PROCESS FOR THE PREPARATION OF A METASTABLE CRYSTAL MODIFICATION OF N-(AMINOIMINOMETHYL)-2-AMINOETHANOIC ACID (IV)

Abstract

The present invention relates to a method for preparing N-(aminoiminomethyl)-2-aminoacetic acid comprising N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystal modification.

Claims

1. A process for preparing N-(aminoiminomethyl)-2-aminoacetic acid comprising N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystal modification, wherein the thermodynamically metastable crystal modification shows in the X-ray powder diffractogram of the crystal modification when using Cu—Kα radiation the strongest reflection bands at 2Θ=20.2° and 23.3° and 23.8° and 25.3° with a measurement accuracy of +/−0.2°, wherein N-(aminoiminomethyl)-2-aminoacetic acid is crystallized from a water-containing solution in the presence of at least one guanidine compound of formula (I), wherein formula (I) represents: ##STR00002## where radicals R.sup.1, R.sup.2 as well as indices m.sup.1, m.sup.2 in formula (I) independently of one another mean: R.sup.1, R.sup.2=independently of one another hydrogen or C1 to C4 alkyl, m.sup.1, m.sup.2=independently of one another 1, 2 or 3, wherein the guanidine compounds of formula (I) are present in an amount of at least 0.01 wt-% (based on the total weight of the solution).

2. The process according to claim 1, wherein the water-containing solution contains at least 40% by weight of water (based on the total weight of the solution).

3. The process according to claim 1, wherein N-(aminoiminomethyl)-2-aminoacetic acid is dissolved in water or a water-containing solution in a first process step, and the N-(aminoiminomethyl)-2-aminoacetic acid comprising N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystal modification is 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).

4. The process according to claim 1, wherein N-(aminoiminomethyl)-2-aminoacetic acid is prepared in a first process step from cyanamide and glycine in water or in a water-containing solution, and the N-(aminoiminomethyl)-2-aminoacetic acid comprising N-(aminoiminomethyl)-2-aminoacetic acid in a thermodynamically metastable crystal modification is crystallized in a second process step from the reaction mixture prepared in the first process step in the presence of the guanidine compound of formula (I).

5. The process according to claim 1, wherein N-(aminoiminomethyl)-2-aminoacetic acid is dissolved or prepared in the water-containing solution in the first process step at a temperature in the range of 20 to 100° C. at normal pressure.

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

7. The process according to claim 1, wherein the thermodynamically metastable crystal modification has the orthorhombic space group P212121 with Z=8 with lattice constants a=7.7685 Å, b=7.7683 Å and c=17.4261 Å at 105 Kelvin and a measurement accuracy of +/−0.001 Å.

Description

DESCRIPTION OF THE DRAWINGS

[0089] The drawings show:

[0090] FIG. 1: X-ray powder diffractogram of N-(aminoiminomethyl)-2-aminoacetic acid of form A of Example 1

[0091] FIG. 2: X-ray powder diffractogram of N-(aminoiminomethyl)-2-aminoacetic acid of form B of Example 2

[0092] FIG. 3: Photomicrograph of N-(aminoiminomethyl)-2-aminoacetic acid of form A prepared according to Example 1 (image width 8 mm)

[0093] FIG. 4: Photomicrograph of spherical aggregates of N-(aminoiminomethyl)-2-aminoacetic acid of form B, prepared by recrystallization from a solution of N,N′-guanidinodiacetic acid according to Example 2 (image width 8 mm)

[0094] FIG. 5: Solubility curve of N-(aminoiminomethyl)-2-aminoacetic acid of form A and form B, respectively, in water

[0095] FIG. 6: Illustration of the two crystallographically independent molecules N-(aminoiminomethyl)-2-aminoacetic acid from single crystal X-ray structural analysis

[0096] FIG. 7: Illustration of the packing of the molecules of N-(aminoiminomethyl)-2-aminoacetic acid in the crystal structure. The direction of view is along the a-axis. Independent molecular chains arranged perpendicular to each other and bound by H bridges can be clearly seen parallel to the a- and b-axis. These chains are stacked along the c-axis.

