed using a Bruker D2 Phaser powder diffractometer with theta / 2theta geometry, a LYNXEYE detector, Cu-Kα 1 radiation with a wavelength of 1.5406 Å, an accelerating voltage of 30 kV, an anode current of 10 mA, a nickel filter, and a step size of 0.02°. The samples under investigation were ground in an agate mortar and pressed onto the sample plate according to the manufacturer's instructions, and the surface was smoothed. Single crystal X-ray structure analysis

[0068] A suitable crystal was prepared by evaporating an aqueous solution of N-(aminoiminomethyl)-2-aminoethanoic acid in the presence of calcium chloride. Single-crystal measurements were performed at 105 Kelvin on a crystal measuring 0.02 x 0.02 x 0.09 mm using monochromatic Mo-Kα (molybdenum K-alpha) radiation with a wavelength of 0.71073 Å using a Bruker D8 Venture TXS dual-circuit diffractometer. The X-ray crystal data were refined using 2072 independent reflections using the least-squares method to an R value (F obs ) of 0.0381. The position of the NH and OH hydrogen atoms was refined, and the CH hydrogen atoms were fixed at the calculated position. The result of the single-crystal X-ray structure analysis is shown in Figure 7 and 8 A powder diffractogram calculated from the single crystal structure analysis agreed exactly with the measured powder diffractogram according to Figure 2agree. Example 1 (Comparison) - Recrystallization of N-(Aminoiminomethyl)-2-aminoethanoic acid from water

[0069] 400 g of water were placed at 80 °C, and a total of 11.66 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.0%, present in crystal form A, were dissolved spoonful by spoonful, with the last portion exceeding the solubility limit. The mixture was then filtered off at 80 °C, the filtrate was treated with a further 100 g of water, and the mixture was heated to 80 °C. A nearly saturated, clear solution formed. N-(aminoiminomethyl)-2-aminoethanoic acid was crystallized by slow cooling to 20 °C over the course of 4 hours. The precipitated crystals were filtered off and dried under vacuum at 60 °C. 6.51 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.1% were obtained.

[0070] The product obtained is in the form of fine needle-like crystals. The fine needle-like crystals were examined microscopically (see Figure 3 ). An X-ray powder diffraction measurement showed that Figure 1 shown powder diffractogram, which indicates the well-known crystal form A. Example 2 (according to the invention) - Recrystallization of N-(aminoiminomethyl)-2-aminoethanoic acid from a 30% calcium chloride solution

[0071] A 30% solution was prepared from 150 g of anhydrous calcium chloride and 350 g of water. N-(aminoiminomethyl)-2-aminoethanoic acid of the same composition as in Example 1 (i.e., 99.0% content, crystal form A) was added spoonful by spoonful to 400 g of this solution at 80 °C. The solubility limit was exceeded only at an added amount of 74.28 g. The small solids content was filtered off at 80 °C without washing. The filtrate was mixed with the remaining 100 g of the 30% calcium chloride solution, and the mixture was stirred at 80 °C for 1 hour. A clear, colorless solution was obtained. N-(aminoiminomethyl)-2-aminoethanoic acid was crystallized by slow cooling to 20 °C over 4 hours. The precipitated crystal aggregates were filtered off, washed three times with water at 20 °C, and dried at 60 °C. 46.42 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.2% were obtained.The amount obtained is thus over 7 times larger than in Example 1, which is due to the greatly increased solubility of N-(aminoiminomethyl)-2-aminoethanoic acid by calcium chloride.

[0072] An analog powder diffractogram (see Figure 2 ) showed the previously unknown crystal form B. The polygonal, rounded crystal aggregates were examined microscopically (see Figure 4 ). Example 3 (according to the invention) - Recrystallization of N-(aminoiminomethyl)-2-aminoethanoic acid from a 15% calcium chloride solution

[0073] Example 2 was repeated analogously using 500 g of a 15% calcium chloride solution prepared from 75 g of anhydrous calcium chloride and 425 g of water. In 400 g of this solvent mixture, the saturation limit was reached at 80 °C with 42.7 g of N-(aminoiminomethyl)-2-aminoethanoic acid. After adding the remaining 100 g of solvent, crystallization of the initially clear solution, filtration, washing, and drying, 27.2 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.2% were obtained.