[0097] FIG. 8: Bulk density depending on concentration form B

[0098] FIG. 9: Calibration curve proportion of crystal form B to crystal form A

[0099] FIG. 10: DSC N-(aminoiminomethyl)-2-aminoacetic acid form A

[0100] FIG. 11: DSC N-(aminoiminomethyl)-2-aminoacetic acid form B

EXAMPLES

Guanidine Compounds Used

1) N,N-guanidinodiacetic Acid

Preparation of N,N-guanidinodiacetic Acid (CAS 94324-66-0)

[0101] The synthesis was analogous to T. S. Leyh, Biochemistry 1985, 24, 308-316. 65.15 g (1.55 mol) cyanamide was dissolved in 65.15 g of water, to which was added 171.6 g (1.29 mol) of iminodiacetic acid and 325 ml of 25% ammonia solution and stirred for 96 hours at 22° C. Then, 628.7 g of 96% acetic acid was added to adjust the pH from 10.63 to 5.00. The thick suspension obtained was stirred overnight, then sucked off and washed with water. After drying at 40° C., 103.8 g of N,N-guanidinodiacetic acid was obtained with correct elemental analysis. The yield was 46.1%. NMR data in d.sup.6-DMSO: .sup.1H: 3.991 ppm, .sup.13C: 171.2 ppm (carboxylate), 157.5 ppm (guanidine), 54.6 ppm (CH.sub.2).

2) N,N′-guanidinodiacetic Acid

Preparation of N,N′-guanidinodiacetic Acid

[0102] 2a.) 1242 g of a 20% sodium hydroxide solution (6.21 mol) were provided at 20° C. Into this, a total of 246 g (2.12 mol) of thiohydantoin was stirred in portions and hydrolyzed at 20° C. for 24 hours. The reaction mixture was diluted with 650 g of water, cooled to 5° C. and precipitated within 45 minutes with 638 ml of a 32% hydrochloric acid (6.55 mol). The precipitated solid was sucked off, washed 2 times with cold water of 5° C. and 1 time with cold ethanol of 5° C. After drying in vacuo at 40° C., thiohydantoic acid 202 g (71%) was obtained in the form of a yellowish solid. The purity determined by HPLC was >99%. The product had the following elemental composition: 26.95% C, 4.40% H, 20.90% N. The melting point was 170 ° C. under decomposition.

[0103] 2b.) 167.8 g (1.25 mol) of thiohydantoic acid from Example 2a.) was provided in 210 ml of methanol at 40° C. Within 2 hours, 221.8 g (1.563 mol) of methyl iodide was added dropwise and stirred for 1 hour at 40° C. The obtained orange clear reaction mixture was evaporated completely in vacuo at 40° C. 345.13 g (1.25 mol) of S-methyl-isothiohydantoic acid hydroiodide was obtained in the form of a brown viscous melt. The yield was quantitative. The reaction product was further reacted without analysis.

[0104] 2c.) 345.13 g (1.25 mol) of S-methyl-isothiohydantoic acid hydroiodide from 2b.) were dissolved in 300 ml of water. In a reaction flask, 225 g (3.00 mol) of glycine was dissolved in 400 ml of water and 1253 ml of 25% aqueous ammonia solution (16.7 mol) was added. At 20° C., the solution of S-methyl-isothiohydantoic acid hydroiodide was dosed to the glycine solution over 4 hours. Then, post-stirring was carried out at 20° C. for 16 hours. A white suspension of pH 11.0 was obtained, which was cooled to 5° C. At 5° C., 1948 g of 32% hydrochloric acid (17.1 mol) was added dropwise to adjust the pH to 3.0. The white suspension obtained was sucked off, washed with water and ethanol and dried at 40° C. in vacuo. 140.6 g N,N′-guanidinodiacetic acid in the form of a white solid was obtained. The yield was 64.2%. The purity determined by HPLC was 96%. The elemental composition was: 34.07% C, 5.49% H, 23.20% N. The chloride content was 0.26%, the water content <0.1%. The substance had no melting point, but decomposed above 230° C., turning black.

[0105] Dissolved in d.sub.6-DMSO, the following NMR spectra were obtained: .sup.13C: 170.08 ppm (COOH), 157.11 ppm (guanidine-C), 54.40 ppm (CH.sub.2); .sup.1H: 7.2 ppm (broad, NH), 4.00 ppm (CH.sub.2). Dissolved in D.sub.2O and mixed with an equimolar amount of NaOD, i.e. as monosodium salt, the following NMR data were obtained: .sup.13C: 175.44 ppm (COOH), 156.32 ppm (guanidine-C), 44.96 ppm (CH.sub.2); .sup.1H: approx. 7 ppm (very broad, NH), 4.80 ppm (CH.sub.2).

3) N′-carboxymethyl-3-guanidinopropionic Acid

[0106] 69.0 g (0.25 mol) of S-methyl-isothiohydantoic acid hydroiodide from synthesis example 2b.) was dissolved in 300 ml of water. In a reaction flask, 53.4 g (0.6 mol) of beta-alanine was dissolved in 400 ml of water and 250 ml of 25% aqueous ammonia solution (3.34 mol) was added. At 20° C., the solution of S-methyl-isothiohydantoic acid hydroiodide was dosed to the beta-alanine solution over 4 hours. Then, post-stirring was carried out at 20° C. for 16 hours. A white suspension of pH 10.9 was obtained, which was cooled to 5° C. At 5° C., 391 g of 32% hydrochloric acid (3.43 mol) was now added dropwise to adjust a pH of 3.0. The white suspension obtained was sucked off, washed with water and ethanol and dried at 40° C. in vacuo. 21.6 g N′-carboxymethyl-3-guanidinopropionic acid in the form of a white solid was obtained. The yield was 45.7%. The purity determined by HPLC was 94%.

4) N′-carboxymethyl-4-guanidinobutanoic Acid

[0107] 69.0 g (0.25 mol) of S-methyl-isothiohydantoic acid hydroiodide from synthesis example 2b.) was dissolved in 300 ml of water. In a reaction flask, 61.8 g (0.6 mol) of 4-aminobutanoic acid was suspended in 400 ml of water and 250 ml of 25% aqueous ammonia solution (3.34 mol) was added, forming a solution. At 20° C., the solution of the S-methyl-isothiohydantanoic acid hydroiodide was added over 4 hours to the solution of 3-aminobutanoic acid. Then, post-stirring was carried out at 20° C. for 16 hours. A white suspension of pH 10.8 was obtained, which was cooled to 5° C. At 5° C., 386 g of 32% hydrochloric acid (3.39 mol) was added dropwise to adjust the pH to 3.0. The white suspension obtained was sucked off, washed with water and ethanol and dried at 40° C. in vacuo. 23.7 g of N′-carboxymethyl-4-guanidinobutanoic acid was obtained in the form of a white solid. The yield was 46.7%. The purity determined by HPLC was 92%.

X-Ray Powder Diffraction Measurement

[0108] In the scope of the present examples, X-ray powder diffraction measurements were performed 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°. The samples for examination were ground in an agate mortar and pressed onto the sample plate according to the manufacturer's instructions and the surface was smoothed.

Calibration Line for the Radiographic Determination of the Proportion Form A/B

[0109] XRD data were obtained using mechanical mixtures of pure GAA form A and form B samples. The peak heights at 20.7° and 20.2° were used for quantitative evaluation via the peak height. The calibration curve (calibration line) determined from this with a very good correlation coefficient was used for unknown samples to determine the proportion of form A/B (cf. Table 1 and FIG. 9).