[0074] The powder diffractogram of the spherical crystal aggregates indicated the sole presence of form B. The spherical, radially radiating aggregates were examined microscopically (see Figure 5 ). Example 3a (according to the invention) - Recrystallization of N-(aminoiminomethyl)-2-aminoethanoic acid from a 10% calcium chloride solution

[0075] Example 2 was repeated analogously with 500 g of a 10% calcium chloride solution prepared from 50 g of anhydrous calcium chloride and 450 g of water. In 400 g of this solvent mixture, the saturation limit was reached at 80 °C with 29.4 g of N-(aminoiminomethyl)-2-aminoethanoic acid. After adding the remaining 100 g of solvent, crystallization of the initially clear solution, filtration, washing, and drying, 23.5 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.3% were obtained.

[0076] The powder diffractogram indicated the presence of a mixture of crystal form A and crystal form B. The ratio of both polymorphs was approximately 1:1. Example 3b (Comparison) - Recrystallization of N-(aminoiminomethyl)-2-aminoethanoic acid from a 1% calcium chloride solution

[0077] Example 2 was repeated analogously with 500 g of a 1% calcium chloride solution prepared from 5 g of anhydrous calcium chloride and 495 g of water. In 400 g of this solvent mixture, the saturation limit was reached at 80 °C with 13.4 g of N-(aminoiminomethyl)-2-aminoethanoic acid. After adding the remaining 100 g of solvent, crystallization of the initially clear solution, filtration, washing, and drying, 11.0 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.4% were obtained.

[0078] The powder diffractogram of the fine-needle crystal aggregates indicated the sole presence of form A.

[0079] Depending on the calcium chloride concentration, the formation of Form A or Form B can be influenced. The solubility (ie saturation limit) of N-(aminoiminomethyl)-2-aminoethanoic acid increases strongly with the calcium chloride concentration. Example 4(Comparison) - Recrystallization of N-(aminoiminomethyl)-2-aminoethanoic acid from a 50% solution of magnesium chloride hexahydrate

[0080] Example 2 was repeated analogously using 500 g of a solution prepared from 250 g of magnesium chloride hexahydrate and 250 g of water. In 400 g of the solvent mixture, the saturation limit was reached at 80 °C with 76.6 g of N-(aminoiminomethyl)-2-aminoethanoic acid. After adding the remaining 100 g of solvent, crystallization, filtration, washing, and drying, 49.1 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.1% was obtained.

[0081] The powder diffractogram of the obtained needle-like crystals indicated the sole presence of form A. Thus, MgCl 2, which is very similar to CaCl 2, does not cause the crystallization of N-(aminoiminomethyl)-2-aminoethanoic acid in form B, although the solubility of N-(aminoiminomethyl)-2-aminoethanoic acid is similarly increased by the presence of the salt. Example 5 (Comparison) - Synthesis of N-(Aminoiminomethyl)-2-aminoethanoic acid from glycine and cyanamide in aqueous solution

[0082] 112.6 g (1.5 mol) of glycine were 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 at 80 °C over the course of 4 hours. The reaction was continued for a further hour at 80 °C. The resulting suspension was cooled to 20 °C, filtered, washed with water, and dried at 60 °C. This yielded 100.6 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.1%. The yield was 85.9%.

[0083] A powder diffractogram of the obtained fine needle crystals indicated the sole presence of form A. Example 6(according to the invention) - Synthesis of N-(aminoiminomethyl)-2-aminoethanoic acid from glycine and cyanamide in a 33% calcium chloride solution

[0084] A solution was prepared from 100 g of anhydrous calcium chloride and 200 g of water. 112.6 g (1.5 mol) of glycine were dissolved in it, and a pH of 8.4 was adjusted with 21.6 g (0.27 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 at 80 °C over the course of 4 hours. The reaction was continued for a further hour at 80 °C. The resulting suspension was cooled to 20 °C, filtered, washed with water, and dried at 60 °C. 99.3 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.2% was obtained. The yield was 84.8%.