TABLE-US-00001 TABLE 1 Calibration curve proportion of crystal form A to crystal form B Weight Weight X-ray X-ray percentage percentage count rate count rate Ratio of Form B Form A Form A Form B count rate (%) (%) (20.7°) (20.2°) B to A + B 0 100 4000 1 0.00025 5 95 3150 150 0.04545 10 90 3500 500 0.12500 20 80 3500 900 0.20455 33 67 3050 1600 0.34409 50 50 2400 2400 0.50000 67 33 1750 3100 0.63918 80 20 950 3250 0.77381 90 10 400 3700 0.90244 95 5 250 4000 0.94118 100 0 1 4100 0.99976

[0110] For the quantitative determination of the ratio of N-(aminoiminomethyl)-2-amino-ethanoic acid crystal form B to crystal form A, mechanical mixtures of powdered samples of the respective pure crystal forms were prepared and measured on the X-ray powder diffractometer. The mixing 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 heights (count rates) at 2theta 20.2° (form B) were related to the sum of the signal heights at 2theta 20.7° (form A) and 2theta 20.2° (form B) and a calibration line was determined from this. With a correlation coefficient R.sup.2=0.998, the following linear relationship was found:

[00001]$\mathrm{Weight}\mathrm{percent}\mathrm{form}B=\left(\left(\frac{\mathrm{count}\mathrm{rate}\mathrm{form}B}{\begin{array}{c}\mathrm{count}\mathrm{rate}\mathrm{form}A+\\ \mathrm{count}\mathrm{rate}\mathrm{form}B\end{array}}\right)-0.0074\right)*102.04$

[0111] This formula was used in the following examples to determine the respective proportions of crystal form A and crystal form B.

Single Crystal X-Ray Structural Analysis

[0112] A suitable crystal was prepared by evaporating a water-containing solution of N-(aminoiminomethyl)-2-aminoacetic acid in the presence of N,N′-guanidinodiacetic acid. The single crystal measurement was carried out at 105 Kelvin on a crystal of dimension 0.02*0.02*0.09 mm using monochromatic Mo—Kα (molybdenum K-alpha) radiation of wavelength 0.71073 Å using a dual-cycle Bruker D8 Venture TXS diffractometer. Refinement of the X-ray crystal data using 2072 independent reflections was performed by the least square error method up to an R value (F.sub.obs) of 0.0381. The position of NH and OH hydrogen atoms was refined, and that of CH hydrogen atoms was fixed at the calculated position. The result of the X-ray single crystal structure analysis is illustrated in FIGS. 6 and 7. A powder diffractogram back-calculated from the single crystal structure analysis exactly matched the measured powder diffractogram shown in FIG. 2.

Example 1 (Comparison)—Recrystallization of N-(aminoiminomethyl)-2-aminoacetic Acid From Water

[0113] 400 g of water was provided at 80° C. and a total of 11.66 g of N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.0%, present in crystal form A, were dissolved therein spoonwise, the solubility limit being exceeded with the last portion. It was then filtered off at 80° C., the filtrate was mixed with a further 100 g of water and heated to 80° C. A nearly saturated clear solution was formed. By cooling slowly to 20° C. within 4 hours, N-(aminoiminomethyl)-2-aminoacetic acid was crystallized. The precipitated crystals were filtered off and dried at 60° C. in vacuo. 6.51 g of N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.1% was obtained.

[0114] The product obtained is in the form of fine acicular crystals. The fine acicular crystals were examined microscopically (see FIG. 3). An X-ray powder diffractometric measurement yielded the powder diffractogram shown in FIG. 1, which indicates the well-known crystal form A.

Example 2—Crystallization of N-(aminoiminomethyl)-2-aminoacetic Acid From a Solution of N,N′-guanidinodiacetic Acid

[0115] A 1% solution was prepared from 5 g of N,N′-guanidinodiacetic acid from Synthesis Example 2c) and 495 g of water. To 400 g of this solution, N-(aminoiminomethyl)-2-aminoacetic acid of the same composition as in Example 1 was added spoonwise at 80° C. At an added amount of 20.38 g the solubility limit was exceeded. The small solid fraction was filtered off at 80° C., the filtrate was added to the remaining 100 g of the 1% solution of N,N′-guanidinodiacetic acid and stirred at 80° C. for 1 hour. A clear, colorless solution was obtained. By slow cooling to 20° C. within 4 hours, N-(aminoiminomethyl)-2-aminoacetic acid was crystallized. The precipitated crystal aggregates were filtered off, washed 3 times with water at 20° C. and dried at 60° C. 11.67 g of N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.4% was obtained. The amount obtained is clearly larger than in Example 1, which is due to the increased solubility of N-(aminoiminomethyl)-2-aminoacetic acid caused by the presence of N,N′-guanidinodiacetic acid.

[0116] An analogously recorded powder diffractogram (see FIG. 2) showed the hitherto unknown crystal form B. The polygonal, roundish crystal aggregates were examined microscopically (see FIG. 4).

Example 3—Recrystallization of N-(aminoiminomethyl)-2-aminoacetic Acid From Water-Containing Solutions of Guanidine Compounds

[0117] Analogous to Example 2, aqueous solutions of various guanidine compounds were prepared in the respective concentrations (C) indicated. In 400 g of the respective 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 indicated aqueous solution of the respective 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 crystal aggregates were filtered off, washed 3 times with water of 20° C. and dried at 60° C. In each case, the indicated amount (A) of N-(aminoiminomethyl)-2-aminoacetic acid with a content (G) was obtained (see Tables 2a/b).

[0118] Powder diffractograms were taken of the respective products and examined for the presence of the respective crystal forms, using the formula given above to determine the proportions of form A and form B.

TABLE-US-00002 TABLE 2a Recrystallization from water-containing solutions of guanidine compounds (not according to the invention) C Guanidine % by M A G Crystal No. compound weight g g % form 3.1 Melamine 0.3 16.98 11.13 99.3 100% Form A 3.2 N-cyanoguanidine 3.0 19.80 10.09 99.1 100% Form A 3.3 L-Arginine 10.0 18.37 11.98 99.2 100% Form A 3.4 N-(aminoimino- 1.0 17.47 8.14 99.2 100% methyl)-N- Form A methyl-2- aminoacetic acid 3.5 Biguanide 50.0 13.72 7.13 99.3 100% hydrochloride Form A 3.6 N,N- 30.0 10.06 5.81 99.1 100% dimethylbiguanide Form A 3.7 N,N- 2.0 18.74 10.98 99.3 100% guanidinodiacetic Form A acid 3.8 N,N- 0.5 19.62 11.05 99.4 100% guanidinodiacetic Form A acid

TABLE-US-00003 TABLE 2b Recrystallization from water-containing solutions of guanidine compounds according to formula (I) - according to the invention C Guanidine % by M A G Crystal No. Compound weight g g % form 3.9 N,N′- 2.0 20.65 11.72 99.2 100% guanidinodiacetic Form B acid 3.10 N,N′- 0.7 20.47 11.44 99.3 97% Form B guanidinodiacetic 3% Form A acid 3.11 N,N′- 0.5 20.40 11.52 99.3 93% Form B guanidinodiacetic 7% Form A acid 3.12 N,N′- 0.2 20.38 11.63 99.4 78% Form B guanidinodiacetic 22% Form A acid 3.13 N,N′- 01. 20.32 11.49 99.4 53% Form B guanidinodiacetic 47% Form A acid 3.14 N′-carboxymethyl-3- 1.0 17.29 9.64 99.2 100% guanidinopropanoic Form B acid 3.15 N′-carboxymethyl-4- 1.0 16.84 8.91 99.3 100% guanidinobutanoic Form B acid

[0119] The guanidine compounds according to formula (I) of the invention thus preferentially induce crystal form B during crystallization of N-(aminoiminomethyl)-2-aminoacetic acid, although in some cases mixtures with form A also occur (cf. Table 2b). Other guanidines not according to the invention are not able to do this (cf. Table 2a).

Example 4 (Comparison)—Synthesis of N-(aminoiminomethyl)-2-aminoacetic Acid From Glycine and Cyanamide in Aqueous Solution

[0120] 112.6 g (1.5 mol) of glycine was dissolved in 300 g of water. To the solution was added 21.6 g (0.27 mol) of a 50% sodium hydroxide solution, resulting in a pH of 8.4. Å 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 post-reaction was carried out at 80° C. for another hour. The obtained suspension was cooled to 20° C., filtered off, washed with water and dried at 60° C. 100.6 g N-(aminoiminomethyl)-2-aminoacetic acid with a content of 99.1% was obtained. The yield was 85.9%.