[0085] A powder diffractogram of the obtained round crystal aggregates of radially radiating single crystals indicated the sole presence of form B. Example 6a(according to the invention) - Synthesis of N-(aminoiminomethyl)-2-aminoethanoic acid from glycine and cyanamide in a 15% calcium chloride solution

[0086] A solution was prepared from 45 g of anhydrous calcium chloride and 255 g of water. 112.6 g (1.5 mol) of glycine were dissolved in it, and a pH of 8.4 was adjusted with 21.5 g (0.27 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 at 80 °C over the course of 4 hours. The reaction was continued for a further hour at 80 °C. The resulting suspension was cooled to 20 °C, filtered, washed with water, and dried at 60 °C. 99.6 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.3% was obtained. The yield was 84.5%.

[0087] A powder diffractogram of the obtained crystals showed that a mixture of form A and form B was present, with form B accounting for the much larger proportion. Example 6b(Comparison) - Synthesis of N-(Aminoiminomethyl)-2-aminoethanoic acid from glycine and cyanamide in a 1% calcium chloride solution

[0088] A solution was prepared from 3 g of anhydrous calcium chloride and 297 g of water. 112.6 g (1.5 mol) of glycine were dissolved in it, and a pH of 8.4 was adjusted with 21.4 g (0.27 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 at 80 °C over the course of 4 hours. The reaction was continued for a further hour at 80 °C. The resulting suspension was cooled to 20 °C, filtered, washed with water, and dried at 60 °C. 100.1 g of N-(aminoiminomethyl)-2-aminoethanoic acid with a purity of 99.2% was obtained. The yield was 84.8%.

[0089] A powder diffractogram of the obtained crystals showed that only form A was present.

[0090] Although N-(aminoiminomethyl)-2-aminoethanoic acid is generated by reaction between glycine and cyanamide, the resulting crystal form can be controlled by the presence of different concentrations of calcium chloride. Example 7 - Physico-chemical characterization of N-(aminoiminomethyl)-2-aminoethanoic acid of form A and form B 7.1 Melting or decomposition point

[0091] For dynamic differential scanning calorimetry (DSC), a Mettler DSC 3+ instrument with a 40 µl aluminum crucible was used. The heating rate was 10 Kelvin per minute at a temperature range of 30 to 350 °C. Approximately 1.4 mg of each of the products from Examples 1 and 2 were weighed into aluminum crucibles and measured at atmospheric pressure (960 mbar at an altitude of 500 m above sea level).

[0092] The sample from Example 1 (= N-(aminoiminomethyl)-2-aminoethanoic acid of 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. The product changed color from white to brown upon melting.

[0093] The sample from Example 2 (= N-(aminoiminomethyl)-2-aminoethanoic acid Form B) was measured analogously. It showed an onset of 272.5 °C and a peak at 280.4 °C. The heat of fusion was 860 J / g, and the color was identical.

[0094] Form B therefore melts approximately 6 to 8 Kelvin lower than Form A and has a 27 J / g lower heat of fusion and a 27 J / g higher lattice energy. In other words, Form B requires 27 J / g less energy than Form A to reach the same energy melting state. Form B thus represents a metastable crystal form, or a polymorph of N-(aminoiminomethyl)-2-aminoethanoic acid that is energetically higher under normal pressure and temperature conditions. 7.2 Determination of water solubility

[0095] 100 g of water at 5 °C were added. The product from Example 1 (= N-(aminoiminomethyl)-2-aminoethanoic acid Form A) was dissolved therein until saturation, and the dissolved amount was determined by backweighing. The temperature was then increased to 20 °C, and sufficient sample was added until the saturation point was reached. The same procedure was repeated at other temperatures, up to a maximum of 95 °C. An analogous measurement was carried out with the product from Example 2 (= N-(aminoiminomethyl)-2-aminoethanoic acid Form B). The solubility data obtained for both products were plotted graphically in Figure 6 summarized.

[0096] Both crystal forms of N-(aminoiminomethyl)-2-aminoethanoic acid dissolve better in water with increasing temperature. Form B of N-(aminoiminomethyl)-2-aminoethanoic acid according to the invention dissolves approximately 20% more effectively than the known form A at all temperatures. 7.3 Determination of density

[0097] Crystals of N-(aminoiminomethyl)-2-aminoethanoic acid Form A from Example 1 were placed in carbon tetrachloride at 20 °C, where they floated on the surface. By dropwise addition of dichloromethane, the density of the liquid medium was lowered until the crystals just began to float in the liquid, without rising and without sinking to the bottom. The density of the liquid phase was determined in a pycnometer. It was measured at 1.50 g / cm³.

[0098] The same procedure was followed with crystals of form B from Example 2. The density at 20 °C was determined to be 1.41 g / cm 3 .

[0099] Form B therefore has a density 6% lower than Form A. This correlates with the lower lattice energy of Form B determined above. The measured crystal densities also agree with the X-ray crystal densities calculated from the respective lattice constants. 7.4 Determination of the dust content

[0100] The product from Example 1 was sieved through a sieve with a mesh size of 63 µm (equivalent to a mesh size of 230). A fines fraction of 46 wt.% was obtained. The same procedure was followed with the sample from Example 2, consisting of polygonal, rounded crystal aggregates. Here, a fines fraction of less than 3 wt.% was determined. Low-dust, and therefore safely handled, materials should have a dust fraction (i.e., grain fraction < 63 µm) of less than 10%. The product from Example 2 (N-(aminoiminomethyl)-2-aminoethanoic acid, crystal form B) meets this requirement, whereas Comparative Example 1 (N-(aminoiminomethyl)-2-aminoethanoic acid, crystal form A) does not. 7.5 Determination of the angle of repose

[0101] The product from Example 1, consisting of intertwined needle-like crystals, was poured through a funnel onto a flat surface using a device according to DIN ISO 4324. After removing the funnel, the angle of repose of the resulting cone was determined using an angle measuring device. This was approximately 45°. N-(Aminoiminomethyl)-2-aminoethanoic acid Form A therefore exhibits poor flow behavior. The granular product from Example 2 was measured analogously. Here, an angle of repose of approximately 25° was obtained. N-(Aminoiminomethyl)-2-aminoethanoic acid Form B therefore exhibits excellent flow behavior. 7.6 Determination of bulk density

[0102] A weighed amount of the product from Example 1 was placed in a measuring cylinder and partially compacted by tapping it firmly twice on the laboratory bench. The bulk density was determined from the fill level of the measuring cylinder to be 0.37 g / cm³. The same procedure was followed with the product from Example 2. A bulk density of 0.62 g / cm³ was determined. Form B N-(Aminoiminomethyl)-2-aminoethanoic acid thus has a significantly increased bulk density, which is advantageous for packaging, transport, and handling of the product. 7.7 Thermal stability of N-(Aminoiminomethyl)-2-aminoethanoic acid Form B

[0103] a) N-(Aminoiminomethyl)-2-aminoethanoic acid, Form B from Example 2, was placed in a drying cabinet at 120 °C for 6 hours. The crystal form was then determined by X-ray powder diffraction. This remained unchanged, pure crystal form B. b) N-(Aminoiminomethyl)-2-aminoethanoic acid, Form B from Example 2, was moistened with 20% water, incubated in a closed vessel at 65 °C for 6 hours, and then dried. The X-ray powder diffraction pattern showed no change; Form B remained stable. c) N-(Aminoiminomethyl)-2-aminoethanoic acid, Form B from Example 2, was made into a 10% suspension in water. This suspension was stirred at 80 °C for 2 hours. The mixture was then cooled, the solid was filtered off, and dried. X-ray powder diffraction revealed that a mixture of crystal forms A and B was present.d) N-(Aminoiminomethyl)-2-aminoethanoic acid Form B from Example 2 was dissolved in water at 80 °C, largely recrystallized by cooling the solution, filtered off, and dried. X-ray powder diffraction revealed pure crystal Form A.

[0104] N-(Aminoiminomethyl)-2-aminoethanoic acid Form B is therefore very stable in solid form, but has a tendency to transform into crystal Form A via aqueous solution. This behavior also confirms the metastable crystal structure of Form B. Example 8 - Synthesis of N-(aminoiminomethyl)-2-aminoethanoic acid according to the prior art in which calcium is present - DE 964 590 B

[0105] Note: The calcium cyanamide used according to DE 964 590 B has a content of only 53%; this corresponds to 15.9% N. In the following example, calcium cyanamide with a content of 68.6% was used; this corresponds to 24% N. The amount used has been adjusted accordingly.