[0121] A powder diffractogram of the obtained fine acicular crystals indicated the sole presence of form A (100% form A).

Example 5 (According to the Invention)—Synthesis of N-(aminoiminomethyl)-2-aminoacetic Acid From Glycine and Cyanamide in a 2% Solution of N,N′-guanidinodiacetic Acid

[0122] A solution was prepared from 6 g of N,N′-guanidinodiacetic acid and 294 g of water. Dissolved therein were 112.6 g (1.5 mol) of glycine and a pH of 8.4 was adjusted with 22.7 g (0.28 mol) of a 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 post-reaction was carried out at 80° C. for another hour. The obtained suspension was cooled to 20° C., filtered off, washed with water and dried at 60° C. 99.6 g of N-(aminoiminomethyl)-2-aminoacetic acid containing 99.3% was obtained. The yield was 85.0%.

[0123] A powder diffractogram of the obtained crystals showed that only N-(aminoiminomethyl)-2-aminoacetic acid of crystal form B (100% form B) was present.

Example 6 (Comparison)—Synthesis of N-(aminoiminomethyl)-2-aminoacetic Acid From Glycine and Cyanamide in a Solution of Different Substances

[0124] A stock solution A was prepared from a mixture of different substances. This comprised:

[0125] 30 g N-cyanoguanidine

[0126] 30 g hydantoic acid

[0127] 10 g urea

[0128] 5 g glycylglycine

[0129] 5 g glycocyamidine

[0130] 0.5 g melamine

[0131] These substances were dissolved in water and the mixture was made up to a total weight of 1000 g.

[0132] In 300 g of this stock solution A, 112.6 g (1.5 mol) of glycine was dissolved and a pH of 8.4 was adjusted with 20.9 g (0.26 mol) of a 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 post-reaction was carried out at 80° C. for another hour. The obtained suspension was cooled to 20° C., filtered off, washed with water and dried at 60° C. 100.5 g N-(aminoiminomethyl)-2-aminoacetic acid containing 99.0% was obtained. The yield was 85.8%.

[0133] A powder diffractogram of the crystals obtained showed that only form A was present.

Example 7 (According to the Invention)—Synthesis of N-(aminoiminomethyl)-2-aminoacetic Acid From Glycine and Cyanamide in a Solution of Various Substances Involving Guanidine Compounds According to the Invention

[0134] A stock solution B was prepared from a mixture of different substances. This comprised:

[0135] 30 g N-cyanoguanidine

[0136] 30 g hydantoic acid

[0137] 10 g urea

[0138] 5 g glycylglycine

[0139] 5 g glycocyamidine

[0140] 0.5 g melamine

[0141] 15 g N,N′-guanidinodiacetic acid

[0142] These substances were dissolved in water and the mixture was made up to a total weight of 1000 g. Compared with stock solution A, stock solution B thus contained an additional 1.5% by weight of N,N′-guanidinodiacetic acid.

[0143] In 300 g of this stock solution B, 112.6 g (1.5 mol) of glycine were dissolved and a pH of 8.4 was adjusted with 21.3 g (0.27 mol) of a 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 post-reaction was carried out at 80° C. for another hour. The obtained suspension was cooled to 20° C., filtered off, washed with water and dried at 60° C. 100.7 g of N-(aminoiminomethyl)-2-aminoacetic acid containing 99.2% was obtained. The yield was 86.0%.

[0144] A powder diffractogram of the crystals obtained showed that only form B was present.

[0145] Thus, the presence of N,N′-guanidinodiacetic acid causes crystallization of N-(aminoiminomethyl)-2-aminoacetic acid in crystal form B even in a complex mixture of substances.

Example 8 Recrystallization of N-(aminoiminomethyl)-2-aminoacetic Acid From Different Concentrations of Stock Solution B

[0146] Different initial concentrations were prepared from x g of stock solutions A and B from Examples 10 and 11, respectively, and y g of water (see table). N-(aminoiminomethyl)-2-aminoacetic acid was added by the spoonful to 400 g of each of these solutions at 80° C. The amount (S) required to reach the saturation limit in each case is given in the table. Then filtering was carried out at 80° C., another 100 g of the respective solution was added to the filtrate and stirred at 80° C. for 1 hour. By slowly cooling to 20° C. within 4 hours, N-(aminoiminomethyl)-2-aminoacetic acid was crystallized. The precipitated product was filtered off, washed with water and dried at 60° C. The respective weights (A) of N-(aminoiminomethyl)-2-aminoacetic acid are shown in the table.

[0147] The powdered products were analyzed for their crystal form by powder diffraction. The results are summarized in Table 3.

TABLE-US-00004 TABLE 3 Recrystallization from stock solutions B Stock x y S A Nr. solution g g g g Obtained crystal form 8.1 A 500 0 20.7 13.34 100% crystal form A 8.2 A 250 250 19.53 13.17 100% crystal form A 8.3 B 500 0 19.49 12.12 100% crystal form B 8.4 B 250 250 22.16 12.26 100% crystal form B 8.5 B 125 375 18.18 12.73 100% crystal form B 8.6 B 50 450 19.40 13.16 Mixture of crystal forms A and B with 46% form B, 54% form A 8.7 B 25 475 23.72 12.11 100% crystal form A

[0148] The result clearly shows that the N,N′ -guanidinodiacetic acid additionally contained in stock solution B causes the crystallization of N-(aminoiminomethyl)-2-aminoacetic acid in form B. At higher dilution, this effect is gradually lost.

Example 9—Physicochemical Characterization of N-(aminoiminomethyl)-2-aminoacetic Acid of Form A and Form B

9.1 Melting or Decomposition Point

[0149] A Mettler DSC 3+ instrument with 40 μl aluminum crucible was used for Dynamic Differential Scanning calorimetry (DSC). The heating rate was 10 Kelvin per minute at a temperature range of 30 to 350° C. Approximately 1.4 mg each of the products of 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).

[0150] The sample of Example 1 (=N-(aminoiminomethyl)-2-aminoacetic 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 (cf. FIG. 10). The product turned from white to brown during melting.

[0151] The sample of Example 2 (=N-(aminoiminomethyl)-2-aminoacetic 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, the discoloration was identical (see FIG. 11).

[0152] Form B thus melts approx. 6 to 8 Kelvin lower than form A and has a 27 J/g lower heat of fusion or 27 J/g higher lattice energy. In other words, 27 J/g less energy is required for form B than for form A in order to achieve the same energy melting state. Form B thus represents a metastable crystal form or a polymorph of N-(aminoiminomethyl)-2-aminoacetic acid that is higher in energy under normal pressure and temperature conditions.

[0153] This new metastable crystal modification form B is stable up to its melting point. A solid transformation from form B to form A or a reversible solid transformation of form A/form B cannot be observed. Thus, form B is an example of monotropic polymorphism.

9.2 Determination of Water Solubility

[0154] 100 g of water at 5° C. were provided. The product of Example 1 (=N-(aminoiminomethyl)-2-aminoacetic acid form A) was dissolved therein until saturation was reached and the dissolved amount was determined by backweighing. Then the temperature was increased to 20° C. and as much of the sample was added until the saturation point was reached again. The same was repeated at further temperatures, maximum at 95° C. An analogous measurement was made with the product of Example 2 (=N-(aminoiminomethyl)-2-aminoacetic acid form B). The solubility data obtained for both products were summarized graphically in FIG. 5.

[0155] Both crystal forms of N-(aminoiminomethyl)-2-aminoacetic acid dissolve better in water with increasing temperature. The inventive N-(aminoiminomethyl)-2-aminoacetic acid form B dissolves about 20% better than the known form A at any temperature.

9.3 Determination of Density

[0156] Crystals of N-(aminoiminomethyl)-2-aminoacetic acid form A of 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 decreased until the crystals just started to float in the liquid without rising and without sinking to the bottom. The density of the liquid phase was determined in a pycnometer. A density of 1.50+/−0.03 g/cm.sup.3 was measured.

[0157] The same procedure was followed with crystals of form B of Example 2. The density at 20° C. was determined to be 1.41+/−0.03 g/cm.sup.3.

[0158] Form B thus has a 6% lower density 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.