[0106] 154.5 g of technical-grade calcium cyanamide with a CaNCN content of 68.6% were suspended in 800 g of water. At 20 °C, a mixture of 191.6 g of 96% sulfuric acid and 300 g of water was added, resulting in the cyanamide dissolving and calcium sulfate precipitating from the solution, resulting in a pH of 7.5. Calcium sulfate and other insoluble components were filtered off, and the filtrate was adjusted to pH 4.9 with a small amount of sulfuric acid. The resulting solution was evaporated under reduced pressure at approximately 10 mbar to a total volume of 200 cm³. Any further precipitated calcium sulfate was filtered off. The resulting aqueous cyanamide solution had a cyanamide content of 26.4% and a calcium content of 0.56 g / liter. (Note: corresponds to a cyanamide yield of 95% and a gypsum solubility of 2.4 g / l).

[0107] This cyanamide solution was treated with 30 g of glycine and adjusted to pH 9.4 with 19.8 g of 50% aqueous sodium hydroxide solution. The reaction mixture was heated to 95 °C for 1.5 hours and then cooled to room temperature overnight. Precipitated N-(aminoiminomethyl)-2-aminoethanoic acid and the resulting dicyandiamide were filtered off, and the filter residue was dissolved in 180 g of water, leached for 2 hours at 50 °C, filtered at 50 °C, and washed with water. After drying at 60 °C, 38.4 g of N-(aminoiminomethyl)-2-aminoethanoic acid were obtained. The yield was 82% based on the glycine used.

[0108] X-ray powder diffraction showed that N-(aminoiminomethyl)-2-aminoethanoic acid was formed exclusively in crystal form A.

Claims

1. Thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoacetic acid, characterised in that the crystal modification in the x-ray powder diffractogram of the crystal modification shows the strongest reflex bands at 2Θ = 20.2° and 23.3° and 23.8° and 25.3° at a measuring accuracy of + / - 0.2° when using Cu-Kα1 radiation.

2. Crystal modification according to claim 1, characterised in that the crystal modification has the orthorhombic space group P212121 with Z = 8 with the lattice constants a = 7.7685 Å, b = 7.7683 Å and c = 17.4261 Å at 105 Kelvin and a measuring accuracy of + / - 0.001 Å.

3. Crystal modification according to claim 2, characterised in that the crystal modification has a cell volume of 1052 Å3 at 105 Kelvin.

4. Crystal modification according to claim 1 or 2, characterised in that the crystal modification has an experimental crystal density of 1.41 g / cm3 + / - 0.03 g / cm3 at 20°C.

5. Crystal modification according to one of the above mentioned claims, characterised in that the crystal modification has an endothermic melt heat within a range of 850 to 870 J / g.

6. Crystal modification according to one of the above mentioned claims, characterised in that the crystal modification has a decomposition point within a range of 270 to 275°C.

7. Method for producing a thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoacetic acid according to one of claims 1 to 6, characterised in that N-(aminoiminomethyl)-2-aminoacetic acid is crystallised from a solution containing 5 to 50 wt.% calcium chloride.

8. Method according to claim 7, characterised in that N-(aminoiminomethyl)-2-aminoacetic acid is crystallised from a solution containing 10 to 40 wt.% calcium chloride.

9. Method according to claim 7 or 8, characterised in that N-(aminoiminomethyl)-2-aminoacetic acid is crystallised within a temperature range of -40 to 100°C.

10. Method according to one of the above mentioned claims 7 to 9, characterised in that N-(aminoiminomethyl)-2-aminoacetic acid is crystallised with a cooling rate within a range of 0.01 to 5 K / min within a temperature range of -40 to 100°C.

11. Method according to one of the above mentioned claims 7 to 10, characterised in that the solution contains a solvent from the group of water, alcohols, esters, nitriles, ketones or mixture of the same as a solvent.

12. Use of the thermodynamically metastable crystal modification of N-(aminoiminomethyl)-2-aminoeacetic acid according to one of the claims 1 to 6 for producing an animal feed additive.

13. Animal feed additive comprising a thermodynamically metastable crystal modification of one of the claims 1 to 6.