9.4 Determination of Dust Content

[0159] The product of Example 1 was sieved through a sieve with mesh size 63 μm (equivalent to 230 mesh-mesh size). 46 wt. % fines were obtained. An analogous procedure was followed with the sample of Example 2 consisting of polygonal, roundish crystal aggregates. Here, a fines content of less than 3 wt. % was determined. Low-dust materials, which can therefore be handled safely, should have a dust content (i.e. grain content <63 pm) of less than 10%. The product of Example 2 (N-(aminoiminomethyl)-2-aminoacetic acid of crystal form B) satisfies this, while Comparative Example 1 (N-(aminoiminomethyl)-2-aminoacetic acid of crystal form A) does not.

9.5 Determination of the Angle of Repose

[0160] The product of Example 1, consisting of matted acicular 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 cone obtained was determined with an angle measuring device. It was approximately 45° . Accordingly, N-(aminoiminomethyl)-2-aminoacetic acid form A exhibits poor flow behavior. The granular product of Example 2 was measured anlogously. Here, a repose angle of about 25° was obtained. N-(aminoiminomethyl)-2-aminoacetic acid form B thus exhibits excellent flow behavior.

9.6 Determination of Bulk Density

[0161] A weighed quantity of the product of Example 1 was placed in a measuring cylinder and partially compacted by tapping it firmly twice on the laboratory bench. From the filling level of the measuring cylinder, the bulk density was determined to be 0.37 g/cm.sup.3. The same procedure was followed with the product of Example 2. Here, a bulk density of 0.62 g/cm.sup.3 was determined. N-(aminoiminomethyl)-2-aminoacetic acid of form B thus has a significantly increased bulk density, which is advantageous for packaging, transport and handling of the product.

9.7 Thermal Stability of N-(aminoiminomethyl)-2-aminoacetic Acid Form B

[0162] a) N-(aminoiminomethyl)-2-aminoacetic acid form B of Example 2 was placed in the drying oven for 6 hours at 120° C. X-ray powder diffraction was then used to determine the crystal form. This remained unchanged pure crystal form B.

[0163] b) N-(aminoiminomethyl)-2-aminoacetic acid form B of Example 2 was wetted with 20% water, incubated for 6 hours at 65° C. in a closed vessel, then dried. The X-ray powder diffractogram showed no change, form B remained stable.

[0164] c) N-(aminoiminomethyl)-2-aminoacetic acid form B of Example 2 was prepared as a 10% suspension in water. This suspension was stirred at 80° C. for 2 hours. It was then cooled, the solid filtered off and dried. X-ray powder diffraction showed that a mixture of crystals forms A and B was present.

[0165] d) N-(aminoiminomethyl)-2-aminoacetic acid form B of Example 2 was dissolved in water at 80° C., largely recrystallized by cooling the solution, filtered off and dried. X-ray powder diffraction yielded pure crystal form A.

[0166] N-(aminoiminomethyl)-2-aminoacetic acid form B is thus very stable in solid form, but has a tendency to change to crystal form A via the water-containing solution. This behavior also confirms the metastable crystal structure of form B.

9.8 Physical Property of Mixtures of Form A and Form B

[0167] In Example 9.6, the bulk density of GAA form A was determined to be 0.37 g/cm.sup.3 and that of GAA form B 0.62 g/cm.sup.3. Starting from pure substance samples of GAA form A or form B, mixtures of the two forms were weighed in and mixed by shaking (not grinding or mortaring!). The bulk densities of the crystal mixtures produced in this way were determined.

TABLE-US-00005 TABLE 4 Bulk density in the crystal mixture Weight proportion Form A Weight proportion Form B Bulk density 100%   0% 0.62 g/cm.sup.3 75% 25% 0.59 g/cm.sup.3 50% 50% 0.53 g/cm.sup.3 25% 75% 0.41 g/cm.sup.3  0% 100%  0.37 g/cm.sup.3

[0168] It can be seen that the bulk density increases as the proportion of GAA form B increases, whereby from 50% form B the bulk density is advantageously above the arithmetic mean of the two end members (cf. also FIG. 8).